HIV & VIROLOGY NEWS Issue 4 • 2013

HIV & VIROLOGY NEWS
Issue 4 • 2013
HIV & Hepatitis News New ARV Drugs: What’s in the Pipeline?
14 EACS Conference in Brussels AIDS Vaccine Congress in Barcelona
HIV treatment guidelines 14th European AIDS conference: Update on ART
HIV-associated lymphoma: Treatment update The price of antiretroviral therapy
The path towards IFN-free therapy of hepatitis C – Part 4: We made it! IFN-free therapy is reality!
th
In this issue:
HIV & VIROLOGY NEWS
HIV & Virology News is a a quarterly publication
with four issues per year.
The magazine is distributed free of charge to
all those specialists in the field of Infectious
diseases in 13 European countries including the
UK, the Netherlands, Belgium, Germany,
France, Spain, Italy, Sweden, Norway, Denmark,
Finland, Austria and Switzerland.
The magazine is in English with all content
being HIV and virology related. It also include
summaries of research results from the above
mentioned countries as well as consensus
relating from the fields of HIV and virology.
Also featured are educational programmes and
excerpts from seminars and conferences.
Editor in Chief:
Magnus Gisslén, MD, Ph.D
Professor of Infectious Diseases
Dpt of Infectious Diseases
Sahlgrenska University Hospital,
Gothenburg, Sweden
[email protected]
Editorial Board:
Graeme J. Moyle, MD, MB BS, Dip. GUM
Director of HIV Research Strategy
Chelsea & Westminster Hospital
London, United Kingdom
[email protected]
José Arribas, MD
Associate Professor of Medicine at
the Autonoma University School of Medicine in
Madrid and Research Director at the HIV unit of
La Paz Hospital, Madrid, Spain
[email protected]
Christine Katlama, Professor of Infectious
Diseases at University Pierre and Marie Curie
and Head of the AIDS Unit in the Department
of Infectious Diseases at the Pitié-Salpêtrière
Hospital in Paris, France
[email protected]
Heiner Wedemeyer, Prof. Dr.
Dept. of Gastroenterology, Hepatology and
Endocrinology
Hannover Medical School
Hannover, Germany
[email protected]
Advertising:
Advertising space within HIV and Virology News
is sold locally in each country.
As a result of placing an advertisement within
this magazine you will reach every specialist
in the field of infectious diseases in these
countries.
For questions concerning advertising contact:
Lars Lundblad
[email protected]
Mediahuset i Göteborg AB, Sweden
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Production:
Mediahuset i Göteborg AB, Sweden
Marieholmsgatan 10 c
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Layout:
Gunnar Brink
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Printing:
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Emmaboda, Sweden
Cover photo: iStockphoto.com
ISSN 2000-8384
More than 3,000 delegates from all over the world attended the 14th European AIDS Conference
in Brussels, Belgium. Page 3.
2 HIV treatment guidelines
Magnus Gisslén
3 14th EACS Conference in Brussels
Per Lundblad
14 14th European AIDS Conference: Update on ART
José Arribas
17 HIV-associated lymphoma: Treatment update
Hans Hagberg
21 AIDS Vaccine Congress in Barcelona
Per Lundblad
26 The price of antiretroviral therapy
Graeme J. Moyle
30 HIV & Hepatitis News
Leo Flamholc
33 New ARV drugs: What’s in the pipeline?
Christine Katlama
37 The path towards IFN-free therapy of hepatitis C
Part 4: We made it! IFN-free therapy is reality!
Heiner Wedemeyer
40 Topical Conferences in 2014
www.hivvirology.com
HIV & VIROLOGY NEWS 4 • 2013
1
Letter from the editor
HIV treatment guidelines
We have just finalized our Swedish national guidelines for
the treatment of HIV. Sweden is a small country in which
there are only about 6,500 known HIV-infected individuals
in the entire nation. So, one might ask, is it really necessary
to write our own national guidelines?
W
hy not simply use one of the others that are already out there, such as the European EACS
guidelines? These are indeed relevant questions,
especially when considering all the time and effort that has been invested in the development of the guidelines.
Nevertheless, circumstances differ in various parts of the
world and even between countries in Europe. For example,
there is economic governance: a recommendation that works
in one country may not be suitable in another. In some places
one is obligated to prescribe drugs in exact accordance with
SPC indications; elsewhere this is not necessary. But I think the
most important reason for doing this exercise is that it forces
participants in the group drawing up the guidelines to carefully
review the literature and to abstract results from many studies
in order to be able to provide well-substantiated recommendations. Discussing the interpretation of findings with intelligent
people who possess a variety of expertise and experience considerably increases one’s own knowledge. We also try, as far as
possible, to report the basis behind the recommendations so
that readers may form their own opinions.
One recommendation that distinguishes the Swedish guidelines from others is that we recommend abacavir/lamivudine
(and not tenofovir/emtricitabine) as the NRTI-backbone when
given together with a boosted PI, as long as the patient is not
HLA-B*5701-positive or co-infected with hepatitis B. Traditionally, we have used a lot of abacavir/lamivudine, not only
together with PIs, but also in combination with NNRTI and integrase inhibitors. The main reason for this recommendation is
to avoid tenofovir-related nephrotoxicity, a risk that is higher
when tenofovir is used together with ritonavir (or cobicistat)
because they increase its serum concentration. The risk that
further increases as patients grow older and attract comorbidities such as diabetes and hypertension. There is also a significant risk when tenofovir in combination with boosted PI is coadministered with other potentially nephrotoxic drugs such as
NSAIDs. Another advantage of abacavir/lamivudine is its lower
price compared to tenofovir/emtricitabine.
Recommendation for initial treatment of ART-naive
HIV-infected adults
The randomised ACTG-5202-study showed a higher failure
rate in patients on abacavir/lamivudine compared to tenofovir/emtricitabine who began treatment at high viral loads (>
100,000 copies/mL). However, other studies have not found an
advantage for tenofovir/emtricitabine. We also could not detect any difference between NRTIs when reviewing our complete national cohort database (InfCare HIV). A retrospective
2
abacavir/lamivudine + atazanavir/r
abacavir/lamivudine + darunavir/r
abacavir/lamivudine or tenofovir/emtricitabine + efavirenz*
abacavir/lamivudine or tenofovir/emtricitabine + raltegravir
*Some experts recommend tenofovir/emtricitabine as first choice in patients
with HIV-RNA > 100,000 copies/mL when given together with efavirenz while
others judge abacavir/lamivudine and tenofovir/emtricitabine as equivalent
also in patients with high viral loads.
cohort analysis certainly does not have the same weight as a
randomised study, but considering that 40% of all treated subjects in the cohort receive abacavir/lamivudine (92% of all diagnosed HIV-positive individuals in Sweden are on treatment)
and that 93% of those treated have HIV-RNA < 50 copies/mL
(snapshot analysis), it is hard to believe that this NRTI backbone is inferior in a clinical setting.
We recommend initiating treatment in asymptomatic patients with CD4 cell counts < 500/µL, a limit that is somewhat
higher than EACS guidelines, but lower than US guidelines that
recommend treatment for all, irrespective of CD4. However,
these differences are of small practical importance, since only
one-third of all newly diagnosed patients have CD4 levels above
350, and only about 15% have CD4 above 500 cells/µL.
Recommendations for initiating treatment in asymptomatic
individuals with chronic HIV
CD4
EACS 2013
DHHS 2013
IAS 2012
Swedish 2013
Consider
Recommend
Recommend
Consider
350–500 Consider
Recommend
Recommend
Recommend
Recommend Recommend
Recommend
Recommend
> 500
< 350
The recommendations are currently only available in Swedish
(www.rav.nu), but a translation into English is currently in process and will soon be published in a scientific journal, for those
interested.
This is the concluding issue of HIV & Virology News for 2013.
We look forward to returning in 2014
and continuing to follow and comment
on relevant topics in the HIV field. In addition, we hope to increase our coverage
of the hepatitis C field where many of
the drugs now in the pipeline will enter
the market. See you then!
Magnus Gisslén
Editor
HIV & VIROLOGY NEWS 4 • 2013
14 EACS Conference in Brussels
th
On October the 16th, European AIDS Clinical Society – EACS – President Manuel
Battegay and Professor Nathan Clumeck welcomed more than 3,000 delegates
from all over the world to the Opening Ceremony of the biennial 14th European
AIDS Conference. 824 abstracts had been submitted from 73 countries, and 555 of
these were accepted.
W
hat followed were four
days with Plenaries, Minilectures, Best Poster discussions, Meet the ExpertSessions and Satellite Symposia.
– Unfortunately, stigma and homophobia are still present, and EACS thought it
was important to react to such political
blindness, said Prof Clumeck.
He presented an EACS statement on
Russia’s legislation that is available on
the web, and read a few sentences from it:
“EACS notes with much concern the
discriminatory legislative and policy
measures that reflect unjustified and
harmful discrimination against gay, lesbian and transgendered persons in Russia…
EACS calls upon the government of the
HIV & VIROLOGY NEWS 4 • 2013
Russian Federation to abolish this harmful
law and respect the rights of all people”.
Prof Battegay highlighted the fact that
2013 was also EACS 25th anniversary. The
first Conference took place in Brussels
1987, and after touring several capitals in
Europe, this year they had returned there.
He underlined that this Conference
could not be possible without substantial
support and innovation from industry
partners.
– It is an excellent collaboration – so
thank you very much!
Interferon-free treatment options for HCV
Prof Heiner Wedemeyer talked about the
treatment of HCV, and he did not hesitate
to call it a revolution.
A revolution is defined by structural
changes and constitutes a challenge of
the established order. They are usually
also violent, he reminded the audience.
– And patients have been dying – from
direct toxicity of drugs, liver disease and
drug-drug interactions to name a few
causes. We are therefore indeed experiencing a revolution! All oral treatment
will lead to a change in treatment paradigm, he said.
Prof Wedemeyer was referring to the
new interferon-free treatment options
that are becoming available from 2014.
We will see new drugs for HCV, and we
will treat the patients in a different way.
– This will lead to the fact that the number of patients treated will dramatically
3
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www.europeanaidsclinicalsociety.org
EACS TREATMENT GUIDELINES
The European Guidelines for treatment of
HIV-infected adults in Europe are produced
by EACS and are regularly updated by our
teams of specialists. The importance and
success of the EACS guidelines are demonstrated by their widespread dissemination.
Over 6,000 copies of the updated version
(Version 6) have been distributed at the 13th
European AIDS Conference in Belgrade, 1215 October 2011. They are available on the
EACS website in 13 different languages.
EACS EDUCATIONAL PROGRAMMES
The European AIDS Clinical Society offers a
number of educational programmes:
ECReCO
(European Clinical Research Course)
A 3-days course to train physicians in the
basics of clinical research and to write clinical research programmes, protocols and
abstracts. The first course was held in Zagreb from June 15-17, 2011, it was attended by 33 medical doctors from 15 different
countries and moderated by a team of
statisticians and clinicians.
Medical Exchange Programme &
One-Year Fellowship Programme
Enable doctors from Europe and developing countries to take part in a four-month or
one-year exchange programme in one of
14 currently participating clinical centres in
8 European countries.
Advanced HIV Course
An intensive 3-day course in Antiretroviral
Therapy and Comprehensive Care for people living with HIV/AIDS focused on the clinical management of HIV and aimed at experienced practitioners. The course is attended
by an average of 60 candidates from 30 different countries every year.
Webcasts of the 13th European AIDS Conference available at
www.europeanaidsclinicalsociety.org
The 13th European AIDS Conference is over!
Save the date for the 14th European AIDS Conference
European AIDS Clinical Society - Hôpital Pitié Salpêtrière
Pavillon Laveran
47, boulevard de l’hôpital • 75013 • Paris
www.europeanaidsclinicalsociety.org • [email protected]
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Manuel Battegay and Nathan Clumeck
increase. Most of them will be cured. It
will also – hopefully – lead to the fact that
more doctors, including GPs, will screen
for HCV. That is my most important point!
What the names mean
The first proof of concept study that
proved that cure of HCV without interferon was possible was published in February 2012. It was followed by other studies published in January, March, April
and August 2013.
There are four main classes of direct
acting antivirals (DAA) against HCV:
Protease inhibitors, so called NS5A inhibitors and polymerase inhibitors – nucs
and non-nucs.
– I have to teach you about names: Protease inhibitors are “… previrs” such as
boceprevir and telaprevir. NS5A inhibitors are “… asvirs” and polymerase inhibitors are “… buvirs”, Prof Wedemeyer
explained.
Next year we will see the first drug approved, sofosbuvir from Gilead. More
drugs will follow – simeprevir from Janssen and faldaprevir from Boehringer Ingelheim. Abbvie have just finished successful Phase III studies on their new
regimen. Daclatasvir and ledipasvir are
two NS5A inhibitors in Phase III. Deleobuvir, setrobuvir and sofosbuvir are
polymerase inhibitors that are in an advanced stage of development.
– And there are more in the pipeline.
There are also therapeutic vaccines in
development.
Data from the NEUTRINO Study
(genotype 1 and 4–6) and FISSION Study
(genotype 2 and 3) on combination therapy with sofosbuvir + ribavirin show that
the therapy works in every patient, and
that no resistance develops.
– This is quite remarkable! However,
relapses do occur. This is a problem, and
raises the question on how long to treat
and how to use the drug.
6
Heiner Wedemeyer
Treat or wait – discuss with the patient
Are there any problems with the new
DAAs? According to Prof Wedemeyer,
pill-burden is probably not a major issue
– it is 1–3 pills, 1–2 times per day. But response depending on host genetics may
be a problem in some of the combinations.
Side effects are so far not a major issue. There have been some GI symptoms, photosensitivity, bilirubin increase
and an increase in alanine transaminase
(ALT) has been reported.
– But we have to wait for the Phase III
study results for more details.
Duration of therapy will be 12 weeks
for most patients – but 24 weeks may not
be the solution for all 12 weeks failures.
Drug-drug interactions are different for
each single drug, and Prof Wedemeyer
underlined the need for studies in patients with HCV infection and advanced
liver disease. Resistance will probably
not be an issue, although maybe in shortterm.
– The key question is the costs. But I’ve
never seen a new development that is
cheaper than the previous therapies. So
it is important that we advocate that we
should be able to treat as many patients
as possible.
So should we treat now, or should we
wait for these new drugs? Prof Wedemeyer said this has to be discussed with
every patient, and consideration taken to
the country’s guidelines and regulation.
– The good news is that there is good
hope for our patients, and I think we will
save many lives in the next years, he stated.
We will see more HIV patients with CVD
Dr Scott Kinlay talked about inflammation and cardiovascular disease (CVD).
– Inflammation is a key component of
CVD due to atherosclerosis, he said.
The biomarkers of inflammation provide insights into plaque inflammation in
groups of patients.
– We cannot take biopsies of arteries to
assess inflammation, so we measure soluble biomarkers in blood. CRP is probably
the best marker we have at the moment.
But there are a number of soluble biomarkers that we can measure in the blood
stream. These include cytokines, TNF-alpha, and interleukin 1 and 6. The concept
is that by measuring these inflammatory
biomarkers, we can get a window into the
inflammation process in arteries.
– The value of measuring biomarkers
in individual patients is still debated, and
we are still working that out. But as far as
understanding the disease, it has brought
enormous insights into the field.
Statins lower cholesterol and also CRP,
which also lower the risk for CVD.
– Therapies to reduce inflammation
without LDL lowering target proximal
cytokines and their value are now being
tested in ongoing clinical trials.
The implications for patients with HIV
is that since these patients now live longer, we will see more HIV patients with
CVD.
– Whether this association with CVD
is related to the underlying activation of
the immune system due to the HIV virus
itself, or with other factors is unclear, Dr
Kinlay summarised.
Arterial stiffness greater in HIV-positives
The prevalence of subclinical CVD is increased in HIV infection, said Dr Katherine Kooij.
– People infected with HIV have a 1.5
to 2-fold increased risk for myocardial
infarction or coronary heart disease, she
stated.
This was the background to a study
Dr Kooij presented. In this, they had assessed the pulse wave velocity (PWV, a
measure of arterial stiffness) in comparable cohorts of aging HIV-1-infected patients and HIV-negative controls in order
to investigate the association with HIV
and PWV.
– We also investigated whether HIVassociated inflammation and HIV-disease characteristics are independent determinants of PWV, she said.
They found that arterial stiffness was
greater in HIV-positives compared to
HIV-negatives, 45 years old or older.
This difference is modest, but clinically
relevant.
– After adjusting for smoking and hypertension, HIV status was not independently associated with greater arterial
stiffness.
HIV & VIROLOGY NEWS 4 • 2013
Higher levels of inflammatory and innate immune markers were associated
with increased arterial stiffness.
– In HIV-positives a lower nadir (=lowest ever) CD4 was associated with greater
arterial stiffness, Dr Kooij said.
Shortages and stockouts
One Session was convened by the European AIDS Treatment Group (EATG) and
concerned standards of HIV care in Europe after the economic crisis. Mr Tamás
Bereczky from EATG talked about a new
landscape emerging.
– We see economic and financial
changes – and changes and a perceived
deterioration of health care services, he
said.
The role of international donors remains important in some countries – especially in Eastern Europe. There is an
uneven availability of drugs, sometimes
in spite of EU membership.
– Tightening budgets cause shortages
and stockouts even in core EU countries
– there have been reports of stockouts in
Spain, Austria and Hungary, Mr Bereczky
said.
Very few countries report adherence
to the EACS’ guidelines, and sometimes
there is a lack of diagnostics – especially
viral load.
– The crisis affects the patients and the
medical community as well. HIV is being considered as any other disease – it is
not regarded as something special. There
HIV & VIROLOGY NEWS 4 • 2013
is an increasing difference between resource rich and poor countries.
The facts he presented came from a
survey that had 32 responses from 24
countries.
– While not representative, it is a good
cover of countries, he said.
Standard of care also a political issue
A lack of knowledge was often mentioned
– and this was joined with lack of information from the state.
– The cascade of care seems to be an
absent concept in several countries. Patient’s requests are sometimes respected,
but rarely actively solicited – the doctor
will not tell the patients that they have a
choice.
Nevertheless, the basic skeleton of
Standard of Care seems to be there, Mr
Bereczky continued.
– So where can we go from here? Patient information and awareness are key
topics – because their own advocacy will
also benefit the care on the whole.
There is also some criticism about the
EACS’ guidelines being based on economic arguments instead of scientific.
– Which is interesting, because the lack
of economic resources is often causing
the problem in the first place!
He ended his lecture with a “lesson
from the community”:
– Standard of Care is not only a medical, but also a political issue. No results
can be attained unless there is a synergy
across the scientific evidence and political advocacy. The patient community can
help in making that happen – that is the
message I want to convey to you, Mr Bereczky finished his talk.
Media campaign in Ukraine resulted in
large price reduction
Director Olga Stefanyshyna reported
about HIV care and support in Ukraine.
– Overall there are 145 AIDS Centres in
Ukraine, and they serve 44,666 persons,
she said.
Coverage of enrolment in HIV care is
not sufficient; less than two thirds of all
people newly diagnosed with HIV are enrolled in HIV care.
– 80% of patients diagnosed with HIV
and enrolled in care had WHO clinical
stages 3 and 4.
TB is the most frequent AIDS-related
disease in people living with HIV (PLHIV) in Ukraine. As of January 2012, 60%
of PLHIV registered at the AIDS centres
had pulmonary or extra-pulmonary TB.
The country is ranked as 144 in the
world on corruption, and this affected
the price for ART. But a media campaign
launched by patients halved the price on
Efavirenz from 2012 to 2013, she told the
audience.
Difference between Spain and Belgium
Diego Garcia reported from Spain.
– The lack of economic resources is
having a terrible impact – not only in the
7
�
© Charly Herscovici, with his kind authorization
c/o SABAm-ADAgP, 2012
14th EuropEan
aIDS ConfErEnCE
oCtobEr 16 - 19, 2013 | bruSSELS · Belgium
Conference Organiser
European aIDS Clinical Society (EaCS)
CHu St pierre - pL709
rue Haute 322 · 1000 brussels · belgium
phone: +33-1-44241796
Email: [email protected]
www.eacsociety.org
Conference Secretariat
EaCS Conference Secretariat
c/o K.I.t. Group GmbH
association & Conference management
Kurfürstendamm 71 · 10709 berlin · Germany
phone: +49-30-24603-0
fax: +49-30-24603-200
Email: [email protected]
www.kit-group.org
Conference Venue
SQuarE - bruSSELS mEEtInG CEntrE
Glass Entrance
rue mont des arts · 1000 brussels · belgium
www.square-brussels.com
Conference Co-Chairs
nathan Clumeck
manuel battegay (EaCS president)
www.EaCS-ConfErEnCE2013.Com
Early registration fee deadline:
June 15, 2013
Scholarship application deadline:
June 15, 2013
Abstract submission deadline:
July 15, 2013
Late Breaker abstract submission opens:
august 1, 2013
Late Breaker abstract submission deadline:
august 28, 2013
Standard registration fee deadline:
September 15, 2013
For the 2nd Announcement and more information,
please click here:
standards of care, but also in the access to
health care for the whole population in
Spain, he said.
There is no budget for AIDS programmes from the central government to
the 17 regional governments in Spain.
– We’ve seen 75% cuts on grants from
the central governments to non-government organisations working on HIV and
AIDS. We have also seen a proliferation
of Regional Boards with their own guidelines on ART treatment and management with serious monetary bias – which
broadens inequity of access to national
guidelines among different territories.
Finally Patrick Reyntiens talked about
the situation in Belgium.
– In HIV, the economical crisis has
luckily not shown any major negative impact, he said.
However, some of the historical problems remain, which calls for continued
activism.
– Activities used by community include, among others, booklets for patients on treatment, living with HIV,
training and information during seminars
and programmes on television.
The HIV-positive community was explicitly invited by the Belgian Minister
of health to help developing the National
Plan on HIV (launched on October 15th
2013) covering testing, prevention, treatment and care.
HIV & VIROLOGY NEWS 4 • 2013
Kidney disease is associated with
higher mortality
People with HIV are living longer, and it
is a chronic disease.
– This means that all specialists have
to be involved in the care, underlined
Dr Antonios Papadopoulos, one of the
Chairs for a Session titled People living
long term with HIV.
Dr Lene Ryom talked about chronic
kidney disease (CKD) in HIV.
– Kidney disease is important because
it is associated with end stage renal disease (ESRD), continuous dialysis or
transplantation, CVD, bone disorders –
and AIDS, she said.
The incidence of chronic kidney disease in the current cART era is relatively low in Caucasians, but considerably
higher among persons of African origin
with genetic disposition. This disease is
associated with increased morbidity and
mortality, Dr Ryom pointed out.
– A number of traditional risk factors,
such as diabetes and hypertension, are
very important risk factors in addition
to HIV, immune suppression, HCV and
certain antiretroviral drugs (ARVs), she
continued.
Prevalence of CKD estimated to rise
Discontinuation of ARVs with nephrotoxic potentials is common in patients
with declining estimated glomural filtra-
tion rate (eGFR) levels, suggesting that
appropriate interventions are already
taking place in resource-rich settings.
– There are a lot of unanswered questions: What would be the consequences
of using ARVs with nephrotoxic potentials – in settings without access to regular renal function screening? Also in
populations with high underlying renal
risk? Another question relates to ARVs
initiated at higher CD4 cell counts, Dr
Ryom said.
The prevalence of CKD is estimated
to increase in the years to follow, partly
due to ageing. Therefore it is important to
focus on regular screening for CKD, and
intervene against modifiable risk factors
to reduce CKD-related morbidity and
mortality.
– This includes treatment of hypertension, diabetes, dyslipidemia and to support smoking cessation. Also it includes
ensuring a high level of cART adherence.
Finally, in case of unexplained renal impairment, consider switching to more
renal friendly ART when possible, she
ended her talk.
Regular screening is crucial
Prof Amanda Mocroft presented a study
that aimed to describe the incidence of
fatal and non-fatal AIDS and non-AIDS
events according to current eGFR. The
study also aimed to determine whether
9
�
current eGFR – or other measures of renal insufficiency – were independent predictors of clinical events.
The data was collected from EuroSIDA
– a large prospective cohort with 18,791
patients from 108 clinics in 34 European
countries, Israel and Argentina.
– We found that lower current eGFR
and a higher proportion at follow-up with
a low eGFR (60 or below) was associated
with death and non-AIDS events. There
is a consistent relationship between renal
function and different non-AIDS events
that we were able to investigate with sufficient numbers, Prof Mocroft said.
However, the relationship between
renal function and AIDS was mainly explained by the fatal AIDS events.
– There is a stronger relationship with
fatal events, which we in an observational cohort study can’t disentangle whether
the renal function is a marker for clinical
disease specifically – or if it is simply a
consequence of underlying deteriorating
health.
Regular screening for non-renal morbidities is therefore crucial in HIV-positive patients with chronic renal impairment, she stated.
ART coverage – and true ART coverage
– It is a misconception that young people
of today don’t care about HIV, said Prof
Anna Mia Ekström.
She was talking about new perspectives of the HIV epidemic at a Satellite
Symposium, sponsored by Gilead.
Prof Ekström presented a diagram on
new HIV infections 2004–2011 in WHO
European regions. It demonstrated that
the curve is very slightly upward in the
Centre region, but it is actually declining in the West. However in the East it is
climbing steeply.
There is 1.6 new infections for every 1
person starting on ART.
– Every day there are more than 6,300
new infections, and 50% of the newly infected are under 24 years of age. So we
have some way to go, she said.
A global target of 15 million people on
ART is set for 2015. 9.7 million individuals are on ART today. But Prof Ekström
pointed out that ART coverage is complex.
– The current way to measure ART is
to take the number of individuals receiving ART and to divide this figure with the
number of individuals eligible for ART.
The quotient you get is the ART coverage. But to measure the true coverage,
10
Amanda Mocroft
Anna Mia Ekström
Brian Gazzard
Adrianna Ammasari
Denize Gökenkin
Sheena McCormack
you should take the number of individuals adhering to ART, and divide it with the
number of individuals in need of ART plus
HIV deaths – that quotient will give you
the true ART coverage!
The net increase of HIV infected per
year is 700,000 people – and then the
people dying have been deducted.
– 80% of all new infections come from
undiagnosed individuals, she underlined.
We have the power and the knowledge
To sum up her lecture, Prof Ekström said
that it is a major achievement that so
many lives have been saved also in poor
contexts.
– It is also fantastic that so many new
infections have been prevented with
ART, including prevention of mother-tochild transmission (PMTCT). The future
is potentially very bright.
But the number of people living with
HIV will increase over the next decade
due to more new infections than deaths
– regardless if we manage to rapidly scale
up ART. We need to build systems that
can cope with this large number of people requiring life long monitoring and
treatment.
– But we have the power and knowledge to make a difference, we can curb
the epidemic, save million of lives and
speed up the decline in new infections
and AIDS-related deaths – by increasing
our efforts to promote gender equality,
fight stigma and discrimination associated with HIV, drug use and homosexuality!
– We can, and must, reduce the number
of new infections – also through the promotion and enabling of safer behaviours,
earlier HIV testing – and by convincing
governments to invest in and strengthen
health systems to provide sustainable and
affordable treatment for all those in need,
Prof Ekström ended her highly appreciated talk.
We have to switch the paradigm
At another Satellite Symposium, sponsored by ViiV Healthcare, Prof Brian Gazzard gave an overview of the current picture for patients with HIV.
– We have seen a success in treatment
and a higher number of individuals on
ART. But they are unevenly spread around
the world.
In the developing world we have to
switch the paradigm – go from the doctor
handling everything to doctor peer support, he said.
Stigma, isolation and discrimination
are the most important obstacles for people living with HIV/AIDS. They affect
HIV prevention, testing, care and treatment globally.
– People need to feel able to take a HIV
test and to potentially live with an HIV
diagnosis. This is of paramount importance to effective HIV prevention – and
treatment programs at local and national
levels.
Therefore Prof Gazzard suggested a
more patient-centred care.
– Health-care personnel are responsible for ensuring compassionate and
non-judgemental care of patients. They
need to work with society to break down
the barriers of stigma, isolation and discrimination that persist almost 30 years
into the global HIV epidemic, he summarised.
HIV & VIROLOGY NEWS 4 • 2013
Baseline viral load correlates
with achievement of viral suppression
Individuals commencing combined anti­
retroviral therapy (cART) experience
high rates of viral suppression. Several
clinical trials have revealed numerically
lower rates of viral suppression at high
baseline viral load.
– However, other confounders could
explain differences in initial viral suppression rates. The impact of high baseline viral load on longer-term virological
outcomes in individuals who achieve viral suppression is unknown, said Dr Laura Waters at a Session on Antiretroviral
therapy.
She presented a study that aimed to
investigate, in individuals achieving viral suppression on first line cART, the
impact of baseline viral load and time
to viral suppression on subsequent virological outcomes within the UK CHIC
study.
UK CHIC collects routine clinical data
– demographics, clinical events, ART
medication history and laboratory test
results – on patients over 16 years of age
in any of 13 centres for HIV care.
– We found that baseline viral load correlated significantly with achievement of
viral suppression on initial cART, Dr Waters said.
Amongst individuals who have achieved
viral suppression on first line cART, higher
baseline load and slower time to suppression were also associated with a higher
chance of subsequent virological rebound.
Limitations of the study include lack of
adherence data and inability to adjust for
unidentified confounders.
– But this study adds to the trial data
that suggests that we may need to investigate new strategies, with modern drugs,
for individuals with high pre-treatment
viral load, she concluded.
Ways to improve adherence
Dr Adrianna Ammasari gave a lecture on
how to best secure long-term adherence.
– We need to have good adherence for
a number of reasons: To avoid virological rebound, to treat HIV in reservoirs, to
achieve newer treatment outcomes and
to limit hospitalisations and health care
costs.
She illustrated the latter with a study
from 2013 that demonstrated that worse
adherence rates, more frequent hospitalisations and higher health care costs were
found in patients treated with more than
2 pills per day.
HIV & VIROLOGY NEWS 4 • 2013
– The last reason is to reduce onward
HIV transmission. A favourable effect of
higher adherence levels on community
viral load is likely, with a benefit on the
treatment as prevention approach.
Recent clinical contexts, such as polypharmacy, may represent a further challenge to ART adherence.
– Use of every-day dosing especially
and single tablet regimens, seem to be key
factor to favour correct treatment intake,
Dr Ammasari continued.
Regarding individually tailored multi-component interventions, we should
also include self-care technology based
products to empower HIV-positive individuals, and to aid over-burdened clinics.
They have the potential to result in cost
containment, while improving ART adherence.
– Future research is needed in terms
of standardizing interventions – and to
compare them, were Dr Ammasari’s final
words.
Stigma leads to fear for testing
One Session had the title Sex, drugs and
stigma.
Stigma is still relevant in 2013, said Dr
Denize Gökenkin.
– HIV-related stigma and discriminations remain highly prevalent around the
globe, she underlined.
She presented the People living with
HIV stigma index – a community research and advocacy initiative developed
by, and for, people living with HIV/AIDS
(PLWHA).
It includes an in-depth questionnaire
developed as a monitoring tool. There is
a huge amount of data, and Dr Gökenkin
presented some of them.
– The rate of PLWHA that is subject to
stigma range from 23% in Turkey to 51%
in Ukraine. The most common form of
stigma is being gossiped about, she said.
But there are also other forms – being
verbally hurt, isolated from family activities and physical harassment or violence
– all due to HIV.
A survey performed in the background
population in Spain revealed that 19% of
them thought that PLWHA were themselves to blame for their status – and that
17% of the population thought that those
who acquired the disease through sex or
drugs deserved it.
HIV related stigma intersects with other pre-existing stigmas.
– Already marginalized groups, such
as ethic minorities, gay/bisexual men
and transgender women, experience the
worst form of stigma.
Stigma leads to fear for testing oneself
for HIV.
– Factors related to late testing are relational concerns – fear of being shunned
by family or friends and being abandoned
by partner. But also fear of being labelled
– as promiscuous, a sex worker or an intravenous drug abuser. There is also a fear
to lose one’s job – and this fear was significantly higher in Turkey, Dr Gökenkin
said.
More reports can be found on www.
stigmaindex.org.
How standard is your care?
The evolution of the standard of care – the
changing face of HIV treatment was the
title of a Satellite Symposium, sponsored
by Bristol-Meyer Squibb.
Prof Hans-Jürgen Stellbrink described
the wealth of data for the standard of
care.
– Treatment guidelines have evolved
with respect to how and when to treat,
he said.
Recommendations are based on clinical data and expert opinion.
– But randomised control trials (RCT)
do not always represent real patient populations, so it is important to consider
RCT and cohort data together.
Clinical trial data provide the most
important basis for clinical practice, but
have to be interpreted and adapted to a
real-life setting, Prof Stellbrink summarised.
The HIV populations are complex and
include an ageing population, late presenters, pregnant women and women of
childbearing age, Dr Paddy Mallon said.
– There are a number of factors involved that influence our treatment decisions in these patients. All major international treatment guidelines recommend
that treatment should be tailored to the
individual. How standard is your care?
Prof Santiago Moreno talked about PI
monotherapy and dual therapy.
– Long term toxicity and patient adherence remain a challenge in treating HIV.
Simplification strategies include using
NRTI-sparing and PI monotherapy or
STRs, he said.
Available data for NRTI-sparing and PI
monotherapy appear to point toward only
a limited benefit in specific scenarios.
– New STRs offer some patient benefits, including improved convenience,
but have fewer years of proven efficacy
11
�
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From left: Diego Ripamonti, Anton Pozniak, José Arribas and Hans-Jürgen Stellbrink.
against fewer classes compared to established therapies, Prof Moreno said.
When to start ART – and fewer pills
or fewer drugs?
What’s the best approach to personalised
treatment was the topic for another Satellite Symposium, sponsored by Janssen
Pharmaceuticals.
In this, three controversial aspects in
current HIV treatment were discussed
between two faculty members. The audience was asked to vote on their view.
The debates topics were: when to start
HIV therapy; if we should simplify treatment by using fewer drugs (PI monotherapy) or fewer pills (STRs); and finally if
one should change therapy given to a
patient, due to new regimens with perceived additional benefits.
Two speakers with different opinions
tackled each subject. Before and after
their talks the audience had to vote for
one of the alternatives.
Dr Anton Pozniak argued for starting
treatment when the CD4 count is below
350/mm3.
– If you dig in the available data, you
will find that there are many uncertainties. Patient adherence will be lower
if they don’t want it – and a lot of them
don’t, he said.
Dr José Arribas advocated for starting
at 500.
– It is good for the individual. There is
a measurable increase in mortality for patients that start between 350 and 500, he
pointed out.
In next debate, Dr Arribas advocated PI
monotherapy.
– If we can control infection with fewer
drugs, we will probably have less toxicity.
HIV & VIROLOGY NEWS 4 • 2013
Dr Diego Ripamonti did not agree.
– One size does not fit all – but almost
all! Once a day-regimens are preferred by
patients, so STRs can improve adherence,
he stated.
Switch – or not?
Dr Ripamonti came back for the third
topic. His view was that there are good
reasons to change an effective regimen.
– It can improve adherence, tolerability
– and reduce toxicity, risk for hospitalisation and costs.
Dr Pozniak argued for keeping the patient on a successful regimen.
– There is a price to pay when switching. Mistakes happen – patients can take
the wrong dose or pills, new side effects
can occur that impact adherence and
control and there can be forgotten drug
interactions or superimposed toxicities,
among others, he underlined.
The accuracy of choosing topics that
there are different views upon was manifested in the surprisingly even distribution of answers from the audience. The
votes were all very close calls – both before and after the presentations.
We need to understand behaviour
The last Session concerned ART for prevention. Prof Sheena McCormack gave a
lecture on the scientific perspective on
treatment as prevention (TasP).
She began by presenting the HPTN
052 trial. This aimed to determine the effectiveness of two treatment strategies
in preventing the sexual transmission of
HIV in HIV-serodiscordant couples.
– It showed that a third of the infected
got infected outside the partnership. So
science has little to do with policy – we
need to understand behaviour, and not
just the behaviour of participants and users, Prof McCormack underlined.
The concerns surrounding TasP are
many: The possibility of risk compensation is one – i.e. uninfected partners on
treatment take more risks.
– This cannot be assessed in a placebocontrolled trial.
There are also concerns for an increase
in sexually transmitted infections, especially HCV and for toxicity and resistance.
PrEP buys time
Prof McCormack presented a research
article that had investigated the attitude
towards antiretroviral pre-exposure
prophy­laxis (PrEP) prescription among
311 HIV specialists.
– 70% said they would prescribe PrEP.
There were also 30% that was negative.
They believed that behavioural interventions were more effective, and had concerns about toxicity.
She ended with some concluding
thoughts:
– We can absolutely not ignore what is
happening – some people have “conversation-less” sex and multiple partners in
a timeframe equivalent to the window period of routine HIV tests.
It is common sense to offer treatment
to HIV positive individuals – and to offer
PrEP to HIV negative individuals, Prof
McCormack continued.
– Both strategies are strongly supported by science. What PrEP does is
that it buys time required for behavioural
change.
Per Lundblad
13
14th European AIDS conference:
Update on ART
The 14th edition of the European AIDS Conference took place in Brussels from October 16th to
October 19th. With respect to clinical trials of antiretrovirals, in my opinion the biggest news
of the conference was a trial of dual therapy with lopinavir/ritonavir and lamivudine in naïve
patients. We also saw interesting data about a new integrase inhibitor, S/GSK1265744, and
relevant updates in well-known trials: Flamingo, STAR and Gilead 102 and 103.
GARDEL: let’s tango!
The use of dual therapies in ART-naïve
patients has been a very intriguing story
full of script twists. Until now it could be
said “No dual therapy regimen has convincingly proven non-inferiority versus
triple therapy in ART-naïve patients”.
The Spartan clinical trial explored unboosted atazanavir plus raltegravir in naïve patients. The results of the trial were
not good enough to support further development [1]. The ACTG 5262 -a single
arm study of darunavir/ritonavir plus
raltegravir-[2] showed disappointing results, specially in patients with high viral
loads at baseline. Only the PROGRESS
clinical trial had shown that a dual combination of lopinavir/ritonavir plus raltegravir had similar results that lopinavir/
ritonavir plus tenofovir/emtricitabine [3].
However, the PROGRESS trial was
not large enough to convincingly prove
non-inferiority. Recently the MODERN
study was stopped after showing that the
combination of darunavir/ritonavir plus
Maraviroc was inferior to darunavir/ritonavir plus tenofovir/emtricitabine. Based
on these unsatisfactory results, there is
justified skepticism about the chances of
dual antiretroviral combinations of ever
matching the activity of triple drug combinations in naïve subjects.
GARDEL [4] is a clinical trial that randomized 426 antiretroviral naïve patients to receive dual therapy (DT) with
lopinavir/ritonavir BID plus lamivudine
150 mg BID, or triple therapy (TT) with
lopinavir/ritonavir BID plus lamivudine
or emtricitabine plus a third investigatorselected nucleoside reverse transcriptase
inhibitor (NRTI) in fixed dose combinations. GARDEL was carried out mainly
in Argentina, Chile, Mexico and Peru
although there were also patients from
Spain (including my center) and Canada.
14
Figure 1. GARDEL. Proportions of patients with < 50 HIV-RNA copies/mL by snapshot
analysis at 48 weeks.
100%
90%
DT
TT
88.3
83.7
80%
70%
60%
50%
40%
30%
20%
10%
0%
BSL
W¤
W8
W12
W24
W36
W48
WEEK
In the TT group NRTIs were selected
according to the availability in each country. Half of the patients in the TT group
received coformulated zidovudine and
3TC. The other half received mainly coformulated tenofovir and emtricitabine.
Approximately 43% of patients had baseline viral loads above 100,000 HIV-RNA
copies/mL.
After 48 weeks of follow-up 88.3% of
patients treated with DT and 83.7% of
patients treated with TT had a viral load
of less than 50 HIV-RNA copies/mL (Fig
1). These results clearly met the non-inferiority criteria for the DT group. What
it is even more striking is that the difference between the groups became larger
in patients with high viral loads – above
100,000 HIV-RNA copies/mL – at baseline. Rates of suppression were 87.2% in
DT versus 77.9% in TT. Confirmed virologic failures were equally distributed
between groups: 10 (4.6%) in DT and 12
(5.9%) in TT. In terms of resistance development there were no protease inhibitor
mutations in either group. Two patients
had M184V in the DT group versus none
in the TT group. There were significant-
ly more discontinuations due to adverse
events in the TT group (4.9% Vs. 0.9%).
The results of GARDEL caught many
EACS delegates by surprise. One immediate criticism of the results is that the
control arm included AZT, which is more
toxic and more prone to discontinuations
than tenofovir or abacavir. Including AZT
might have compromised the efficacy of
the control arm. This is a reasonable criticism but the efficacy of the TT group was
rather high and quite comparable with
the efficacy of lopinavir/ritonavir plus
tenofovir/emtricitabine in ARTEMIS [5]
or CASTLE [6]. Although it is true that
there were more discontinuations due to
adverse events in the TT group, results of
observed treatment analysis and evaluation of pure virologic failures does not
suggest worse “pure” virological efficacy
in the DT group. Nevertheless, we are
waiting for a subgroup analysis comparing DT versus TT with tenofovir or abacavir instead of AZT.
The prospect that plain old 3TC could
be the best candidate to accompany a
boosted protease inhibitor in dual therapy regimens is somewhat ironic. There
HIV & VIROLOGY NEWS 4 • 2013
Figure 2. LATTE Study Design.
Oral Induction Phase
HIV ART-naive
HIV-RNA > 1,000 c/mL
1:1:1:1 Randomization
Stratified by VL
and NRTI
Oral Maintenance Phase
744 10 mg + 2 NRTIs*
744 10 mg + RPV 25 mg
744 30 mg + 2 NRTIs
744 30 mg + RPV 25 mg
744 60 mg + 2 NRTIs
744 60 mg + RPV 25 mg
EFV 600 mg + 2 NRTIs
24
*ABC/3TC or TDF/FTC
Figure 3. FLAMINGO. Snapshot at 48 Weeks by Baseline HIV-1 RNA and NRTI Background Therapy.
Favors
DRV/r
Favors
DTG
DTG 50 mg
QD
DRV/r
800/100 mg
QD
Baseline ≤100,000 c/mL
ABC/3TC at Day 1
TDF/FTC at Day 1
n=134
n=228
89%88%
88%86%
Baseline >100,000 c/mL
ABC/3TC at Day 1
TDF/FTC at Day 1
n=25
n=97
92%67%
94%71%
-20 -10
0
10 20
30
40
50
60
Difference in proportion (DTG- DRV/r; unadjusted)
are theoretical reasons why 3TC could
be better than an integrase inhibitor or
maraviroc in dual therapy regimens: lack
of pK interactions, high activity and, last
but not least, very long intracellular halflife. To me, prolonged intracellular halflife is the most important characteristic
of NRTIs in terms of increasing the forgiveness of antiretroviral regimen. There
are other trials testing the activity of a
boosted protease inhibitor plus 3TC in
suppressed patients, one named “SALT”
explores 3TC with atazanavir/ritonavir
[7] and the other named “OLE” evaluates
3TC with lopinavir/ritonavir [8]. Very
preliminary results of SALT were also
presented at the EACS conference [9]. In
the next year we are going to hear much
more about dual therapies with boosted
protease inhibitors and 3TC.
LATTE
S/GSK1265744 (to simplify we are calling it just “744”) is a new integrase strand
transfer inhibitor that has oral, long-act-
HIV & VIROLOGY NEWS 4 • 2013
ing subcutaneous and long-acting intramuscular formulations. Clinical trials are
already testing the long-acting 744 along
with long-acting rilpivirine [10]. We are
all excited about the possibility of treating some patients with monthly of bimonthly administrations of long acting
formulations.
In Brussels the results of LATTE [11]
were presented for the first time. LATTE
included ART naïve patients who were
randomized to receive 2 NRTIs plus three
different doses – 10, 30 or 60 mg – of QD
744 or efavirenz (Fig 2). Patients randomized to 744 would switch to dual oral therapy with 744 plus rilpivirine if at week 20
they had virological suppression below
50 HIV-RNA copies/mL. After 24 weeks
of follow-up 87% of patients randomized
to 744 had virologic success compared
to 74% in the efavirenz arm. There were
very few differences in terms of virological efficacy among the three 744 doses.
There were three virologic failures in the
744 arms and three in the efavirenz arms
without any resistance development. The
60 mg dose arm experienced more liver
enzyme elevations and more discontinuations due to adverse events. Based on the
results of this trial the dose of 30 mg has
been selected for further development.
Flamingo subgroup analysis
Flamingo is a clinical trial comparing two
NRTIs (ABC/3TC or TDF/FTC) plus either darunavir/ritonavir or dolutegravir
in antiretroviral naïve patients. The primary endpoint of the trial showed superiority of dolutegravir over darunavir/
ritonavir and was presented at the last
ICAAC [12]. At EACS a subgroup analysis of FLAMINGO was presented [13]. In
patients with more than 100,000 HIVRNA copies/mL at baseline by snapshot
analysis, dolutegravir showed superiority over darunavir/ritonavir: proportions
with less than 50 HIV-RNA copies/ml at
week 48 were 93% vs. 70% respectively. In
patients with less than 100,000 HIV-RNA
copies/mL at baseline dolutegravir was
15
�
not superior (proportion with less than 50
HIV-RNA copies/mL were 88% vs. 87%).
When investigators analyzed the high viral load strata by NRTI combination there
was superiority for the TDF/FTC-dolutegravir combination vs. the TDF/FTC-darunavir/ritonavir combination.
Although differences between ABC/­
3TC-dolutegravir and ABC/3TC-darunavir/ritonavir in patients with high
viral loads were even larger, due to the
small sample size superiority could not
be claimed (Fig 3). Interestingly none of
the virological failures in any combination
was associated with resistance development. Therefore “inferiority”, as in many
other trials including boosted protease inhibitors, does not translate in bigger losses of therapeutic options.
Updates of other clinical trials
At EACS the 96-week update of the STAR
clinical trial [14] showed that in patients
with less than 100,000 HIV-RNA copies/
mL at baseline TDF/FTC/rilpivirine continued to be statistically superior to TDF/
FTC/efavirenz. In patients with more
than 100,000 HIV-RNA copies/mL at
baseline TDF/FTC/rilpivirine remained
non-inferior. There were very few new
virological failures in either arm between
year one and year two.
The 144-week updates of the Gilead 102
[15] and 103 [16] studies comparing TDF/
FTC/elvitegravir/cobicistat vs. TDF/FTC/
efavirenz or TDF/FTC-atazanavir/ritonavir respectively were also presented at
Brussels. Take home messages from both
studies: 1) Very few new virological failures, 2) No new cases of proximal renal
tubulopathy and 3) no further increases in
creatinine since week four.
Based partly on these long-term data
the latest update of the DHHS guidelines
[17] has included coformulated TDF/
FTC/elvitegravir/cobicistat as a preferred
recommended regimen in ART-naïve patients. Also TDF/FTC or ABC/3TC plus
dolutegravir appear for the first time as
preferred recommended regimens.
References:
1. Kozal MJ, Lupo S, DeJesus E, Molina J-M, McDonald C, Raffi F, et al. A Nucleoside- and Ritonavir-Sparing Regimen Containing Atazanavir
Plus Raltegravir in Antiretroviral TreatmentNaïve HIV-Infected Patients: SPARTAN Study
Results. HIV Clinical Trials 2012; 13:119–130.
2. Taiwo B, Zheng L, Gallien S, Matining RM,
Kuritzkes DR, Wilson CC, et al. Efficacy of a
nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV1-infected patients (ACTG A5262). AIDS 2011;
25:2113–2122.
16
3. Reynes J, Trinh R, Pulido F, Soto-Malave R,
Gathe J, Qaqish R, et al. Lopinavir/ritonavir
combined with raltegravir or tenofovir/emtricitabine in antiretroviral-naive subjects:
96-week results of the PROGRESS study.
AIDS Research and Human Retroviruses 2013;
29:256–265.
4. Cahn P et al (GARDEL Study Group). Dual
therapy with lopinavir/ritonavir (LPV/r) and
lamivudine (3TC) is non-inferior to standard
triple drug therapy in naive HIV-1 infected
subjects: 48-week results of the GARDEL study. 14th European AIDs Conference (EACS
2013). Brussels. October 16-19, 2013. Abstract
LBPS7/6.
5. Ortiz R, DeJesus E, Khanlou H, Voronin E, van
Lunzen J, Andrade-Villanueva J, et al. Efficacy
and safety of once-daily darunavir/ritonavir
versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS
2008; 22:1389–1397.
6. Molina J-M, Andrade-Villanueva J, Echevarria J, Chetchotisakd P, Corral J, David N, et al.
Once-daily atazanavir/ritonavir versus twicedaily lopinavir/ritonavir, each in combination
with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected
patients: 48 week efficacy and safety results of
the CASTLE study. The Lancet 2008; 372:646–
655.
7. Simplification to Atazanavir/Ritonavir + Lamivudine as Maintenance Therapy - Full Text
View - ClinicalTrials.gov. clinicaltrials.gov.
http://www.clinicaltrials.gov/ct2/show/NCT
01307488?term=salt+atazanavir&rank=1 (accessed 9 Nov2013).
8. Study to Evaluate the Activity and Tolerability
of Lopinavir/Ritonavir and Lamivudine Bitherapy in HIV Patients With Viral Suppression Full Text View - ClinicalTrials.gov. clinicaltrials.gov. http://clinicaltrials.gov/ct2/show/NC
T01471821?term=LOPINAVIR+OLE&rank=1
(accessed 9 Nov2013).
9. J.A. Perez-Molina, A. Rivero, J. Pasquau et al.
Safety and Efficacy of Switching to Dual Therapy (Atazanavir/Ritonavir+Lamivudine)vs.
Triple Therapy (Atazanavir/Ritonavir+Two
Nucleos(t)ides) in Patients on Virologically
Stable Antiretroviral Therapy: 24-week Interim Analysis from a Randomized Clinical Trial
(SALT Study). 14th European AIDs Conference (EACS 2013). Brussels. October 16-19, 2013.
Abstract PE7/1
10.W Spreen, P Williams, D Margolis, et al. First
study of repeat dose co-administration of
GSK1265744 and TMC278 long-acting parenteral nanosuspensions: pharmacokinetics,
safety and tolerability in healthy adults.7th International AIDS Society Conference on HIV
Pathogenesis, Treatment and Prevention. Kuala Lumpur, June 30-July 3, 2013. Abstract
WEAB0103..
11. Margolis D, Bhatti L, Smith G, et al. Once-daily
oral GSK1265744 (GSK744) as part of combination therapy in antiretroviral naive adults:
24-week safety and efficacy results from the
LATTE study (LAI116482). 14th European
AIDS Conference (EACS 2013). October 16-19,
2013. Brussels. Abstract PS7/1..
12.J Feinberg, B Clotet, MA Khuong, et al. Oncedaily dolutegravir (DTG) is superior to darunavir/ ritonavir (DRV/r) in antiretroviral naive adults: 48 week results from FLAMINGO
(ING114915). 53rd Interscience Conference
on Antimicrobial Agents and Chemotherapy (ICAAC). Denver, September 10-13, 2013.
Abstract H-1464a.
13. FB Clotet, MS Khuong, A Antinori, et al. Oncedaily dolutegravir versus darunavir/ritonavir
in antiretroviral naive subjects: 48 week subgroup analyses from FLAMINGO. 14th European AIDS Conference (EACS 2013). Brussels.
October 16-19, 2013. Abstract PS4/6.
14.Cohen C, Wohl D, Arribas J, Henry K. STaR
Study: Single-Tablet Regimen Rilpivirine/Emtricitabine/Tenofovir DF Maintains
Non-Inferiority to Efavirenz/Emtricitabine/Tenofovir DF in ART-Naïve Adults Week
96 Results. 14th European AIDS Conference
(EACS 2013). Brussels. October 16-19, 2013.
Abstract LBPE7/17
15.Wohl D, Cohen C, Gallant JE, et al. Elvitegravir/cobicistat/emtricitabine/tenofovir DF
(STB) has durable efficacy and differentiated
long-term safety and tolerability versus efavirenz/emtricitabine/tenofovir DF (ATR) at
Week 144 in treatment-naive HIV patients.
Program and abstracts of the 53rd Interscience Conference on Antimicrobial Agents and
Chemotherapy; September 10-13, 2013; Denver, Colorado. Abstract H-672a.
16. Clumeck N, Molina JM, Henry K, et al. Elvitegravir/cobicistat/emtricitabine/tenofovir
DF (STB) has durable efficacy and differentiated safety compared to atazanavir boosted by
ritonavir plus emtricitabine/tenofovir DF at
Week 144 in treatment-naïve HIV-1 infected
patients. Program and abstracts of the 14th European AIDS Conference. October 16-19, 2013;
Brussels, Belgium. Abstract LBPS7/2.
17.DHHS Panel on Antiretroviral Guidelines
for Adults and Adolescents Updates Recommendations on INSTI-Based Regimens for
ART-Naive Individuals | HIV/AIDS News |
AIDSinfo. aidsinfo.nih.gov. http://aidsinfo.
nih.gov/news/1392/hhs-panel-on-antiretroviral-guidelines-for-adults-and-adolescentsupdates-recommendations-on-insti-basedregimens-for-art-naive-individuals (accessed
4 Nov 2013).
Conflict of Interests
Dr Arribas has received advisory fees,
speaker fees and grant support from
Tibotec, Janssen, Abbott, BMS, Gilead,
MSD. He has received advisory fees and
speaker fees from Viiv.
Dr. JosÉ R Arribas
Servicio de Medicina Interna,
Unidad VIH Hospital La Paz, IdiPAZ
Madrid, Spain
[email protected]
HIV & VIROLOGY NEWS 4 • 2013
Clinical update on opportunistic complications in HIV
HIV-associated lymphoma:
Treatment update
Introduction
HIV is a well-known risk factor for lymphoma, mediated by infectious antigen
activation due to the immune suppression. The lower the number of CD4 cells
the higher the risk for lymphoma. The
use of combination antiretroviral therapy
(cART) has improved the CD4 counts in
the HIV population, which has reduced
the incidence of lymphoma considerably.
The most common histological HIVassociated lymphoma (Table 1) is subgroups in the category of “aggressive Bcell non-Hodgkin’s lymphoma (NHL)”.
The most common is diffuse large B-cell
lymphoma (DLBCL), which includes
primary CNS lymphoma, followed by
Burkitt’s lymphoma. Hodgkin’s lymphoma is a rather common diagnosis but not
as common as DLBCL. An interesting observation is that primary CNS lymphoma
is associated with very low CD4 counts
while classical Hodgkin’s lymphoma and
Burkitt’s lymphoma are more common
in less immune compromised patients
indicating that the development of the
lymphoma subtype is dependent on the
immune surveillance. HIV-associated
lymphoma has more often advanced
stage and extranodal disease compared
to the general lymphoma population.
The goal of treatment of a HIV-associated lymphoma is almost always cure.
As a rule, however, HIV-associated lymphoma is more difficult to treat compared
to comparable HIV-negative patients due
to drug interactions and more treatment
related toxicities, mainly infections. The
prognosis is almost comparable with the
general lymphoma population except in
the nowadays small bad prognostic subgroup of patients with CD4 counts < 50
cells/µl. The risk for death is reported
to increase with 26% for every 10 cells/
µl decrease below this level (Barta et al
2013). Lymphoma treatment differs according to the special subgroup. The difference has been more pronounced in the
antibody era and will increase in the coming years due to the new targeted thera-
HIV & VIROLOGY NEWS 4 • 2013
Table 1: Subgroups of lymphoma associated with HIV in the western world.
Histological Subgroup
Diffuse large B-cell lymphoma
(not primary CNS)
%
Special characteristics
60–70
CD20+ (10–15% CD30+)
Primary CNS
5
CD20+, EBV-positive in the cerebrospinal fluid
Hodgkin’s lymphoma
10–15
CD30+
Burkitt’s lymphoma
10–15
CD20+
Peripheral T-cell lymphoma
1–2
CD4+ and or CD 8+
Plasmablastic lymphoma
2–3
CD20-, CD138+
Primary effusion lymphoma (PEL)
1
CD20+, KSHV
Abbreviation: KSHV – Kaposis sarcoma herpesvirus
pies. Targets for antibody treatment are
shown in Table 1. The treatment of the
most common subgroups will be discussed.
Lymphoma treatment in general
Chemotherapy is the backbone in the
treatment of aggressive non-Hodgkin’s
lymphoma. A lot of different regimens
are used, the most common presented
in Table 1. The classical chemotherapy
regimen in DLBCL is 6–8 cycles with
the 4-drug regimen CHOP (cyclophosphamide, doxorubicin, vincristine and
prednisone). In Burkitt’s lymphoma and
DLBCL with high proliferation more intensive regimens, often including methotrexate and cytarabine, are used. In these
regimens some of the drugs are distributed during 3–5 days and not in one only
day as in the CHOP regimen. The addition of the CD20 antibody rituximab
has improved the results considerably
for DLBCL (almost all are CD20+). In
Burkitt’s lymphoma the value of rituximab is less obvious (Wästerlid et al 2013),
even if they normally are strongly CD20+.
Treatment for Hodgkin’s lymphoma
consists of chemotherapy alone for patients with advanced disease and combined chemotherapy and radiation, for
patients with limited disease. The most
common used regimen in Hodgkin’s
lymphoma is ABVD (doxorubicin, bleo-
mycin, vinblastine and dacarbazine). In
some countries, especially in Europe, the
more intensive BEACOPP (bleomycin,
etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) is used in patients with advanced
disease.
Treatment of HIV-associated lymphoma
Diffuse large B-cell lymphoma (DLBCL)
Historically, in the HIV-associated
DLBCL, many opinion leaders have recommended reduced chemotherapy regimens without addition of rituximab due
to the higher risk for toxicity, especially
infections. Rituximab is associated with
a slight increase for bacterial infection
due to B-cell depression but also for opportunistic infections like pneumocystis
jiroveci pneumonia and hepatitis B activation indicating that also the T-cells are
affected, which is especially problematic for the HIV-infected population. One
argument against rituximab has been a
small randomized phase III trial (Kaplan et al 2005), which failed to show
improved survival with the antibody.
The reason was increased risk of infectious deaths in the rituximab arm, which
occurred almost exclusively in patients
with CD4 counts of < 100/µl. However,
the recently published meta-analysis including 1,546 patients with NHL (mainly DLBCL) concludes that rituximab
17
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Clinical update on opportunistic complications in HIV
improve the treatment results and that
chemotherapy regimens with reduced
intensity, defined as less than the CHOP,
have inferior outcome (Barta et al 2013).
Which of the regimens in Table 1
should be used? In patients with DLBCL
without risk factors R-CHOP given every
third week (R-CHOP-21) is still the most
used. If granulocyte colony stimulating
factor (G-CSF) is used R-CHOP can be
given every 14 day (R-CHOP-14). A randomized study, in patients without HIV,
has shown that there are no differences
in outcome or toxicity (Cunningham
et al 2013) between R-CHOP-21 and RCHOP-14. In HIV-associated DLBCL, GCSF is usually recommended as prophylaxis against infections for all patients.
Therefore R-CHOP-14 is a more attractive choice than CHOP-21, due to the advantage of the shorter duration of chemotherapy. A regimen called dose-adjusted
EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) (Dunleavy et al 2010) has reported
the most promising phase II results. The
R-EPOCH regimen includes 96 h infusion of doxorubicin and vincristine during 4 days, which may increase the efficacy especially in lymphomas with a high
proliferation. In addition, compared to
CHOP, etoposide is included. This regimen used dose adjustment, based on the
degree of immune suppression and toxicity and temporarily suspended cART.
This strategy was not reported to be more
toxic than R-CHOP. In the meta-analysis
(Barta et al 2013), EPOCH had the highest CR rate and OS in the univariate model but not when adjusted for other covariates, in the multivariate model.
Before changing therapy from RCHOP to R-EPOCH one must be aware
of the many phase II chemotherapy studies in the non-HIV population, reporting
better results than CHOP throughout the
years, which have failed to beat CHOP in
a randomized phase III setting. A randomized study with R-EPOCH versus RCHOP is ongoing and will probably give
the answer. Another more intensive regimen option compared to CHOP is ABCVP
(doxorubicin, bleomycine, cyclophosphamide, vindesine and prednisone),
a standard regimen in France. A randomized study (Mounier et al 2006) in the
pre-rituximab era reported no statistical
difference in outcome in patients without
18
risk factors defined as CD4 < 100µ/l, bad
performance status and known AIDS at
lymphoma diagnosis.
Cardiovascular disease is common in
HIV-infected persons. Heart failure is a
well-known side-effect of doxorubicin.
This is a problem especially in DLBCL,
due to the high accumulated dose of
doxorubicin used in the recommended
regimens compared to the others. In patients with manifest heart insufficiency
liposomal doxorubicin (Caelyx), which
is much less cardiotoxic, is an alternative. Another alternative is to substitute
doxorubicin with etoposide (CEOP) or
pixantrone (Pettengell et al 2012) in the
R-CHOP treatment. However, these less
cardiotoxic regimens have not been compared in phase III trials and may have
inferior efficacy. Mini R-CHOP includes
50% of doxorubicin and cyclophosphamide compared to R-CHOP. Mini RCHOP has been reported to be valuable
in patients too frail for full dose R-CHOP
(Peyrade et al 2011), but it is important to
realize that this reduction also decrease
efficacy (Barta el al 2013).
Prognostic bad factors in newly diagnosed DLBCL are the same as in the
HIV-negative population with higher
age, large tumour burden and elevated
S-LD as the most important factors. In
addition, a low number of CD4 cells is
associated with bad prognosis as earlier
discussed. Another bad prognostic factor
is CNS involvement. DLBCL arising in
the CNS, called primary CNS lymphoma,
has due to the blood-brain barrier completely different treatment regimens.
High-dose methotrexate is the most important drug. The low CD4 count, which
is a rule, makes the prognosis even worse.
The addition of cytarabine and/or temozolamide to methotrexate seems to
improve the outcome (Rubenstein et al
2013). Rituximab has a rather low distribution in CNS but is included in modern
protocols for non-HIV patients with primary CNS lymphoma. Radiotherapy to
the whole brain has been used and decreases the relapse rate, but dementia is a
common late side effect. An HIV-infected
brain has probably an increased risk to
develop this deleterious side effect. Radiotherapy against CNS is, however, an important alternative in the palliative care.
In HIV-infected DLBCL patients with
primary refractory or relapsing disease
26-year-old male with skeletal pain since
one month ago. PET/CT scan showed multiple bone and spleen infiltrations. Biopsy
from the iliac crest showed diffuse large B-cell
lymphoma (DLBCL). HIV infection was found
with a CD4 count of 180/ul. Treatment with
CHOEP-14 x 6 + CART resulted in complete remission. Two episodes of neutropenic sepsis
occurred during the treatment.
platinum based therapy with high dose
therapy with stem cell support (autologous bone marrow transplantation), has
successfully been performed in selected
patients.
Burkitt’s lymphoma
Burkitt’s lymphoma is a rare disease in
the immunocompetent population, but
is disproportionally more common in
the HIV-infected population. Treatment
experience comes mainly from small retrospective studies. These studies have in
common that they have used short intensive regimens regardless of the HIV status. Examples of these regimens, also often used for acute lymphatic leukaemia,
are Berlin-Frankfurt-Munster (BFM),
hyper-CVAD and CODOX-M/IVAC
(Wästerlid et al 2013). High dose cytarabine and methotrexate are important
components in these regimens. A recently published prospective study reported
almost the same result for HIV-negative
and HIV-positive patients (Ribera et al
2013) with an overall survival at 4 year
of 63% and 78%, respectively. The use of
high dose methotrexate and cytarabine
has been challenged by the infusional
R-EPOCH (Noy et al 2010) regimen not
containing these drugs. The controversy surrounding these regimens lies
in whether R-EPOCH can be sufficient
as CNS prophylaxis without CNS pene-
HIV & VIROLOGY NEWS 4 • 2013
Clinical update on opportunistic complications in HIV
Table 2: Common chemotherapy regimes* for HIV-associated lymphomas.
TreatmentDrugsIndication
Comments
ABVD
Do, B, Vb, Da
HL
standard
BEACOPP
B, E, Do, C, Vc, Proc, Pred
HL
different variants exist
CHOP
Cy, Do, Vc, Pred DLBCL
standard
CHOEP
Cy, Do, Vc, E, Pred
DLBCL
young patients (< 60 yrs)
CEOP Cy, E, B, Vc, Pred
DLBCL
manifest heart failure
Caelyx – CHOP
Cy, Caelyx, Vc, Pred
DLBCL
manifest heart failure
EPOCH E, C, Do, Vc, Pred
DLBCL, Burkitt´s
infusional Do and Vc
HyperCVAD
Cy, Vc, Do, M, Cy
DLBCL, Burkitt´s
intrathecal M and Cyt
M
high-dose M
Primary CNS-lymphoma
cytarabine and/or temozolamide added
in different combinations
Abbreviations: DLBCL – diffuse large B-cell lymphoma, HL – Hodgkin´s lymphoma, PCL- Primary CNS lymphoma, B-bleomycin, Cy-cyclophosphamide, Cyt – cytarabine,
Da –dacarbazine Do-doxorubicin, E-etoposide, Pred – prednisone, Proc- Procarbazine, M – methotrexate, Vc- vincristine, Vb - vinblastine .
*Rituximab is added to the regimen if CD 20+ lymphoma.
trating drugs like high-dose methotrexate and cytarabine. Rituximab is used in
all modern reports although not proven
to increase efficacy. However, a recently
published study (Dunleavy 2013) using a
double dose of rituximab combined with
a low-intensity R-EPOCH reports that
100% (11 patients) are still progressionfree.
Hodgkin’s lymphoma
Patients with HIV-associated Hodgkin’s
lymphoma have higher CD4 counts than
the average among the HIV-associated
lymphomas. The choice of anti-lymphoma treatment in HIV-associated lymphoma is almost always the same as for
the HIV-negative patient with ABVD as
the most common chemotherapy regimen, either alone or in combination with
radiotherapy. G-CSF, which as a rule is
recommended for HIV-associated lymphoma treatment, is not recommended
using the ABVD regimen. A serious problem with the addition of G-CSF to ABVD
is the higher incidence of bleomycine associated pneumonitis (Nqeow et al 2011).
G-CSF should therefore be avoided in the
ABVD combination. In the bleomycine
including regimen BEACOPP the lung
toxicity seems to be less common, probably due the high amount of corticosteroids included in this regimen and thus GCSF can be used.
The prognosis for patients with HIVassociated Hodgkin’s lymphomas have
been reported to approach that of HIVnegative patients (Hentrich et al 2012).
HIV & VIROLOGY NEWS 4 • 2013
Table 3: Common prophylactic treatments.
Prophylactic indication
DrugSchedule
Neutropenic sepsis G-CSF 300ug–480 ugx1 during 8-12 days
Pneumocystis jiroveci trim-sulfa pentamidine inhalations
1 every second day
300 mg/every month
Herpes zoster
aciklovir
400 mg x 2
Hepatitis B reactivation cART with effect on hepatits B
Candida albicans fluconazole
100 mg x 1
Tumour lysis syndrome allopurinol
rasburicase
300 mg x 1
0,20 mg/kg/day during 3–7 days
In HIV-infected Hodgkin’s patients with
primary refractory or relapsing disease
platinum based therapy with high dose
therapy with stem cell support (autologous bone marrow transplantation), has
successfully been performed in selected
patients.
cART
Historically it is obvious that cART has
improved the clinical outcome since the
introduction in the late 1990s both regarding less opportunistic infections
but also greater likelihood of achieving
complete remission. There are many potential drug interactions between cART
and chemotherapy or drugs used in supportive care and one problem observed
has been greater myelotoxicity (Mounier
et al 2009). Especially the problem with
interactions between vinblastine used in
the ABVD regimen and protease inhibitors giving myelosuppression, has been
reported (Cingolani et al 2010). There has
been a debate if cART could be postponed
until the end of lymphoma therapy. Dunley et al 2012 reported a series of patients
with DLBCL and Burkitt’s lymphoma
using 4 courses of R-EPOCH with cART
postponed until end of therapy, which is
a delay of cART treatment of roughly 10
weeks. The authors claim that the benefit
of avoiding drug interactions is more pronounced than the disadvantage of cART
therapy delay. It is important to emphasize that the experience comes from a
very short treatment period and can not
be translated to standard therapy such as
CHOP and ABVD. The large meta-analysis, earlier mentioned, recommends the
concomitant use of cART with anti- lymphoma treatment (Barta et al 2013). The
bad prognosis of a high HIV virus load
is shown in a study where exposure to
each additional 1-unit log 10 in HIV RNA
throughout the 6 months after lymphoma
diagnosis was associated with a 35% increase in subsequent mortality suggest-
19
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Clinical update on opportunistic complications in HIV
ing that early and effective cART during
chemotherapy is important (Gopak et al
2013). It should be emphasised that it often is possible to adjust a cART regimen
if interactions with chemotherapy is a
problem, for example to one that is integrase inhibitor based.
Prophylaxis
Infection prophylaxis is more important
in patients with HIV-associated lymphoma than in HIV-negative patients. Hepatitis infections in the history are more
common. Standard prophylaxis is shown
in Table 2 and consists of G-CSF to avoid
neutropenic sepsis, trim-sulfa to avoid
pneumocystis jiroveci, aciklovir to avoid
herpes zoster and cART with effect also
on hepatitis B in patients with risk of reactivation of hepatitis B.
The role of EBV
EBV is the most common etiological
agent for HIV-associated lymphomas.
EBV can usually be detected in the lymphoma cells by immunohistochemistry
for example staining LMP or EBNA. EBV
could often be detected in peripheral
blood and cerebrospinal fluid with PCR.
Although EBV is one of the main players
for initiate the lymphoma its role may be
lost and the question arise: Is EBV a hijacker in the malignant cell or just a passive passenger? The answer has implication for the use of rituximab in CD20
negative lymphomas. In these cases
rituximab can be used for reducing the
number of EBV copies. Today there are
no reports recommending rituximab in
CD20 negative patients.
Future
There are a lot of new targeted drugs
which probably will increase efficacy of
the anti-lymphoma treatment and maybe especially valuable in the frail patients
like those with low CD4 counts. Some
of them may also decrease toxicity if the
amount of chemotherapy used today can
be reduced. Brentuximab-vedotin, for
example, is a highly tumour cell selective
antibody-chemotherapy complex which
seems to be one of the most active drugs
for CD30+ lymphomas which includes
all Hodgkin’s lymphoma and 10–15% of
DLBCL. Brentuximab-vedotin has a tubulin inhibitor connected to the CD30
antibody and was approved 2012 by FDA.
20
Brentuximab-vedotin can maybe replace
vinblastine in the ABVD regimen and
hopefully this change will reduce the myelotoxicity and increase efficacy. Tyrosine
kinase inhibitors against the b-cell receptor signalling chain (ibrutinib and idelalisib) may increase the R-chemotherapy
efficacy in subgroups of DLBCL without
adding toxicity. New CD20 antibodies
for example obinutuzumab, seems to be
a stronger anti-lymphoma antibody compared to rituximab.
Conclusion
The majority of patients with HIV-associated lymphoma shall be treated with
anti-lymphoma therapy in the same manner as HIV-negatives, but with a higher
attention of prophylaxis against infections. An exception are patients with CD4
counts < 50 µ/l. The optimal therapy in
this group is not yet defined and hopefully the new promising more specific drugs,
now in clinical studies for HIV-negative
patients, can be used with less toxicity
and more efficacy.
References:
Barta Sk, Xue X, Wang D, Tamari R, Lee JY et al.
Treatment factors affecting outcomes in HIVassociated non-Hodgkin´s lymphoma: a pooled analysis of 1546 patients. Blood 2013; 122:
3251-62.
Cingolani A, Torti L, Pinneti C et al. Detrimental
clinical interaction ritonavir-boosted protease inhibitors and vinblastine in HIV-infected patients wit Hodgkin´s lymphoma. AIS
2010;24:2408-12.
Cunningham D, Hawkes EA, Jack A et al. Rituximab plus cyclophosphamide, doxorubicin,
vincristine, and prednisolone in patients with
newly diagnosed diffuse large B-cell lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet
2013;381:1817-26
Dunleavy K, Little RF, Pittaluga S et al. The role of
tumor histogenesis, FDG-PET, and short course EPOCH with dose-dense rituximab (SCEPOCH-RR) in HIV-associated diffuse large
B-cell lymphoma. Blood 2010;115:3017-24.
Dunleavy K, Pittaluga S, Shoulin M et al. Low intensity therapy in adults with Burkitt´s lymphoma.
New Engl J Med 2013;369:1915-25
Dunleavy K and Wilson WH. How I treat HIV-associated lymphoma. Blood. 2012;119 (14): 3245
-3255.
Gopak S, Patel MR, Yanik EL, Coke SR, Achenbach
CD et al. Association of early HIV viremia with
mortality after HIV associated lymphoma.
AIDS 2013; 27: 2365-73.
Hentrich M, Berger M, Wyen C, Siehl J, Rocksroh JK et al. Stage-adapted treatment of HIVassociated Hodgkin´s lymphoma : Results of a
prospective multicentre study. J Clin Oncol.
2012;30:4117-23
Kaplan LD. HIV-associated lymphoma. Best Practice & Research Clinical Haematology 25 (2012)
101-117
Kaplan LD, Lee JY, Ambinder RF et al. Rituximab
does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without
rituximab in patients with HIV-associated
non-Hodgkin´s lymphoma: AIDS-Malignancies
Consortium Trial 010. Blood. 2005;106:1538-43.
Mounier N, Spina M, Gabarre J et al. AIDS-related
non-Hodgkin´s lymphoma: final analysis of 485
patients treated with risk-adapted intensive
chemotherapy. Blood 2006;107:3832-40
Mounier N, Katlama C, Costagliola D, Chichmanian R, Spano J. Drug interactions between
antineoplastic and antiretroviral therapies:
Implications and management for clinical practice. Critical reviews in Oncology/Hematology
2009; 72:10-20.
Noy A. Controversies in the treatment of Burkitt´s
lymphoma in AIDS. Curr Opin Oncol 2010;22:
443-448.
Nqeow J, Tan IB, Kanesvaran R et al. Prognostic
impact of bleomycine-induced pneumonitis on
the outcome of Hodgkin´s lymphoma. Ann Hematol 2011; 90:67-72.
Ribera JM, Garcia O, Grande C et al. Dose-intensive
chemotherapy including rituximab in Burkitt´s
leukemia or lymphoma regardless of human immunodeficiency virus infection status. Cancer.
2013;119:1660-8.
Pettengell R, Coffier B Narayanan G et al. Pixantrone dimeleate versus other chemotherapeutic
agents as single-agent salvage treatment in patients with relapsed or refractory aggressive
non-Hodgkin´s lymphoma a phase 3, multicentre, open-label, randomised study. Lancet Oncol
2012; 13: 696-706.
Peyrade F, Jardin F, Thieblemont C et al. Attenuated immunochempotherapy regimen (R-miniCHOP) in elderly patients older than 80 years
with diffuse large B-cell lymphoma: a singlearm, phase II trial. Lancet Oncol 2011;12:460-8
Rubenstein JL, Gupta NK, Mannis GN, Lamarre AK
and Treseler P. How I treat CNS lymphomas.
Blood 2013; 122:2318-30.
Wilson WH, Dunleavy K, Pittaluga S et al. Phase
II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and postgerminal center biomarkers. J Clin Oncol.
2008;26:2717-24.
Wästerlid T, Brown PN, Hagberg O, Hagberg H et
al. Impact of chemotherapy regimen and rituximab in adult Burkitt lymphoma: A retrospective
population-based study in the Nordic Lymphoma Group. Ann Oncol 2013:24:1879-86.
Conflict of Interests
Dr Hagberg has received honoraria as
speaker and/or advisor from Mundi­
pharma, Roche and Takeda.
Hans Hagberg
Associate professor
Dpt Oncology Akademiska sjukhuset
Uppsala, Sweden
HIV & VIROLOGY NEWS 4 • 2013
AIDS Vaccine Congress in Barcelona
The Congress AIDS Vaccine 2013 was held in the second week of October.
More than 900 of the world’s leading vaccine researchers, funders
and policy makers gathered for four days in Barcelona, Spain.
It was the 13th Congress, and also the last in this format.
Next year it will be a part of a new Congress in Cape Town.
B
ehind the Congress stands Global HIV Vaccine Enterprise, an
alliance of organisations dedicated to accelerating the development of preventive HIV vaccines. It
is organised in co-operation with a local
conference host every year – in Barcelona this was HIVACAT, a Catalan program
for the development of an effective vaccine against the HIV virus.
The Congress is the only scientific
meeting in the world dedicated exclusively to HIV vaccine research. Normally
it attracts more than 1,000 delegates, but
due to the fiscal shutdown of the US government that coincided with the Barcelona Congress in 2013, several US delegates
could not come. This reduced the number
by approximately a hundred.
HIV & VIROLOGY NEWS 4 • 2013
Global HIV Vaccine Enterprise
Nevertheless, more than 450 research
studies outlining the latest advances and
obstacles for an AIDS vaccine were presented and debated at the Congress.
– Progress, partnerships and perseverance are the themes of this conference,
and all three will be on display at AIDS
Vaccine 2013, said Bill Snow, director of
the Global HIV Vaccine Enterprise.
He tells HIV & Virology News that the
organisation took over the Congress in
2007.
– Originally it was run by the Institute
of Health, but as it got bigger they passed
it on the Enterprise. It is a collaboration of
all organisations all around the world that
aim to develop an HIV vaccine – including
private giants like Sanofi, Novartis, Merck
and Johnson & Johnson. Our job is to coordinate that.
A vaccine the world has never seen before
Dir Snow underlines that the research
that will lead to a product always has
been a cooperative, private-public concern.
– We have been working to create an
industry “think-tank”, he says.
At the Opening Session, Dir Snow stated that the three P’s – progress, partnerships and perseverance – of the conference’s theme were adequate.
– The diversity of our research programme demonstrates progress: More
than 450 abstracts – selected from a record high score of submissions – and
many new breaking data will be heard on
21
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this stage. I have little doubt that important scientific advances at this moment
lies deep in an abstract session – or even
in a yet unnoticed poster.
He concluded that Barcelona was a
very suitable choice for the Congress.
– We are trying to make a vaccine of a
type the world has never seen before –
and like the work on Barcelona’s famous
church Sagrada Família, the construction
of which commenced in 1882, we have
not finished our work yet!
A decrease in new infections
The last speaker in the Opening Session
was Dr Anthony Fauci, who was not present in Barcelona. Instead he gave his lecture via video.
– I have to apologize for not being able
to be there with you personally, but the
extraordinary situation of closing of the
US government made it impossible for
me to travel to Barcelona, Dr Fauci said
on the screen.
The title of his talk was Toward ending
the HIV/AIDS pandemic, and he stated
that he was going to emphasize the issue
of the synergy between vaccine and nonvaccine related interventions.
– But before we get there, let’s take a
look at the landscape where we are right
now, taken from the UNAIDS Global Report.
There are in total more than 70 million HIV infections and a total of 36 million deaths in AIDS. 35.3 million people
are living with HIV. In 2012 there were
1.6 million deaths – which is a decline by
30% compared to 2005 – and 2.3 million
new HIV infections, Dr Fauci continued.
Anthony Fauci talked via videolink.
– 2.3 million new HIV infections is a
decrease with 33% if compared to 2001,
he underlined.
A very depressing number
Therefore one could ask the question if
an HIV vaccine is essential for ending the
HIV/AIDS pandemic.
In order to address that question, Dr
Fauci first talked about the “Care continuum” – i.e. access, retention and adherence to therapy.
– Take the US for example: In our
country we have 1.1 million people infected with HIV. Only about 80% of those
know they are infected. Of the total, 66%
are linked to care, 37% retained in care,
33% are receiving ART and in mere 25%
we see suppressed viral load, which is not
only life-saving to them – but would also
prevent them from transmitting their infection to a non-infected sexual partner.
25% is a very depressing number, and
these figures go for most of the countries
in the developed world, Dr Fauci continued.
– Looking to the future, we must consider human behaviour when we are implementing biomedical interventions!
An HIV vaccine is essential
There are also social and cultural barriers, such as lagging of scale-up of circumcision, stigma and legal impediments.
– Condoms meant for protection by
commercial sex-workers, are used as
evidence by the police. Even in my own
country – the US – we’ve seen this happening! Homosexuality is illegal in 76
countries – this must not stand!
Finally there is the issue of human nature. There are examples from other diseases that when you get to a point when
things are looking as if they are turning
around, what one does is recede in the effort that one puts into it – and there will
be a rebound.
– So I have come to the conclusion that
an HIV vaccine is essential to durably –
and I underscore durably – control and
to ultimately end the HIV/AIDS pandemic!
Two ways forward
Having said that, what is the pathway to
an HIV vaccine?
Dr Fauci took a look at this from three
standpoints. The first of these was the
years of disappointments.
22
HIV & VIROLOGY NEWS 4 • 2013
Bill Snow
Louis Picker
– Using predominantly envelope, we
were not able to induce a response that
would be protective.
But there has also been an unsuspected
success.
– We are all familiar with the RV144
trial that was conducted in Thailand, Dr
Fauci continued.
The way forward toward an HIV vaccine is twofold:
– One is the B-cell pathway, and the
other is the potentially important role of
T-cells – and, of course, the interdigitation and the complementing of these with
each other.
Dr Fauci also quoted a study published
in 2013 on T follicular helper cells (Tfh
cells). The frequency of Tfh cells actually correlated with the development of
broadly neutralizing antibodies against
HIV in a large group of HIV-infected individuals.
– The implications for the induction of
Tfh-cells by an HIV vaccine are very important, since these may play an enhancing role.
A clear scientific pathway
Another study from 2013 demonstrated
that live CMV vector vaccine induces
potent CD8+ T-cell response in monkeys
that results in profound early control and
progressive immune clearance of highly
pathogenic SIV (= simian immunodeficiency virus).
– The implications for preventive – and
therapeutic – HIV vaccines in this particular approach are obvious.
One might think that the potential role
of a therapeutic HIV vaccine might be
important in the achievement of a “functional cure” for HIV infection, in which
the reservoir has been attenuated greatly
by early and intensive treatment.
– If you have an effective vaccine you
may be able to control the rebound of this
virus upon discontinuation of therapy.
HIV & VIROLOGY NEWS 4 • 2013
Kelly MacDonald
There is a clear scientific pathway toward an HIV vaccine, Dr Fauci summarised at the end of his talk.
Three new studies that stem from RV144
In his talk, Dr Fauci mentioned the success of RV144.
In 2009, the RV144 Thai vaccine trial
provided the first evidence in humans
that a safe and effective preventive HIV
vaccine is possible. Although efficacy
was 31% at the end of the study, there
was a higher early effect – 60% – at 12
months.
The Pox-Protein Public-Private Partnership (P5) is a diverse group of organisations that has planned future efficacy
studies. Their members are working with
governments and communities within
potential host countries to develop collaborative clinical development plans, as
well as initiating regulatory planning and
access agreements.
– This has led to three new studies, said
Dr Merlin Robb.
These are called RV305, RV306 and
RV328.
– RV305 is taking 162 individuals who
were vaccine recipients in RV144. It started in May 2012, and all vaccinations are
complete.
RV306 is a large Phase II trial to evaluate late boosting strategies after the six
months of priming.
– RV328 is a smaller study, and will collect mucosal and cellular examples that
will allow us to better discriminate and
finally describe the responses in regimen
that failed, compared to the RV144 regimen that succeeded.
In August 2013, the Government of
Thailand announced commitment to
build on RV144 by supporting the future
HIV vaccine efficacy study – and a flexible biologics manufacturing capability
that could support the production of an
efficacious vaccine, Dr Robb said.
Merlin Robb
Glenda Grey
CMV as a vector
Dr Louis Picker talked about pre-clinical
development of Cytomegalovirus (CMV)
vectors. He initially named CMV as the
“Goldilocks” vector for a T-cell targeted
vaccine.
– These viruses are very old, they have
been around and involving with mammals since the dinosaurs. Therefore they
have essentially co-evolved with their
hosts, he stated.
CMV in particular, for biologic reasons of its own, has evolved to persist in
their host at just the right level to elicit
robust, life-long, effector memory T-cell
responses. It uses the immune response
to contain itself and to be non-pathogenic
to its host.
– It’s actually more of a parasite than a
pathogen. Most people in the developed
world are infected with this virus.
The T-cell responses are not too high
– which would result in T-cell “exhaustion”.
– And not too low, which like conventional vectors would result in T-cell response contraction and return to a resting
state. It’s just right – hence the “Goldilock” analogy.
Armed T-cells can interface
with the virus early
Dr Picker told the audience that when
Rhesus macaques CMV is engineered to
express SIV proteins, these RhCMV/SIV
vectors generate and indefinitely maintain high frequency, effector-differentiated, SIV specific CD4+ and CD8+ T-cells.
– Even in monkeys that are naturally
infected with CMV!
Phenotypically, these responses – and
the CD8 responses in particular – are
strikingly effective memory phenotype.
Four years after RhCMV vaccination one
can still see very high frequency responses that can respond to autologous SIV-infected CD4 and CD8 T-cells. �
23
– All you need is one shot, and you will
have immune responses like this for life!
The working hypothesis was that highfrequency, effector-differentiated, HIV/
SIV-specific T-cells would intercept a
nascent HIV/SIV infection immediately,
prior its irrevocable establishment – thus
providing for stringent control and possible clearance.
– It was based on the idea that if you
have “armed” T-cells that could interface
with the virus very early, prior to the amplification that lead to immune escape,
then you would have a better shot at efficacy.
Memory T-cells can control
and clear lentivirus
This turned out to be exactly what happened.
Dr Picker presented three groups of animals that had been challenged in studies
– intra-rectally, intra-vaginally and intravenously. In the first group, 24 were vaccinated and 13 were protected.
– By protected we mean that they
showed an initial viral burst that immediately was brought down under control
below the level of detection. One animal
had a relapse, but the other 12 were protected long-term.
24
16 vaccinated macaques were intra-vaginally challenged, and 9 of these were protected. Of 6 vaccinated and intravenously
challenged, 2 were long-term protected.
– To date, we have observed 48 protected Rhesus macaques, among a total of 96
RhCMV/SIV vector vaccinated.
His conclusion was that effector memory T-cells elicited by a persistent vector – that “knows what it is doing” – can
stringently control and clear a highly aggressive lentivirus.
VZV as a vector
Another virus is that has been used in animal models as a replicating viral vector is
Varicella zoster virus (VZV). It is a member of the alpha-herpesvirus family and
infects epithelial cells and T-cells.
– It is the only virus from this family for
which we have a vaccine. It’s been used
around the world for almost 25 years as a
successful vaccine to prevent chickenpox
and shingles, said Dr Kelly MacDonald.
VZV is safe – non-integrating and nononcogenic.
She presented the VZV-SIV study in
which 8 macaques were vaccinated with
VZV and SIV antigen, and a control group
of 9 with VZV only. The macaques were
challenged with multi low-dose SIV-
mac239 challenge in an escalating dose
protocol over a long time – 52 weeks.
Vaccination resulted in a subset of
animals demonstrating durable and sustained control of SIV viral load. The difference for the benefit of the vaccinated
group was significant for one year. Vaccinated non-controllers demonstrated
degree of viral control not previously realised with RhCMV-based approaches.
– I think this virus is particularly interesting since it is an already licensed human vaccine, which has the potential to
move into trials in the human setting, Dr
McDonald summarised.
Negative results for Ad5 vector
Adenoviral (Ad) vaccine vectors represent both a vehicle to present a novel
antigen to the immune system as well
as re-stimulation of immune responses
against the Ad vector itself. Ad5 vectors
transduce a wide range of cell types and
utilize the Coxsackie-Adenovirus Receptor (CAR) to enter cells.
At the AIDS Vaccine Congress in Barcelona a meta-analysis of Ad5 vector HIV
vaccine trials and the results caused a lot
of attention.
In total there were three studies included in the meta-analysis: Step, Pham-
HIV & VIROLOGY NEWS 4 • 2013
bili and 505. The object of the metaanalysis was to evaluate the effect of Ad5
vector vaccines on the rate of HIV infection pooled over the three trials. It was
presented by Dr Peter Gilbert.
– Overall, there were 200 vaccinated
individuals infected and 147 placebo recipients infected (!). That represents a
33% elevation in risk – for the vaccinated
group, Dr Gilbert said.
This effect was constant over time.
There was no dose response – instead it
was similar among those who received 1,
2 or all 3 Ad5/placebo vaccinations.
– Pooling data from Step, Phambili and
505 gives evidence for a greater infection
rate for vaccine compared to placebo, Dr
Gilbert clarified.
He ended his talk by pointing out that
as long as vaccine trials present data on
efficacy, both negative and positive efficacy trial results provide progress toward
an efficacious vaccine.
– Negative results inform about the
vaccine constructs and immune responses to down-prioritize for future vaccine
development. Positive results give us answers on what to prioritize for vaccine development in the future!
Brings participants back
– There is no such thing as a failed trial
– we learn from them too. A major scientific breakthrough is that we now know
that we should not use the platform Ad5
for an HIV vaccine, said Dr Glenda Grey.
She presented a background to the
Phambili study that took place in South
Africa. The enrolment and the vaccinations there ceased when the Step study in
America was found to be non-efficacious
at its first DSMB (Data and Safety Monitoring Board). Participants were then unblinded and follow-up was extended.
– We finished the study more than 2
years ago, and in our long-term followup on data we found that in the Phambili
participants there were more infections
in the vaccine arm as compared to placebo, Dr Gray continued.
Therefore they rapidly designed a follow-up study and re-opened sites to bring
participants back. This study is a substudy called HVTN 503-S – for iv testing
and behavioural risk assessment for former Phambili (HVTN 503) participants.
She presented an example of an advertisement that they had put in newspapers
in order to locate these participants.
– We have been open for 18 weeks, and
during this time we’ve been able to enrol
HIV & VIROLOGY NEWS 4 • 2013
369 individuals, and we have 331 to go. I
think this is quite good for 18 weeks, Dr
Grey stated.
Reasons to be optimistic
At the Closing Session, Nina Russell who is
President of the Board of Global HIV Vaccine Enterprise said that she was going to
leave Barcelona feeling quite optimistic.
– I say this because at this meeting I did
not see us doing the same thing over and
over again. I saw the field moving forward
with promise on many different fronts at
the same time. We’ve heard perplexing
results from the Step and Phambili trials, but we’ve also heard other emerging
clinical trial data – and new analysis on
existing trial data – that continue to help
us refine our knowledge on vaccine immune responses.
We know more today than ever before
about the structure of the virus envelope,
the pathways for the formation of broadly
neutralising antibodies against the envelope, she underlined.
– And we heard this week about a number of creative approaches that are moving forward to test different hypothesis
for how to induce these neutralising antibodies.
A novel T-cell immunologic paradigm
is surfacing, through studies with the
CMV vector, presented at the Meeting.
– An exciting approach that is working
its way toward evaluation in human clinical studies. And other viral and non-viral
vector vaccines based on herpes virus,
VZV – and a very interesting approach
that uses self-amplifying RNA – all of this
are reasons to be optimistic, Dr Russell
summarised.
A new Congress is born
As already mentioned, this 13th Congress
was the last that was solely dedicated for
research for a vaccine.
– But this is not the end. Actually, it is a
beginning, said Dr Robin Shattock, who
is one of the Co-chairs for the new conference HIV Research for Prevention
(HIVR4P) 2014 Meeting in Cape Town,
South Africa, next October.
The AIDS Vaccine Congress will be a
part of that.
– We will need you and your research
there, Director Bill Snow stated.
Afterwards, HIV & Virology News asked
Director Snow on his feelings about this.
– I feel fine about it. What has happened in the field now is that treatment
for prevention, pre-exposure prophylaxis
and other interventions have proved their
value. It is logical to assemble all research
for prevention in one Congress.
Each risk person in each country has a
unique profile that suits him or her to use
these interventions.
– Obviously there are universal items
on the agenda: Treating everyone that is
infected – the sooner the better, testing
– this is crucial, prevention of mother-tochild transmission and circumcision for
men where this is practiced.
– But apart from all this, it is really a
vaccine that will determine what will
happen in the future, says Director Bill
Snow at the end of the Congress 2013 in
Barcelona.
Per Lundblad
25
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The price of antiretroviral therapy
Health economists’ work involves
placing a price on the benefits of an intervention, typically in terms of Quality adjusted life years saved (QALYS).
It is then up to the payers of healthcare, in Europe, Canada and Australia
mainly government health systems,
in the US both government and insurance companies, to decide whether
that cost per QALY is worth paying or
if the insurance policy funds will cover
the costs.
C
ost-effectiveness is often judged
against the countries’ gross domestic product (GDP) per capita. The so called ‘rationing’ of
health care is becoming a widespread
phenomenon in the EU, most typically
with regards to highly expensive anticancer drugs that lead to very modest
(weeks-months) extensions in life. Analysis of the early years of combination ART
suggested antiretroviral therapy was
more cost effective than common medical interventions such as coronary artery
bypass grafting (CABG) or cervical smear
programs.
There is clearly no agenda for developed
world governments to stop paying for
antiretroviral therapy regardless of price,
but there is a clear interest in gaining the
best value for money from antiretroviral
therapy. This may be done through restricted prescribing of more expensive
agents or ‘pre-approval’ of certain drug
choices, generic substitution including
the breaking of single tablet and fixed
26
dose formulations, narrow guidelines on
who should receive therapy (ignoring the
treatment-as-prevention public health
imperative) and aggressive negotiations
around discounts. Medical systems can
have seemingly unlimited expenditure.
In the EU national health systems typically consume 7% more of GDP. As medication makes up a significant proportion
of care costs, limiting prescription costs
and prescribing in the most cost effective
way is key not bankrupting our health
systems and may enable diverting of resources into other services that support
better treatment outcomes.
Antiretroviral medication normalises
life expectancy in (often) young individuals, preventing the premature loss, or
returning to society, of potentially highly
productive individuals for many years.
Estimates of years of life lost for a 25 year
old acquiring HIV pre-1996 were around
40 years, i.e. individuals died in their 30s
not 70s. In the current treatment era this
number of years of life lost to disease is
less than 10 and may be 0. These factors
are key drivers in making therapy cost
effective but also mean lifetime costs of
therapy are rising substantially.
More recently, the cost effectiveness of
treatment as prevention has been demonstrated in models based on costs and GDP
in South Africa and India. In the South
African model, early ART prevented opportunistic diseases (notably TB) and was
cost-saving over a 5-year period. Over a
lifetime, it was very cost-effective ($590
per life-year saved). In India, early ART
was cost-effective ($1,800 per life-year
saved) over a 5-year period and very costeffective ($530 per life-year saved) over
a lifetime. In both countries, early ART
prevented HIV transmission over short
periods, but the main driver of life-years
saved was the clinical benefit for treated
patients [1]. These costs are of course
based on generic drug prices in these
countries and so are a far cry from the
costs in the developed world were most
treatment is with high priced on-patent
medications.
Current HIV therapies provide a model of chronic care (unlike a say a CABG,
which tends to be a one off ) and thus
lifetime therapy costs mount with each
passing year. With earlier treatment, at
CD4 >500, the cost effectiveness of intervention relative to treating at <500 (the
updated WHO and EU guideline recommendations) or even <350 (the current
UK guidelines) is difficult to assess. Most
costs are driven by drug cost, not laboratory testing or inpatient expenses related
to treating opportunistic diseases.
In 2004, when treatment standards in the
US were to begin at CD4<350, the lifetime
cost was estimated to be US$618,900 for
adults based on a per person projected
life expectancy of 24.2 years. Seventythree percent of the cost was antiretroviral medications, 13% inpatient care,
9% outpatient care, and 5% other HIVrelated medications (e.g. cotrimoxazole)
and laboratory costs. The authors noted
that the results were sensitive to drug
costs (discounts) and ART efficacy [2].
HIV & VIROLOGY NEWS 4 • 2013
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In inflation adjusted terms, these lifetime cost would now be >$1 million and
with further extension of life expectancy
>$1.5million/person.
Costs of antiretrovirals have risen
faster than inflation. When Abbott (now
Abbvie) arbitrarily quadrupled the price
of their pharmacoenhancer ritonavir in
December 2003, managed care organisations in the US did not blink at the new
price for a product that had an established market monopoly. Abbott charged
what the market could bear. Patients and
payers were given the choice of pay up or
use lopinavir/r, its formerly high priced
co-formulated PI that was suddenly the
cheapest boosted PI on the market. In
some other countries ritonavir was never
made commercially available, thus facilitating an lpv/r monopoly of the PI/r
market. The attitude of Abbott executives to patients and payers, as revealed
in a 2007 Wall Street Journal expose
(http://online.wsj.com/news/articles/
SB116778411362865429) was staggering and a low point in the perception of
the pharmaceutical industry. This price
change remains the subject of on-going
law suits in the US. The near monopolistic or hegemonic positions of some therapies in the HIV (and Hepatitis C) market
has been associated with annual price rises in the US of the most widely prescribed
antiretrovirals that vastly outstrip inflation. Price restriction as part of regulatory arrangements in the EU has limited
this ‘price gouging’ in these markets. New
product launches, even in products that
don’t clearly add value, are being priced
exceptionally. For examples, rilpivirine,
a product with poorer viral efficacy than
efavirenz, was launched at a higher price
in the US. Paying more for lower efficacy
HIV & VIROLOGY NEWS 4 • 2013
makes no sense in pharmacoeconomics
as demonstrated in a recent analysis [3],
let alone having no place in good clinical
care.
Inventing and developing new drugs is ex-
pensive. Many therapeutic areas still rely
on clinical endpoint studies for approval,
hence require large and long studies. In
HIV, the use of viral load as a surrogate
marker enables ‘accelerated’ approval
of antiretrovirals with filing typically
based on 48 week phase 3 data plus post
approval commitments. This means the
costs of bringing an HIV drug to market
is a relatively low (by industry standards)
$1 billion. The HIV/AIDS therapeutics
market is estimated to have reached $13.5
billion in 2011 in the seven top markets
(the United States, the United Kingdom,
Germany, France, Italy, Spain and Japan)
and is predicted to continue to growth at
7 percent to reach $21.8 billion by 2018.
Given many HIV drugs sell more than
>$1 Billion per annum in the US alone
and have relatively long product life cycles (Efavirenz sales for example have
been growing year on year even as it approaches patent expiry, this is uncommon in other disease areas) and the cost
of goods, based on ‘at cost’ sales prices in
developing countries is <10% and often
<7% of US list price, meaning the products have an excellent margin, so all in all
the return on investment is evident.
So why are new therapies for HIV being
launched at such unrealistically high
prices?
The US list price for Atripla is approximately $20,000 (its ‘at cost’ sales price is
$600, so it’s a high margin product in the
US), a little lower across the EU market.
However, Stribild was launched in the US
at a list price of $28,000. Stribild has been
compared directly to Atripla in a placebo
controlled phase 3 randomised controlled
trial, and the outcome was ‘non-inferiority’, or similar, efficacy. The products have
different safety and drug interaction profiles, similar rates of ‘3rd agent’ resistance
emergence (slightly more NRTI resistance with Stribild) but no difference in
overall rates of failure. Stribild has not
been recommended by the influential US
DHHS guidelines committee (nor indeed
by any other national guidelines). Yet, it
comes with a 40% price premium to Atripla. It appears another example of paying
more without getting extra advantage.
Given that drug costs are the main driver
of annualised and lifetime management
costs for HIV infected individuals, what
does this mean to cost-effectiveness and
lifetime costs? A recent analysis (done
by Bristol-Myers Squibb, who make Efavirenz and Atazanavir) indicated that
when compared with patients initiating
Atripla, patients initiating Stribild were
estimated to have higher lifetime costs.
Stribild added 0.041 QALYs over a lifetime at an additional cost of $6,886, producing an incremental cost-effectiveness
ratio of $166,287/QALY gained. Results
in the model were most sensitive to firstline response rates, product costs, and
likelihood of renal adverse events. When
equivalent efficacy was assumed, Atripla was preferred to Stribild with lower
costs and greater QALYs. The authors
noted that in US healthcare system that
has shown a willingness to pay $100,000/
QALY, Stribild was not cost-effective
compared with Atripla for first-line HIV
treatment [4]. Of course just in terms
27
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of drug prices, 5 people can be treated
with Atripla for a year for $100,000 but
you couldn’t treat 4 people with Stribild.
With a limited funding pool for therapy
this cost-inefficient use of resources potentially means the unnecessary denial of
therapy for individuals.
Dolutegravir (Tivicay) from ViiV is the lat-
est example of high pricing of new therapies. The US wholesale price of Tivicay,
which is independently set by the manufacturer with no input from the FDA,
was announced at $1, 175 for 30 pills, or
$14,105 per year. That’s more-or-less in
line with Merck’s Isentress (raltegravir),
the first FDA-approved integrase inhibitor, whose wholesale price is $12,976 per
annum. (Note, however, that this class
was invented by Merck after a long and
complex development program that
included a number of initial lead compounds that were discontinued, so their
initial development was more expensive
than usual. The subsequent integrase
inhibitor programs have merely built
on Merck’s achievements.) Add in the
costs of Truvada, approximately another
$14000 and we have a price remarkably
similar to Stribild. Of course, for patients
with resistance to integrase inhibitors,
who require twice the daily 50mg dose
of dolutegravir, will have to pay twice the
amount, or over $28,000 per year plus
the cost of additional therapies. While
dolutegravir has shown advantage over
raltegravir and Atripla in clinical studies, the differences were largely driven
by tolerability and the studies included
few women, older patients or persons
with high viral load/low CD4 count. Of
note, the study against Atripla included
multiple questionnaires about sleep quality and dreams, the typical side effects of
efavirenz, which resulted in Atripla dis-
28
continuation rates higher than in other
recent studies of Atripla, which employed
fewer questionnaires. So again, a high
price for a product with modest differences to established therapies.
The availability of generic efavirenz will
further shift the pharmacoeconomic arguments towards this drug with more
expensive therapies either restricted
or forced to discount to make clinical
formularies. Manufacturers of alternative agents are already doing their best
to besmirch the potential advantages of
efavirenz via questionnaires embedded
in studies and switch studies targeting
the subset of individuals with on-going
CNS symptoms potentially related to efavirenz. US analyses of the potential savings from generic-based ART compared
with branded ART suggest branded therapy increases lifetime costs by a surprisingly low $42,500 and per-person survival gains of an unaffordable $114,800/
QALY based on the rather uncertain assumption that generic therapy is slightly
less effective. The cost per QALY would
be even higher if efficacy was similar. Estimated first-year savings, if all eligible
U.S. patients started or switched to generic-based ART, are $920 million. This
generic-based ART in the United States
could yield substantial budgetary savings
to HIV programs [5].
In summary, pharmacoeconomics will
play an increasing role in HIV drug
choice as annual and lifetime costs rise,
survival normalises and treatment becomes universal. The arrival of generic
drugs from preferred regimens will potentially pressure Pharma companies to
manage down prices albeit potentially
reducing the incentives for new drug development.
Conflict of Interests
Dr Moyle has received research grants
from Abbott, Ardea Biosciences, Bionor,
Bristol-Myers Squibb, Gilead Sciences,
GlaxoSmithKline, Merck, Pfizer, Thera­
technologies and Tibotec.
He has received honoraria as speaker
and/or advisor from Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer,
Theratechnologies, Tibotec and ViiV
Healthcare.
Dr Graeme Moyle
Chelsea and Westminster Hospital,
London, UK
[email protected]
References:
1. Walensky RP, Ross EL, Kumarasamy N, et al.
Cost-effectiveness of HIV treatment as prevention in serodiscordant couples. N Engl J
Med. 2013 Oct 31;369(18):1715-25.
2. Schackman BR, Gebo KA, Walensky RP, et al.
The lifetime cost of current human immunodeficiency virus care in the United States.
Med Care. 2006 Nov;44(11):990-7.
3. Bonafede M, Juday T, Lenhart G, et al. Costeffectiveness of efavirenz vs rilpivirine in
HIV patients initiating first-line combination antiretroviral therapy. J Med Econ.
2013;16(4):552-9.
4. Juday T, Correll T, Anene A, et al. Cost-effectiveness of the once-daily efavirenz/emtricitabine/tenofovir tablet compared with the
once-daily elvitegravir/cobicistat/emtricitabine/tenofovir tablet as first-line antiretroviral
therapy in HIV-infected adults in the US. Clinicoecon Outcomes Res. 2013 Sep 2;5:437-45.
5. Walensky RP, Sax PE, Nakamura YM et al.
Economic savings versus health losses: the
cost-effectiveness of generic antiretroviral
therapy in the United States. Ann Intern Med.
2013 Jan 15;158(2):84-92.
HIV & VIROLOGY NEWS 4 • 2013
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Go to www.hivvirology.com in order to find out more.
HIV & HEPATITIS NEWS HIV & HEPATITIS NEWS HIV & HEPATITIS NEWS
HCV reinfection in HIV positive gay men
Data presented by the European AIDS treatment network
(NEAT) at EACS showed that many HIV-infected patients who
cleared HCV were reinfected. In some patients even a third and
fourth reinfection occurred. The study included 646 HIV positive patients who had acute hepatitis C of whom 12% cleared
the virus spontaneously while 88% cleared the virus after treatment. 113 men with a second episode of HCV infection were
identified. CD4 count and the use of ART did not predict spontaneous clearance. The median time from first to second HCV
infection was 162 weeks. Patients with IL28B had a higher rate
of spontaneous clearance but the numbers were too small to
reach statistical significance. Patients who cleared the virus the
first time were more likely to clear the virus after reinfection
compared to those who cleared HCV after treatment.
Ingiliz et al PS9/1 EACS 2013
Comment: HIV positive patients who have been successfully treated for hepatitis C should be monitored and informed
about the risk of reinfection.
Avoid diclofenac in combination with tenofovir
In a retrospective analysis of the HIV-cohort in Frankfurt
all patients who had received diclofenac from 2008–2012, it
was shown that 14.6% of 69 patients on tenofovir developed
acute kidney injury. Normoglycemic glucosuria and hypophosphatemia were the most common manifestations of kidney injury. In four patients the diagnosis was confirmed by biopsy.
Bicke et al PS1/1 EACS 2013
Comment: It is probably quite common that patients on tenofovir are taking diclofenac. Patients should be made aware of
the potential renal toxicity and advised to avoid the combination of diclofenac and tenofovir.
Turmeric for hepatitis C?
Turmeric curcumin was shown to inhibit entry and thus the
infectivity of all hepatitis C viruses in human liver cells. In an
experiment with HCV pseudo-particles in hepatoma cell lines
the effect of turmeric curcunim was evaluated. The experiment
showed that the fluidity of the HCV envelop was affected leading to impaired viral binding and fusion. However, it had no effect on virus replication, assembly and replication. It was also
tried in combination with antiviral drugs and it was shown to
increase the effectiveness of available antivirals.
Anggakusuma et al, Gut. 2013 Jul 31
Comment: Turmeric definitely sounds cheaper than the new
directly acting antivirals!
Incidence Rate (SIR) for cancer was 1.82 (1.67-1.97). Not unexpectedly the SIR for hepatic carcinoma was high with a value of
40.6. However, the incidence was also increased for cancer of
the upper aerodigestive tract, lung, kidney, thyroid, lymphoma
and acute myeloid leukemia.
Sundquist et al, J Med Virol. 2013 Sep 13
Comment: Patients with hepatitis B need surveillance not only
for hepatocellular carcinoma but also for other malignancies.
Repeated lumbar punctures in Cryptococcal meningitis
In a study from Buenos Aires 80 HIV positive patients with
cryptococcal meningitis were studied with lumbar punctures
on day 0, 3 and 5. High intracranial pressure (HICP) was defined as a pressure above 250 mm H2O. Repeated lumbar percutaneous drainage of CSF was performed in patients with HICP.
Therapy was given with amphotericin B plus fluconazole for
14 days followed by fluconazole only. Overall mortality was
33.75%. There was a weak correlation between HICP on day 0
and mortality. The correlation was stronger on day 3 and even
more so on day 5. HICP on day 3 and 5 was not restricted to
patients who had HICP on day 0 but also developed in patients
with initial normal pressure. Almost 40% of patients with baseline normal intracranial pressure had HCIP at subsequent
measurements. The authors conclude that in contrast to the
present recommendations that patients with baseline normal
intracranial pressure should have a repeat lumbar puncture
only after 2 weeks, all patients should also have new measurements performed during the initial phase of therapy.
De Vedia et al Infection. 2013 Oct 14
Comment: The mortality in cryptococcal meningitis is still
high and perhaps repeated lumbar punctures with measurement of intracranial pressure in all patients may improve outcome.
Is it necessary to use 3 drugs in HIV therapy?
The GARDEL study
Treatment naïve patients without baseline resistance mutations were randomized to treatment with either a traditional combination of lopinavir/r together with 2 NRTI or to
lopinavir/r together with lamuvidine. The study was designed
as a non-inferiority study. After 48 weeks 88.3 in the lamuvidine arm versus 83.7% in the triple arm had viral load below 50.
In the strata with baseline viral load above 100,000 the corresponding figures were 85.8 vs 84.8%. Side effects and treatment
interruptions were somewhat more common in the triple arm.
The criteria for non-inferiority were met.
Cahn et al, LBPS7/6 EACS 2013
Increased risk of non-hepatic cancers in HBV-infection
The cancer incidence in 10,197 Swedish patients with hepatitis
B infection was compared to the population without hepatitis
B. Besides hepatocellular carcinoma seven other cancers were
increased in the HBV-infected patients. The overall Standard
30
Comment: A number of studies with PI monotherapy have
been performed. As far as I know this is the first study with a
PI in combination with only one NRTI. The results so far are
promising. By using only two active drugs cost and long term
adverse effects may be reduced.
HIV & VIROLOGY NEWS 4 • 2013
HIV & HEPATITIS NEWS HIV & HEPATITIS NEWS
The MODAT study
In an “NRTI sparing” study patients on stable therapy with
atazanavir/r with 2 NRTI and viral load below 50 copies/ml
for at least 24 weeks were randomized to continued unchanged
therapy or monotherapy with atazanavir/r. Viral failure was
defined as two consecutive measurements with viral load
>50 copies/ml. In the 48 weeks interim analysis 37/51 (73%)
in the monotherapy arm and 44/52 (85%) in the control arm
remained virologically suppressed. Further recruitment was
stopped by DSMB. 11 patients in the monotherapy arm and 2
in the control arm had viral failure. No resistance mutations
against PI or NRTI were found and all virologically failing patients were successfully suppressed to viral load < 50 copies/
ml by “re-intensification”. Grade 3–4 adverse event were more
common in triple therapy.
Castagna et al PS4/2 EACS 2013
Comment: Monotherapy with a boosted PI may still be an option in selected patients. Failure did not lead to any detectable
resistance development and all failing patients were successfully re-suppressed on treatment intensification with triple
therapy.
Tb-associated Immune Reconstitution Inflammatory
Syndrome (IRIS). The CAMELIA study.
Treatment naïve HIV positive Cambodian patients with tuberculosis and CD4 count below 200 were randomized to early
initiation of ART after start of tb-therapy (within 2 weeks) or
late initiation (8 weeks). All patients were evaluated for the occurrence of IRIS. Of 597 patients 308 were given early ART
and 289 were randomized to late initiation. The two groups
were comparable with very low median CD4 count of 27 and
viral load 5.6 log. About 70% in both groups had pulmonary
tb and 90% had culture proven tb. Median follow up time was
26 months. Overall mortality was 15.9%. There was a statistically significant increase in IRIS in the patients who initiated
early ART with 36% developing IRIS compared to 16% in the
arm with deferred therapy. Low CD4 count and high viral load
were associated with increased risk. The most common manifestations of IRIS were emergence or worsening of lymphadenopathy and fever. In most cases IRIS was easily managed and
the conclusion of the authors was that early ART should be
initiated in HIV positive patients with tb and low CD4 count
despite the increased risk of IRIS.
Laureillard et al, AIDS 2013, 27:2577-2586
Comment: Several studies have shown a survival benefit for
early vs. deferred ART initiation in HIV infected patients with
tb. The benefits of early initiation outweigh the increased IRIS
risk in patients with low CD4 count.
Coffee protects against hepatocellullar cancer (HCC)!
In a meta analysis of the protective effect of coffee on HCC development it was concluded that coffee does protect. The studies were either case control or cohort studies. Original English
HIV & VIROLOGY NEWS 4 • 2013
DR. Leo Flamholc
Skåne University Hospital
Malmö, Sweden
language articles from 1966 to September 2012 were included in the analysis. The risk ratio (RR) for any consumption of
coffee versus no consumption was calculated to be 0.6. There
was also a “dose response” effect with an RR of 0.7 for low consumption and 0.44 for high consumption. The cut off value for
low versus high consumption varied from 1 to 3 cups per day.
Bravi et al Clinical Gastroenterology and Hepatology Volume 11,
Issue 11 , Pages 1413-1421.e1, November 2013
Comment: Another potential money saver in the era of expensive directly acting antivirals! One may wonder if strong coffee
is more effective than weak coffee. Maybe we should urge our
North American friends to make stronger and tastier coffee?
Hepatitis B reactivation
An FDA alert about the risk of Hepatitis B reactivation with
the use of rixumitab and ofatumumab was recently issued. In
patients with prior Hepatitis B reactivation may occur causing fulminant hepatitis, hepatic failure and death. It is recommended that all patients should be screened for hepatitis B surface antigen and hepatitis B core antibodies before initiating
therapy with rituximab or ofatumumab. Patients with signs of
hepatitis B should be closely monitored and antiviral therapy
should be considered. Reactivation may occur several months
after rituximab or ofatumumab are discontinued.
Mitka JAMA October 23/30, 2013 Volume 310, Number 16
Comment: What are the risks of hepatitis B reactivation with
other immunosuppressive and biological response modifying
agents? Should screening be widely applied?
PREP in injecting drug users
2,413 intravenous drug users in Bangkok Thailand were included in a randomized placebo controlled trial of tenofovir to
prevent HIV infection. All participants received risk reduction
and adherence counseling. HIV-testing was performed once a
month. 50 participants became HIV-positive during the study.
17 in the tenofovir group (0.35 per 100 person years) and 33 in
the placebo group (0.68 per 100 person years). The risk reduction was 48.9% and the difference between the groups was statistically significant (p=0.01). Overall side effects were similar
but nausea was more common in the tenofovir arm.
Choopanya et al, Lancet:381: June 15 2013: 2083-2090
Comment: PREP is a hot topic. IVDU may be a difficult to
reach group but nevertheless the incidence of HIV-infection
declined significantly with tenofovir for PREP.
Conflict of Interests
Dr Flamholc has received honoraria as speaker and/or advisor from Abbott, Bioinvent, Boehringer-Ingelheim, BristolMyers Squibb, Gilead Sciences, GlaxoSmithKline, JanssenCilag, Merck, Pfizer, Roche and Janssen.
31
SAVE THE DATE!
Chairman
Président
Alain LAFEUILLADE, France
Steering Committee
Comité de Pilotage
Jean-François DELFRAISSY, France
Jose GATELL, Spain
Guido POLI, Italy
Jean-Pierre ROUTY, Canada
Christine ROUZIOUX, France
Vicente SORIANO, Spain
Hans-J. STELLBRINK, Germany
Stefano VELLA, Italy
iStockphoto.com
New ARV Drugs
What’s in the Pipeline?
HIV is now considered a chronic infection. The vast majority of treated patients are
fully suppressed, half of them having a CD4 count above 500 cells/µL. All the current
drugs provide efficacy and satisfactory tolerability, according to the longest followup provided by clinical trials.
M
ost researchers are now convinced that virological suppression can be maintained
life-long. The next wave of
clinical research in the management of
antiretroviral therapy needs to address
the following challenges:
• Optimal treatment initiation in early
naïve patients with low viral loads and
high CD4 cell counts
• Long-term ART success in the large
population of patients who are virologically suppressed on conventional
three-drug ART
• Management of patients with longterm drug toxicities that overlap agerelated co-morbidities
HIV & VIROLOGY NEWS 4 • 2013
It remains to be seen whether the treatment of HIV and host-related parameters can be individualized beyond CD4
and HIV RNA, such as on cell HIV DNA
blood reservoirs, HIV profile, or specific
pharmacologic parameters to better predict the right dose of an antiretroviral
drug needed for each immune virological
situation. Treatment individualization
should be able to deliver the best and the
most appropriate therapy for each individual.
To ensure life-long treatment we need
new drugs with different tolerability and
toxicity profiles, mechanisms of action,
and schedules of administrations in order to better prevent or treat illness in
millions of patients over decades at the
lowest cost.
Reverse transcriptase inhibitors
BMS-986001, formerly known as festinavir, is a thymidine analogue similar
to stavudine that has been developed to
maintain the in vitro antiviral activity
demonstrated by other NRTIs without
the associated toxicity concerns. Recent
data have shown that BMS-986001 does
not degrade mitochondrial DNA in longterm primary cultures of cells isolated
from human kidney, muscle, and adipose
tissue [1].
A randomized, double blind, placebocontrolled, dose-escalating, monothera-
33
�
py-controlled phase IIA study enrolled
32 treatment-experienced HIV-1-infected subjects, who had been off ART for
the last 3 months (3:1), to receive BMS986001 (100, 200, 300, and 600 mg, all
once daily) or placebo for 10 days. Overall, the short-term safety was good. The
pharmacokinetics of BMS-986001 was
dose proportional. The median decrease
in plasma HIV-1 RNA from baseline to
day 11 was 0.97,1.15, 1.28, and 1.15 log10
copies/mL for BMS-986001 at 100, 200,
300, and 600 mg, respectively [2]. A phase
2b study in combination with 3TC and
efavirenz in antiretroviral naïve patients
is ongoing (ClinicalTrials.gov Identifier:
NCT01489046).
Tenofovir alafenamide (TAF) is a prodrug of tenofovir that produces higher
intracellular concentrations of tenofovir-diphosphate (TFV-DP), with plasma
concentrations of the parent drug lower
than seen with tenofovir disoproxil fumarate (TDF). The potential benefit is
a reduction of the renal or bone toxicity
induced by tenofovir. In a 10-day monotherapy study of TAF versus TDF, the
median reduction in viral load ranged
from –0.76 to 1.08 log10 copies/mL with
TAF from 8 mg to 40 mg/day as compared with –0.48 log10 copies/mL with
TDF. In parallel, the plasma TDF AUC
was reduced by 80% with TFV-DP intracellular concentrations increased from 7
to 20-fold higher, depending on the TAF
dose [3].
A phase 2 randomized (2:1) study of 150
ART naïve patients has compared TDF to
TAF in combination with FTC,cobicistat,
and elvitegravir. The rate of virological
success with HIV RNA < 50 copies/mL
was 86.6% and 89.7 % at W24, and 90.2%
vs. 89.7% at W48, in the TAF and TDF
arms, respectively [4-5].
Entry inhibitors
BMS-663068 is an investigational oral
HIV attachment/entry inhibitor. HIV-1
attachment inhibitors represent a new
class of entry inhibitors that prevent the
initial interaction between virus and host
cell by binding to the viral envelope protein gp120 and blocking the attachment
of the virus to the CD4 receptor on CD4+
T-cells. In a proof of concept 8-day monotherapy study [7], BMS-663068 has been
shown to decrease HIV-1 plasma RNA by
1–2 log10 copies/ml. However, a minority
of HIV strains appears to exhibit primary
resistance to the drug due to a polymor-
34
TDF versus TAF with FTC/cobicistat /elvitegravir in ART naïve patients
From Sax P et al. ICAAC 2013. Denver. Abstract H-1464d.
phism in the HIV-1 env gene. In patients
harboring susceptible virus strains, the
antiviral activity was greater, averaging
2–3 log10 copies/ml in monotherapy studies [8]. A phase 2b study in antiretroviralexperienced patients is ongoing (ClinicalTrials.gov Identifier: NCT01384734).
Without underestimating the fact that
BMS-663068 will require pretreatment
resistance screening, there is a need for
new classes of drugs in our armamentarium for long-term HIV therapy management.
CCR5 antagonists
Cenicriviroc (CVC) is an investigational oral antagonist of CCR5 that prevents
virus entry into host cells by blocking
the CCR5 chemokine coreceptor. In addition, CVC also blocks the binding of
CCR5 ligands RANTES and macrophage
inflammatory protein (MIP-1) to CCR5,
and monocyte chemotactic protein-1
(MCP-1) to CCR2 [6]. This is potentially
of considerable interest in clinical practice and suggests that CVC could have anti-inflammatory effects. The CVC plasma
half-life is long (30–40 hours), allowing
once daily dosing.
In a randomized, double-blind phase
2b trial in treatment-naïve patients, 24
weeks of CVC 100 mg or 200 mg in combination with emtricitabine (FTC) and
TDF led to viral suppression (< 50 copies/
mL) in 76% with CVC 100 mg, 73% CVC
with 200 mg daily, and 71% with EFV/
FTC/TDF. CVC appears well-tolerated
causing no increase in lipid profile. CVC
induced a dose-dependent increase in
MCP-1, the native ligand for CCR2, and a
decrease in sCD14, a monocyte activation
biomarker [9]. Given its low mass dose of
100 or 200 mg daily (q.d.), CVC has the
potential of being combined with companion drugs. Although as a necessity in
its drug class CVC requires a tropism test
prior to prescription. Like maraviroc, early initiation of treatment at higher CD4
cell counts should favor the rate of suitable patients with CCR5 tropic viruses
and thus increase the potential use of this
drug.
Integrase inhibitors (INSTI)
Dolutegravir has recently been approved
in the US and in Europe. Given its viral
potency, which extends to INSTI resistant strains; its apparent high genetic barrier to resistance in the few failing patients in clinical studies of naïve patients;
its tolerability and apparent safety; and its
once-daily dosing, there is no doubt that
this drug is an attractive component of future regimens.
GSK1265744 is a potent in vitro HIV-1
INSTI analogue of dolutegravir that inhibits integrase at subnanomolar concentrations. It is a once-daily oral drug
with a plasma half-life of approximately 40 hours. In a phase IIa trial performed among 11 HIV-infected patients,
GSK1265744 used at 5 or 30 mg in monotherapy induced a viral reduction of
about 2 log10 copies/mL [10]. A phase II
trial with GSK1265744 vs. efavirenz, both
in combination with an NRTI backbone,
is ongoing. GSK-1265744 is also being developed as a long-lasting injectable parenteral agent (see below).
Long-acting injectable anti-HIV drugs
One of the biggest challenges to attaining a life-long therapy is to ensure opti-
HIV & VIROLOGY NEWS 4 • 2013
mal compliance on an individual level,
that is, regular delivery to patients in urgent need of therapy. The development of
long-acting injectable ARV agents based
on nanoparticle formulations that are capable of being administered on a monthly
or less frequent basis would represent a
major advance in the management of
ART. This is particularly important for
patients who have difficulties accepting
HIV and, for that reason, ART; or patients
with treatment fatigue; or those in subSaharan African countries where ART
delivery is a major issue for patients in
remote areas.
Long-acting injectable (LA) GSK1265744
The long-acting injectable formulation
of GSK1265744 is made of active drugs
in crystalline nanosuspension [11]. A first
phase I study in healthy volunteers has
tested different dosages of GSK1265744
in the form of a long-acting injection, either as a single intramuscular injection of
100, 200, 400, or 800 mg at different dosages, or a subcutaneous abdominal injection of 100, 200, or 400 mg. Plasma drug
concentrations increased rapidly over the
first week, with sustained mean plasma
concentrations above the PA–IC90 for
approximately 24 weeks or longer for
doses of at least 200 mg. Mild injection
site reaction was the most common adverse event.
A second phase I study [12] evaluated
four different schedules of IM or SC administration of long-acting GSK1265744
in 47 HIV-negative adults following a
14-day period of orally administered
GSK1265744; two groups receiving IM
doses of rilpivirine (RPV) completed the
regimen. All doses achieved therapeutically-relevant plasma concentrations
within 3 days of the initial injection, with
prolonged exposure exceeding IC90 for
both drugs. RPV plasma concentrations
following TMC278 LA dosing were similar to steady-state concentrations observed in phase III studies of oral RPV
dosed at 25 mg per day. Pharmacokinetic
data suggest a once-monthly regimen.
Side effects of the injections tended to be
more frequent with SC administrations.
TMC278 LA injection is the investigational nanosuspension formulation of
RPV. A phase I study of TMC278 LA 300
mg/ml nanosuspension evaluated the
pharmacokinetics and safety of single
IM or abdominal SC injections in 51 HIVnegative adult patients at doses of 200,
HIV & VIROLOGY NEWS 4 • 2013
400, and 600 mg, or placebo. RPV was
slowly released from the injection site
into plasma, with dose-proportional drug
concentrations of more than 10 ng/mL
for 12–26 weeks showing no difference
between IM and SC administration [13].
4. Zolopa A, Ortiz R, Sax P, Brar I, Elion R,
Wang H, et al. Comparative study of tenofovir alafenamide vs tenofovir disoproxil
fumarate, each with elvitegravir, cobicistat,
and emtricitabine, for HIV treatment. Presented at: 20th Conference on Retroviruses
and Opportunistic Infections (CROI); March
3–6, 2013; Atlanta, GA. Paper 99LB.
In summary, long-acting nanoparticle in-
5. Sax P, Brar I, Elion R, Zolopa A, Ortiz R,
Wang H, et al. 48 week study of tenofovir
alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF), each in a single tablet regimen with elvitegravir, cobicistat, and
emtricitabine for initial HIV treatment. Presented at: 53rd Interscience Conference on
Antimicrobial Agents and Chemotherapy
(ICAAC); September 10–13, 2013; Denver,
CO. Abstract H1464D.
jectable formulations of the NNRTI RPV
and the INSTI GSK1265744 have enabled
the preliminary investigation of a oncemonthly, two-drug regimen for maintenance of virologic suppression.
Conflict of Interests
Professor Katlama has received research
grants from Bristol-Myers Squibb, Gilead
Sciences, GlaxoSmithKline, Merck, Pfizer,
and Tibotec. She has received honoraria as
speaker and/or advisor from BoehringerIngelheim, Bristol-Myers Squibb, Gilead
Sciences, GlaxoSmithKline, Merck, Pfizer,
Tibotec and ViiV Healthcare.
Professor Christine Katlama
Department of Infectious Diseases
Hopital Pitié-Salpetriere
Pierre et Marie Curie University
INSERM U943 Research Unit
Paris France
[email protected]
References:
1. Wang F, Flint OP. BMS-986001, an HIV
nucleoside reverse transcriptase inhibitor,
does not degrade mitochondrial DNA in
long-term primary cultures of cells isolated
from human kidney, muscle, and adipose
tissue. Antimicrob Agents Chemother 2013;
57:6205–6212.
2. Cotte L, Dellamonica P, Raffi F, Yazdanpanah Y, Molina J-M, Boué F, et al. Randomized placebo-controlled study of the safety,
tolerability, antiviral activity, and pharmacokinetics of 10-day monotherapy with BMS986001, a novel HIV NRTI, in treatment-experienced HIV-1-infected subjects. J Acquir
Immune Defic Syndr 2013; 63:346–354.
3. Ruane PJ, Dejesus E, Berger D, Markowitz
M, Bredeek UF, Callebaut C, et al. Antiviral
activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide
as 10-day monotherapy in HIV-1-positive
adults. J Acquir Immune Defic Syndr 2013;
63:449–455.
6. Henrich TJ, Kuritzkes DR. HIV-1 entry inhibitors: recent development and clinical
use. Curr Opin Virol 2013; 3:51–57.
7. Nettles RE, Schürmann D, Zhu L, Stonier M,
Huang SP, Chang I, et al. Pharmacodynamics, safety, and pharmacokinetics of BMS663068, an oral HIV-1 attachment inhibitor
in HIV-1-infected subjects. J Infect Dis 2012;
206:1002–1011.
8. Ray N, Hwang C, Healy MD, Whitcomb J,
Lataillade M, Wind-Rotolo M, et al. Prediction of virologic response and assessment of
resistance emergence to the HIV-1 attachment inhibitor BMS-626529 during 8-day
monotherapy with its prodrug BMS-663068.
J Acquir Immune Defic Syndr 2013; 64:7–15.
9. Gathe J, Cade J, DeJesus E, Feinberg J, Lalezari J, Morales-Ramirez J, et al. Week-24
primary analysis of cenicriviroc vs efavirenz,
in combination with emtricitabine/tenofovir, in treatment-naive HIV-1+ adults with
CCR5-tropic virus. Presented at: 20th Conference on Retroviruses and Opportunistic
Infections (CROI); March 3–6, 2013; Atlanta,
GA. Abstract 106LB.
10.Spreen W, Min S, Ford SL, Chen S, Lou Y,
Bomar M, et al. Pharmacokinetics, safety, and monotherapy antiviral activity of
GSK1265744, an HIV integrase strand transfer inhibitor. HIV Clin Trials 2013; 14:192–
203.
11.Spreen WR, Margolis DA, Pottage JC Jr.
Long-acting injectable antiretrovirals for
HIV treatment and prevention. Curr Opin
HIV AIDS. 2013; 8:565–571.
12.Spreen W, Williams P, Margolis D, Ford S,
Crauwels H, Lou Y, et al. First study of repeat dose coadministration of GSK1265744
and TMC278 long-acting parenteral nanosuspensions: pharmacokinetics, safety and
tolerability in healthy adults. Presented at:
7th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment
and Prevention; June 30–July 3, 2013; Kuala
Lumpur, Malaysia. Abstract WEAB0103.
13.van ’t Klooster G, Hoeben E, Borghys H,
Looszova A, Bouche MP, van Velsen F, et
al. Pharmacokinetics and disposition of rilpivirine (TMC278) nanosuspension as a
long-acting injectable antiretroviral formulation. Antimicrob Agents Chemother 2010;
54:2042–2050.
35
The path towards IFN-free
therapy of hepatitis C
Part 4: We made it!
IFN-free therapy is reality!
In the last issues of the magazine, I summarized the recent steps forward on the path
towards interferon-free therapy of hepatitis C. Initially, I questioned if this path would
be really as smooth as expected without major steps back. However, the development
in recent months was enormous and for many of us also unexpected and sometimes
even breathtaking.
S
imeprevir, a new once daily HCV
protease inhibitor, was approved
in Japan in September and in
Canada in November. During
the American Liver Meeting, which was
held this year in Washington D.C., many
new exciting phase 2 and phase 3 data
on extremely promising DAA combinations were presented suggesting cure of
almost every patient – even in previously so called “difficult-to-treat” cohorts.
Mid of November, Abbvie released first
results of a phase 3 trial in non-cirrhotic
HCV genotype-1 infected patients demonstrating sustained virological response
rates of 96% with a 3 months course of
all-oral therapy! And just recently, both
simeprevir and the polymerase inhibitor
sofosbuvir have been approved for the
treatment of chronic hepatitis C by the
FDA. Thus, both drugs are already available in the United States.
Finally, also the European Medicines
Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended approval of sofosbuvir on November 22nd. This does mean that the
new era of IFN-free therapy of chronic
hepatitis C will start in many European
countries already in January 2014! We are
currently experiencing a complete shift
in treatment paradigms to an extent that
has very rarely happened in medicine before. The new therapies open many exciting opportunities for patients at risk
to develop clinical complications of liver
disease. However, the drugs also represent to some extent a challenge for treat-
HIV & VIROLOGY NEWS 4 • 2013
ing physicians. How to use the new expensive therapies in the absence of phase
3 data for selected subgroups of patients?
Will off-label combination of different
direct-acting antivirals be possible? Are
there any safety concerns for the new
drugs, in particular in patients with liver
cirrhosis?
Highlights on new IFN-free DAA
combinations presented at the
American Liver Meeting, in Washington
DC (November 1st-November 5th 2013)
Various dual or triple drug combinations
of HCV protease inhibitors, NS5A inhibitors and non-nucleosidic and nucleotidic
polymerase inhibitors are currently explored in phase 2 and 3 studies. The table is summarizing selected findings and
highlights the diversity of future therapeutic possibilities. Combinations were
explored either with or without ribavirin. Moreover, different treatment durations are currently explored suggesting
that a large proportion of HCV-infected
patients maybe cured with a 6–8 weeks
treatment course!
Overall, future treatment of HCV genotype 1 will likely be not only interferon
free but also ribavirin free. Depending
on the genotype 1 subtype (1a vs. 1b), different therapies will be possible. While
nucleotide-based therapies and threedrug combinations will cover all patients,
there might be reasonable alternatives
with PI/NS5A-I or PI/NNuc-I combinations for HCV genotype 1b, which is the
most prevalent HCV G1 strain in Europe.
Treatment options for chronic
hepatitis in 2014/15
Treatment of hepatitis C will more and
more personalized. Physicians will be
able to select from different treatment
possibilities, both IFN-containing and
IFN-free. PEG-IFNa/RBV without adding a direct acting antiviral may still be a
reasonable option for selected patients
with beneficial response profiles including absence of liver cirrhosis, an IL28bCC genotype and a low HCV viral load. A
short course of 24 weeks of therapy with
this regimen would be very cost-efficient
and may apply to 10–20% of patients.
Response-guided therapies with PEGIFNa/RBV/protease inhibitor triple therapy will be the second treatment option.
While boceprevir and telaprevir increased
response rates but also caused various additional side effects, the next wave of Pis
will be slightly more effective but most
importantly much better tolerated. Simeprevir (Janssen Therapeutics) became
available in several countries including
Japan, Canada and the USA during the
last quarter of 2013. Approval for Europe
is expected for the 2nd quarter of 2014.
Faldaprevir (Boehringer) has been granted accelerated assessment by EMA and
should reach the market in summer 2014.
HCV genotype 1 infection can now also
be treated with the nucleotide polymerase inhibitor sofosbuvir in combination
with PEG-IFNa and ribavirin for a fixed
treatment duration of 3 months irrespective of on-treatment response. The phase
3 “Neutrino” trial showed a sustained vi-
37
�
Table 1: Selection of phase 2 and phase 3 trials on IFN-free therapies of HCV genotype 1-infection presented during
the International Liver Congress (by EASL) 2013 and the American Liver Meeting (AASLD) 2013.
Company/Classes
Drugs
Ribavirin?
Duration
Findings
Boehringer:
PI + NNPol-I
BMS:
PI + NS5A-I
Merck:
PI + NS5A-I
BMS:
PI + NS5A-I + NNPol-I
Boehringer:
PI + NS5A-I + NNPol-I
AbbVie:
PI + NS5A-I
AbbVie:
PI + NS5A-I + NNPol-I
Faldaprevir + Deleobuvir
Yes
16 weeks
Asunaprevir + Daclatasvir
No
12 weeks
MK5172+ MK8742
Yes/No
12 weeks
Asunaprevir + Daclatasvir + No
BMS791325
Faldaprevir + PPI-668 +
Yes/No
Deleobuvir
ABT-450r + ABT-267 +
No
12 weeks
ABT-450r + ABT-267 +
ABT-333
Yes/No
8–12 weeks
Gilead:
NPol-I + NS5A-I
Gilead/Janssen TE/Medivir:
NPol-I + PI
Gilead:
NPol-I
Sofosbuvir + Ledipasvir
Yes/No
8–12 weeks
High response Genotype 1b n=20 (SVR 95%);
frequent relapses in Genotype 1a/Il28b CC n=12 (SVR 17%)
IFN ineligible (n=135) / IFN-nonresponder (n=87)
Phase III trial (Japan only): SVR12 81%–87%
2 different MK8742 doses; N=65
SVR 12 89%-100%
IFN naive, (n=166); BID FDC
SVR12: 92%
Genotype 1a; <F4; n=47
1 Breakthrough; SVR 4 all 13 patients with EOT
Only Genotype 1b; no cirrhosis
90–95% SVR
85–98% SVR;
press release phase 3 trial for non-cirrhotic patients
(n=473): SVR 96% with 12 weeks
95–100% SVR
Sofosbuvir + Simeprevir
Yes/No
12–24 weeks
93–100% SVR
Sofosbuvir
Yes
24 weeks
Photon study: HCV/HIV-coinfected patients: 76%
NIAID + Quantum study monoinfected patients: 65%
12 weeks
12 weeks
PI: Protease inhibitor; NS5A-I: NS5A inhibitor; NPol-I: nucleotide polymerase inhibitor; NNPol-I: nonnucleotide polymerase inhibitor
rological of 91%. Of note, the trial did also
include 28 subjects with HCV genotype
4 infection and 27 of those also achieved
a SVR.
Very importantly, sofosbuvir + ribavirin will now also be available to be used
without PEG-IFNa. Data from four phase
3 trials are now available for HCV genotypes 2 and 3 in monoinfected patients
(treatment durations 12, 16 or 24 weeks).
In addition, a phase 3 trial in HIV-HCV
coinfected patients explored sofosbuvir
and ribavirin for 24 weeks also in HCV
genotype 1 infection.
Overall, the following key findings arose
from these trials:
• Sofosbuvir and ribavirin leads to ontreatment HCV-RNA suppression in
almost every patient irrespective of the
underlying HCV genotype. Thus, there
is no primary “non-response” to therapy
and the drug has pan-genotypic activity.
• There are no breakthroughs during
therapy – meaning that no resistant
variants become dominant during
therapy!
• Relapses can occur after therapy.
• Sustained virological responses are
much better in HCV genotype 2 infection compared with genotype 3.
• Higher relapse rates occur in patients
with liver cirrhosis and in male patients. SVR rates do not depend on
IL28b genotypes, BMI, race, age of
baseline HCV viral load.
38
PPI-668
MK8742
ACH-3102
GS-5816
GSK2336805
ABT -267
PPI-668, etc.
Hepatitis C Treatment Concepts in 2014/15
HIV & VIROLOGY NEWS 4 • 2013
• Relapse rates can be reduced by prolonging therapy. Thus, in some conditions (e.g. genotype 3 infected patients
with liver cirrhosis 24 weeks of therapy are recommended).
• Treatment of patients with liver cirrhosis will remain a challenge, in particular for patients with genotype 3 infection.
As no phase 3 data for sofosbuvir/ribavirin are available in HCV-genotype 1
monoinfection, there is currently a debate how to treat these patients if PEGIFNa cannot be applied. Off-label combination of sofosbuvir with simeprevir
(once officially approved) or other agents
provided in early-access/compassionateuse programs seems to be a reasonable
alternative. Indeed, for simeprevir and
daclatasvir extremely promising phase
2 data are available showing high SVR
rates even in patients with advanced liver fibrosis or cirrhosis or in subjects who
failed a previous “standard” triple therapy with telaprevir/boceprevir, PEG-IFNa
and ribavirin. The usage of these off-label
combinations will likely differ between
countries and health-care settings.
HIV & VIROLOGY NEWS 4 • 2013
The photon-1 study studied sofosbuvir
+ ribavirin without PEG-IFNa in HCVHIV coinfected patients. Treatment naïve-patients infected with HCV genotype
1 (n=114) were treated for 24 weeks while
individuals infected with genotypes 2 or 3
(n=68) received 12 weeks of therapy. SVR
rates were 76%, 88% and 67% for patients
infected with genotypes 1, 2 and 3, respectively. Several important conclusions
arose from this study: 1. HIV-coinfected
patients seem to have similar response
rates than HIV-monoinfected patients;
2. 24 weeks of treatment with sofosbuvir
and ribavirin only (without another class
of direct-acting antivirals) seems to be a
reasonable treatment option for all HCV
genotype 1 infected patients; 3. no clinically-significant drug-drug interactions
became apparent which could limit the
use of sofosbuvir in the context of antiHIV therapies.
prospective cohort studies and registries
to ensure safety and efficacy of the new
therapies in real-world settings.
Concluding remarks
The era of IFN-free therapy of chronic
hepatitis C has started! By the end of 2015
several additional treatment choices will
become available. It will now be important to collect as many data as possible in
Heiner Wedemeyer
Dept. of Gastroenterology, Hepatology and
Endocrinology
Hannover Medical School
Hannover, Germany
[email protected]
Conflict of Interests
Honoraria for consulting or speaking
(last 5 years): Abbott, Abvie, Biolex, BMS,
Boehringer Ingelheim, Gilead, ITS, JJ/
Janssen-Cilag, Medgenics, Merck/Schering-Plough, Novartis, Roche, Roche Dia­
gnostics, Siemens, Transgene, ViiV.
Research grants: Abbott, BMS, Gilead,
Merck, Novartis, Roche, Roche Diagnostics, Siemens.
39
Topical Conferences in 2014
January 13–14
4th International Workshop on HIV & Women – From
Adolescence through Menopause
Washington, DC, United States
http://www.virology-education.com/
January 15–17
Bangkok International Symposium on HIV Medicine
Bangkok, Thailand
www.hivnat.org/bangkoksymposium
May 22–25
26th Annual National Conference on Social Work
and HIV/AIDS
Denver, CO, United States
www.bc.edu/schools/gssw/academics/ce/conferences.html
February 3–7
6th Africa Conference on Sexual Health and Rights
Yaounde, Cameroon
http://www.africasexuality.org
June 18–20
6th Conference on Peer Education, Sexuality, HIV & AIDS
Nairobi, Kenya
http://www.nope.or.ke/conference
March 3–6
CROI 2014 – Conference on Retroviruses and
Opportunistic Infections
Boston, Massachusetts, United States
http://www.croi2014.org/
June 25–26
2nd International Conference on HIV/AIDS, STDs & STIs
Valencia, Spain
http://72.167.32.140/hiv-aids-std-conference-2014/
March 9–14
Keystone Symposia- HIV Vaccines:
Adaptive Immunity and Beyond (X3)
Banff, Alberta, Canada
http://www.keystonesymposia.org
March 9–14
Keystone Symposia – HIV Pathogenesis –
Virus vs. Host (X4)
Banff, Alberta, Canada
http://www.keystonesymposia.org
March 26–28
12th European Meeting on HIV & Hepatitis
Treatment Strategies & Antiviral Drug Resistance
Barcelona, Spain
http://www.virology-education.com/
May 9-11
HANSA 2014 (North European Workshop on
HIV Infection in the CNS)
Berlin, Germany
www.seeuthere.com/2014/HANSA-Berlin
40
May 7–10
2014 HIV in the Americas
Rio de Janeiro, Brazil
www.hivamericas.org/
July 18–19
6th International workshop on HV Pediatrics
Melbourne, Australia
http://www.virology-education.com/
July 20–25
20th International AIDS Conference
Melbourne, Australia
http://www.aids2014.org/
September 24–27
Southern African HIV Clinicians Society Conference 2014
Cape Town, South Africa
http://www.sahivsoc2014.co.za
October 12–14
3rd Antivirals Congress 2014
Amsterdam, Netherlands
http://www.antivirals.elsevier.com/index.html
November 2–6
HIV Glasgow
Glasgow, United Kingdom
http://www.hivglasgow.org
HIV & VIROLOGY NEWS 4 • 2013
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