Risk perception, ARV-based prevention strategies and grassroot conversations – a preview of the upcoming Mapping Pathways monograph

Original content from our Mapping Pathways blog team

Risk perception and the consequent behavioral responses has been a theme that has fascinated Philip Smith throughout his professional career.

Smith, a Ph.D. candidate at the Desmond Tutu HIV Foundation (DTHF), a Mapping Pathways partner organisation, first encountered the subject of risk perception as he was completing his masters degree in social science and psychology at the University of Cape Town. Smith realised that scaring people with death as part of a prevention strategy may actually end up leading people to deny their own vulnerability.

“Smoking is an example where a key prevention strategy involves subjecting people to images of death. My research indicates that this kind of messaging actually leads to a psychological tension that can lead to risk-denial or even an increase in self-esteem boosting risky behavior to relieve that tension,” says Smith.

Smith’s interest in risk and the HIV field led him to DTHF and subsequently to a key role in the Mapping Pathways project; writing up the results of the 2011 Online Survey as part of a monograph to be published this spring by project partner, RAND.. The online survey is one of four data collection mechanisms of the Mapping Pathways project: the other three being the ExpertLens, the Literature Review and the Stakeholder Interviews.

“The Online Survey, which happened in India, South Africa, and the U.S. in 2011, seeks to understand what people at the grassroots were thinking about implementation and what the specific challenges are on successfully implementing ARV-based prevention strategies, such as PrEP and TLC+, also known as treatment as prevention, in their communities,” says Smith

The methodology involved first creating a questionnaire with two different sections: a multiple choice section and a qualitative section where respondents were asked about information they wanted and concerns they may have about ARV-based prevention strategies.

Over 1,000 individuals participated in the survey across the three countries. Among other questions, participants were asked how important they thought ARV-based prevention strategies were and what would they find useful in their work. In addition to asking participants to quantify how important they believed the different strategies are in preventing HIV infection in their communities, they were also given the opportunity to share their perspectives of the barriers to implementing successful ARV-based prevention strategies.

Lastly, participants were asked to suggest what kinds of information they would find helpful in implementing community friendly, impactful, ARV-based prevention strategies.

“Most participants felt positively about ARV-based prevention strategies and their implementation. TLC+ was the most favoured strategy and some valid concerns were raised about cost and the lack of access to healthcare, especially in South Africa and India but also in the U.S.,” says Smith.

Smith says that a key conversation that developed revolved around how healthcare systems around the world, currently tailored towards treatment, would have to adapt with a twin focus on prevention to successfully implement ARV-based prevention strategies.

Consequently, participants wanted to know how best to raise awareness about the different prevention strategies, with some participants requesting that information be made available comparing the different strategies to maximise informed choices in communities. Participants also expressed interest in understanding what policy-makers thought about ARV-based prevention methods because this would act as a useful guide for implementation.

Besides data collection and gathering an evidence base, the key mission of the Mapping Pathways project is to disseminate findings and liaise with the global HIV-treatment and prevention community at large around the use of ARVs for prevention. The upcoming monograph, “Developing evidence-based, people-centered strategies for the use of antiretrovirals as prevention” will touch on all these themes and more, including the theme of risk that has so intrigued Smith throughout his professional career.

Stay tuned for the Mapping Pathways monograph, coming soon

[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position. Please look for us on Facebook here www.facebook.com/MappingPathways and you can follow us on Twitter @mappingpathways as well.]

Clinical Trials Have Gone Global: Is This a Good Thing?

via plosmedicine.org, by Trudie Lang and Sisira Siribaddana

Why Do We Need Trials and What Makes a Trial a Trial?

Clinical trials are needed globally to reduce disease burdens by helping developing safe and effective new therapies and vaccines. These solutions may be for non-communicable diseases like cancer and diabetes, or, as is especially needed in the poorest regions of the world, infectious disease. Developing countries are under-represented in research due to lack of commercial viability and trained researchers, yet it is in these poorest regions where research-led solutions could bring the greatest impact to high rates of early mortality.

As a research tool clinical trials are fundamental in the effort to develop new products by gaining the data required by regulators, whether for product license extensions for existing therapies for common ailments or to bring cutting edge new therapies and vaccines into approved use. However, there is also a need for clinical trials to bring evidence to determine how to improve the management of health issues; these studies often do not involve a medicinal product but instead compare different options, such as different types of management of an illness in hospital with community-based care. Or, for example, a clinical trial might be used to assess different mechanisms to improve patient adherence to therapy. These pragmatic disease management trials can bring about significant improvements in public health and often require large yet simple trial designs.

The World Health Organization and journal editors define clinical trials as “any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes” [1]. Patients may be randomised to an intervention involving either an investigational new product or the standard-of-care treatment, or the patient might be randomised to be cared for by nurses who have been trained in one of two or more comparative ways.

Why Go Global?

Clinical trial data are often collected from varied populations to support a license application because geographically different trial sites are needed to ensure the product is safe and works in the same way in varying ethnic groups. This requirement is true whether it is a pharmaceutical company working on the next blockbuster drug or a non-for-profit partnership (which typically have a pharmaceutical partner involved in a non-for-profit capacity) developing a new drug or vaccine for a neglected disease. Here scientific and regulatory factors combine to encourage the globalisation of clinical trials.

Read the rest. 


[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position. Please look for us on Facebook here www.facebook.com/MappingPathways and you can follow us on Twitter @mappingpathways as well.]

AVAC Launches Research Literacy Database!

via AVAC

AVAC is pleased today to launch the Research Literacy Database at www.avac.org/researchliteracy, an important new resource for the biomedical HIV prevention field.

The Research Literacy Database is the first central portal for educational resources on biomedical HIV prevention including:

• Global and country-specific materials;

• Resources specific to given prevention interventions including AIDS vaccines, ARV-based prevention and
voluntary medical male circumcision; and

• General information on clinical trials and the research process.

The tools featured in the database were developed by a range of stakeholders worldwide to meet specific needs. We will continue to expand the database and encourage our users to share their favorite materials on an ongoing basis. The database focuses on materials that won’t necessarily change substantially over time; for trial updates, timelines, recent results and their implications and current issues, please see other areas of the AVAC website.

Using an innovative design, the database allows users to search for what they need based on key criteria. For example, a journalist in South Africa who wants to learn more about the basics of microbicide research can use the database to find relevant fact sheets, e-learning courses and other helpful tools. Research organization staff members who need tools for training and outreach to wider audiences can use the database to get a tailored toolkit according to location, audience and specific content.

We all know that the science behind HIV prevention research is challenging. AVAC believes that building
basic research literacy among key stakeholders is fundamental to effective advocacy, to moving research forward as quickly and ethically as possible, and ultimately to getting new prevention options to people who need them. Whether you are a researcher, advocate, journalist, policy maker or someone interested in learning more about clinical trials and new ways to prevent HIV, we hope this database will make learning and outreach efforts easier and more effective.

The database is an iterative tool, and will be constantly updated with new materials and other user input. We need your help in ensuring that useful materials are available and used! Please contact us at researchliteracy@avac.org with any and all feedback you have as you use the database—and we are especially keen to receive additional relevant resources to be shared with the field.

[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position.]

NYT: PrEP Trial Results are Re-examined

via The New York Times, by Donald G. McNeil Jr.

The failure of a daily pill to protect healthy African women against AIDS may not have been the pill’s fault but the women’s reluctance to take it, scientists at an important AIDS conference in Seattle were told this week.

Last April, a promising trial of “pre-exposure prophylaxis” — giving small protective doses of antiretroviral drugs to uninfected people — was stopped early because women were getting infected anyway. It was a discouraging setback.

But scientists at this week’s Conference on Retroviruses and Opportunistic Infections who analyzed blood samples taken from the women reported that only a quarter of those who got infected had any of the drug, Truvada, in their blood. That suggested they had not taken their pills.

Papers presented at the four-day conference offered findings both optimistic and scary. There were hints at a possible way to flush the virus out of its hiding places in cells, and at ways to let some patients safely take “vacations” from triple therapy.

It is not known why so few African women took their Truvada, but there is still an enormous stigma about AIDS in Africa, and a bottle of AIDS drugs in the home implies that someone there is sick, said Mitchell Warren, executive director of AVAC, a prevention advocacy group. Mr. Warren pointed out that Truvada had protected women in a different study that enrolled established couples in which only one partner was infected.

In a different study, researchers from the University of North Carolina at Chapel Hill showed that they had used a cancer drug, vorinostat, to purge the virus hiding in the CD4 cells of six men who were already doing well on triple-therapy cocktails.

Although the cocktails can make the virus vanish from the blood, it hides in different types of cells, ready to roar back if the patient stops taking the cocktails.

Rooting some out with vorinostat “may not be the magic bullet,” said Dr. David Margolis, the study’s lead researcher, “but it suggests we can build a path that may lead to a cure.”

Another small trial, at the Wistar Institute in Philadelphia, gave patients synthetic interferon — a virus-blocker normally made by the human body — while they took “holidays” of up to six months from triple therapy. Nine of the 20 patients did not see their viruses rebound to dangerous levels. That result will not change clinical practice right away, said Dr. Luis J. Montaner, who led the study, but suggested an alternative to lifelong triple therapy, which can be debilitating.

Read the Rest.


[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position.]

BHIVA Reports on the Need for Additional PrEP Studies

via AidsMap.com, by Gus Cairns

A position statement by the British HIV Association (BHIVA) and the British Association for Sexual Health and HIV (BASHH) has concluded that as yet the data on the efficacy of pre-exposure prophylaxis (PrEP) is not compelling enough for it to be offered to patients on demand, and that it should only be prescribed in the context of a clinical research study until more data on its efficacy is gathered.

The BHIVA/BASHH position contrasts with that of the US Centers for Disease Control, which issued guidance for doctors prescribing PrEP to patients last year.

The two UK organisations, which represent HIV and STI healthcare workers respectively, conducted a consultation on PrEP last year which included in-person and telephone conferences with a variety of UK treatment and prevention stakeholders in the UK (including NAM), and the creation of an ongoing PrEP Working eGroup.

The finalised position statement notes that in 2010 there was the highest-ever number of new HIV infections in gay men in the UK (over 3000, 81% acquired here) and adds that this “continued increase in infections...underscores the urgent need to...rethink our overall strategy for HIV prevention at a time when the NHS is undergoing change.”

It also however notes that the data on the efficacy of PrEP has so far been widely disparate (see Aidsmap reports on the iPrEx, PartnersPrEP, TDF2, FemPrEP and VOICE trials), in contrast to convincing evidence both for the efficacy of condoms when used consistently and correctly and of treatment as prevention.

It also notes that these are many unanswered questions in the case of PrEP: will it be affordable and cost-effective? Will it increase the likelihood of drug resistance? Are there long-term toxicity concerns for HIV-negative people taking it? And will it induce people to abandon condom use? It also notes there has never been a systematic evaluation of behaviour-change programmes in the UK, also in contrast to the US.

It concludes that “it is imperative to gather [more] evidence for the value of PrEP in the UK” and that therefore “We recommend that ad hoc prescribing is avoided, and that PrEP is only prescribed in the context of a clinical research study”. Until then, “regular HIV testing, the diagnosis and treatment of other STIs, and intensive health promotion activities...should be implemented in preference to PrEP.”

[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position.]

CROI 2012: Results of iPrEx Trial Show Effective Dosage of PrEP

via AidsMap.com, by Gus Cairnes

Further testing of drug levels in the blood and immune cells of gay men participating in the iPrEx trial of tenofovir/FTC (Truvada) pre-exposure prophylaxis (PrEP) has found that HIV infection in men assigned to Truvada was associated with a lapse in taking the drug after initially adhering reasonably well, rather than never having taken it at all, which was what the researchers originally thought. The research was presented at the 19th Conference on Retroviruses and Opportunistic Infections (CROI), in Seattle.

The testing also found that only a minority of participants appeared to be taking their drugs as prescribed, seven days a week, but that protection levels were very high – in the order of 96% of infections prevented – as long as participants took four or more doses a week.

Drug levels plummet three months before infection

 The results of iPrEx, a large multi-country study of PrEP in gay men, were announced in 2010 and showed an overall efficacy of 42% – in the trial subjects as a whole, four out of ten HIV infections that would otherwise have happened were prevented if subjects were given Truvada pills to take daily rather than placebo pills. When drug levels were tested in the 48 participants who became HIV-infected on Truvada, and a random sample of uninfected participants, it was found, perhaps not surprisingly, that drug was detectable in only 10% of the infected participants but also, perhaps more surprisingly, in only 50% of the uninfected ones.

New measurements have now looked back at drug levels in stored samples in the months prior to infection and compared with drug levels in the same time period in uninfected participants. In the uninfected participants, consistently 45% or so had detectable drug in their samples across the whole length of the study – confirming that at least half of the participants simply never took their pills. In the infected participants average adherence rates started off the same as in the uninfected. They showed a slight decline in the first year of the trial but then declined to 10% in the three months preceding infection. This suggests a role for quarterly adherence reinforcement.

What levels of tenofovir are protective?

 The researchers also wished to find out what levels of tenofovir in the blood were associated with protection against HIV. They did this by comparing drug levels in iPrEx participants with drug levels in a small study called STRAND, presented at last year’s conference (Liu),which gave participants directly-observed doses of tenofovir twice, four time or seven times a week and then measured drug levels in their hair. By then comparing the levels of protection seen in participants with specific drug levels in iPrEx, the researchers were able to compute what drug level was protective.

In iPrEx the average drug levels seen in infected people were consistent with less than one dose of tenofovir a week, but drug levels in those who were not infected were consistent with only about three doses a week. Only 18% of iPrEx participants had drug levels consistent with taking seven doses a week. The investigators used very sensitive tests to look at levels of metabolised tenofovir inside cells and found that a reduction of 90% in the risk of HIV infection correlated with a drug level of 16 femtomols per mol (fm/M – 16 in every million billion molecules by weight). The average level associated with seven doses a week in STRAND was about 38 fm/M and with four doses a week about 32 fm/M.

This enabled them to calculate that the protection offered by taking four doses of tenofovir a week was high, and more or less the same as taking seven doses – that is, in the order of 96%, with a minimum likely protectiveness of 90%. They also calculated that absolutely perfect adherence would offer 99% protection. Taking two doses a week (consistently) would still offer 72% protection, though within wide confidence intervals (56% to 96%) while the 42% level of protection actually seen in iPrEx was consistent with participants taking, on average, one dose a week.

This study has important limitations. STRAND did not measure FTC levels so the iPrEx researchers could not calculate what extra protection was offered by that drug. They also could not measure drug levels at the actual moment of exposure – they were measured at anything between 15 and 90 days after infection. And of course the ‘number of doses a week’ measure is purely an average – most participants probably had much more irregular patterns of taking their pills, with (amongst the 50% who took it at all) periods of good adherence interspersed by periods off drug, maybe correlated with times on and off sex. But it does give a guide to the likely minimum levels of tenofovir that people need to maintain in order to be protected from HIV.



[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position.]

CROI Reports First Trial Results on HIV Injectable Treatment

via AidsMap.com, by Gus Cairns

The first trial in humans of an injectable, once-a-month formulation of an HIV drug has found that drug levels were maintained at a level that should in theory be high enough to protect recipients against infection, and that the drug has so far produced very few side effects. The research was presented at the 19th Conference on Opportunistic Infections (CROI), in Seattle.

The small trial at the St Stephen’s AIDS Trust (SSAT) at London’s Chelsea and Westminster Hospital gave 27 women and six men a single injection of the long-acting formulation of the drug rilpivirine, which was licensed as an oral HIV treatment last year as Edurant and is also in the tenofovir/FTC/rilpivirine pill Complera. Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) drug and is especially suitable to be turned into a long-lasting injectable form because the daily dose of it required to suppress HIV is very small.

No other HIV drugs are currently in a usable long-lasting injectable form, which will limit the use of long-acting rilpivirine (RPV-LA) in combination therapy, but it could conceivably make an ideal candidate as a prevention drug, as people would not need to remember to take it every day. Other preventative drugs already formulated as monthly injections include the injectable contraceptive Depo Provera and some anti-psychotic drugs.

SSAT recruited 27 HIV-negative women aged 18 to 50, more than 50% of them black African or Caribbean, for the trial and gave them one of three doses of RPV-LA as an intramuscular injection: 300, 600 or 1200mg (the oral dose of RPV is 25 mg/day). Drug levels were then measured over the course of the next twelve weeks in blood, vaginal fluid and in vaginal tissue samples. A substudy gave six men the 600mg dose and measured RPV-LA levels in blood, rectal fluid and rectal tissue samples.

Thirty days after injection, blood and vaginal fluid levels of rilpivirine were about 60 nanograms per millilitre (ng/ml) in both blood and vaginal fluid in women given the 600mg dose, and about 80 and 120ng/ml respectively in women given the 1200mg dose. Blood levels in men given the 600mg dose were about 70ng/ml at 30 days. For comparison, the trough levels of rilpivirine in people taking daily oral doses is about 140ng/ml; but the EC50 (the amount needed to reduce viral replication by 50%) in newly-infected T-cells is 27ng/ml. It is thought these levels should be adequate to prevent HIV infection. 

Read the Rest.


[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position.]

In Conversation with Nomita Chandhiok: Exploring the ‘tool box’ of HIV prevention strategies

Original content from the Mapping Pathways blog team

“If a woman, for whatever reason, is unable to negotiate the use of a condom during sex, at least she can have something else to protect herself with – something that can help put her in control.”

Doctor Nomita Chandhiok is one smart lady. A gynaecologist by training, she is a scientist and researcher in the Division of Reproductive Health at the Indian Council of Medical Research (ICMR), the premiere research body of the government of India. Her job is to identify issues related to women’s health, sexual reproductive health, women’s infection, and HIV prevention that are relevant to India, and then conduct and coordinate studies that push forward research on these issues.

“HIV is a high priority for the Council,” says Dr. Chandhiok. “ARVs as prevention have really evolved.” She explains that all HIV prevention and treatment policies fall under the Indian government’s NACO programme. “As part of this programme, we would promote HIV prevention strategies such as PrEP or microbicides. Our focus so far has been on promoting condom use and safe sex practices, but now there could possibly be these new tools as well.”

Creating the toolbox
In particular, the ICMR is currently running a number of pre-clinical trials for product development and screening for microbicides. The organisation recently finished a Phase 1 trial that looked at an indigenously produced microbicide called Basant (the product is curcumin/turmeric based). The product was tested on 30 women and was found to be safe, says Dr. Chandhiok. Further studies would explore the post-coital efficacy of Basant and its male tolerability in 30-40 men. A study is also ongoing to identify and prepare six sites in the country for phase III microbicide trials. Dr. Chandhiok explains that these sites are located in three high-prevalence Indian states – Maharashtra, Andhra Pradesh, and Karnataka. The ICMR is seeking to determine the HIV incidence and prevalence rate amongst 9000 commercial sex workers in six districts in these areas. “Once we know the incidence rate, and if it is high enough (say 3-4% or more), we will then develop these sites for future HIV prevention trials.”

An empowerment tool for Indian women
Dr. Chandhiok has been working in this area for almost a decade. In 2003, she received a Fogarty Fellowship at Brown University, where she was exposed to research on microbicides as an HIV prevention tool.  “In early 2000, people thought HIV was going to spread like wildfire in India,” explains Dr. Chandhiok. As a result, the ICMR was looking ahead to find new prevention tools that they could possibly add to the government’s existing arsenal of HIV prevention strategies. As it turns out, the epidemic did not spread as imagined. “HIV is still a big issue in our country, but our numbers are better now… We don’t have a general epidemic. So, given the nature of the epidemic in India, any tools we develop will be for specific populations.”

Dr. Chandhiok explains further, “We talk in terms of a prevention toolbox. We don’t talk about one general tool. The aim is to provide several options that a person could  use through their entire sexual life. So, for example, you have a choice – if you can use a condom, great; if not, then you have the option of using a microbicide also.”

Dr. Chandhiok feels that prevention tools such as microbicides, once their efficacy has been proven and effective products created, could serve to empower Indian women. “As an empowerment tool for women these prevention tools need to be developed.” She explains, “These are very important for us to look at because if a woman, for whatever reason, is unable to negotiate the use of a condom during sex, at least she can have something else to protect herself with—something that can help put her in control.”

Concerns and challenges
Dr. Chandhiok is quick to point out that a lot of this discussion, though, is still theoretical. “At this point, we don’t have enough data to roll out tomorrow. There are still questions to be answered. We’re not at the point of saying we are ready to roll.”

For instance, she explains that oral PrEP, even were its efficacy to be proven, would still run into a huge implementation challenge in India. “In India, we don’t have strong regulation. You could be able to buy an ARV without prescription. So for something like PrEP, which is pill based, you don’t want people using it just like that without a proper prescription or a trained professional administering it and providing proper information and counselling.”

Dr. Chandhiok also feels that because HIV isn’t seen as such a priority issue amongst the majority of the population, adherence issues are another challenge, “Prevention is different from treatment. Only if I perceive myself at risk, only then will I think of preventing it.” And, as Dr. Chandhiok explains, in India most people do not perceive themselves as being at risk – HIV is perceived as a problem relegated to those at the margins of society, commercial sex workers or men who have sex with men. “Basically, for us to be able to roll out something like PrEP, we need government commitment, we need the funds to procure it, and we need a system to reach all the people who require it.” And, as it stands now, all three of these factors remain unclear.

The first and most important hurdle, however, is to prove the efficacy of these new prevention tools, says Dr. Chandhiok. “Only once efficacy is proven, can we even begin to think of all the implementation issues. And as it stands now, the trial results are contradictory; so we are still not too certain about how to proceed.” (Learn more about the various HIV prevention trials here).

Particularly disappointing was the closure of the VOICE trial’s study arm testing tenofovir gel last November, says Dr. Chandhiok. “I’m a little confused because of all the conflicting results. There is no one direction as yet, so we don’t know the clear path ahead. We can’t move forward until we have clear-cut evidence that these tools work.”

Note: The VOICE trial announced on November 25, 2011 the closure of its study arm testing tenofovir gel. The decision was made due to futility – while tenofovir gel was found to be safe, the trial was not able to prove the gel worked to prevent HIV. See the statement from the Microbicide Trials Network  for more information. Previously, the trial had to drop its tenofovir tablet arm due to futility as well. The Truvada tablet arm in the trial is continuing.

Nomita Chandhiok is the Deputy Director General in the Division of Reproductive Health at the Indian Council of Medical Research, the premiere research body of the government of India.



[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position.]

New Approach to Phase 3 Clinical Drug Trials

viaThe Sacremento Bee, by the Forum for Collaborative HIV Research

As the war on HIV/AIDS begins its fourth decade, medical researchers, pharmaceutical manufacturers, patient advocates and government regulators face a new and unexpected scientific challenge: how to demonstrate the safety and efficacy of promising new antiretroviral drugs when the two traditional study designs – the superiority trial and the non-inferiority trial – are no longer useful in showing improvements in both "treatment experienced" patients and those who have never received drug therapy (treatment-naive patients).

Because this challenge could have a dampening effect on what is now a robust drug development pipeline for HIV, the Forum for Collaborative HIV Research has just released a new scientific paper that lays out a substantially different approach for conducting Phase 3 HIV clinical trials. 

Published in the journal AIDS, the paper summarizes the insights of specialists from the Food and Drug Administration, European Medicines Agency, academia, the patient advocacy community and industry that overcoming the current difficulties in conducting new HIV drug trials requires moving from the large-scale study model to a new approach where clinical improvements are demonstrated through a sequence of short, step-wise efficacy and safety studies.

"Despite the many valuable antiretroviral drugs now available to treat HIV, new antiretrovirals can bring important benefits, such as fewer side effects, less frequent dosing and a lower risk of drug resistance. That is why overcoming the barriers to innovation in HIV drug development is so critical," said Veronica Miller, Ph.D., Director of the Forum and one of the authors of the paper. "Our paper offers a new pathway for regulatory approval of promising new HIV drugs and reflects the best thinking of the top experts in the field."
The new pathway described in the paper calls for a multi-phased study design, which includes:

•A short study (10-14 days) comparing the investigational compound versus placebo, with the patient's current failing regimen as background, to evaluate short-term efficacy in viral load reduction
•A follow-on study where all participants receive the investigational drug (at a single or different doses) and are assessed at 24 weeks to evaluate dose response, safety, durability of initial response and development of resistance
•The possibility of a second comparative safety trial in patients with a minimum of two active drugs available where participants are randomized to the investigational agent plus a new optimized background regimen of antiretroviral drugs versus patients on a new optimized background regimen plus placebo

Read the Rest.


[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position.]

First Phase III European PrEP trial for gay men launched by ANRS!

via iPrEx News

The ANRS (French National Agency for Research on AIDS and Viral Hepatitis) is about to launch in Europe the first pre-HIV exposure prevention trial in men who have sex with men.

This phase III trial—ANRS IPERGAY—will start at the end of January 2012, in Paris (Hôpital Saint-Louis, Professor Jean-Michel Molina and Hôpital Tenon, Professor Gilles Pialoux) and Lyon (Hôpital de la Croix-Rousse, Dr Laurent Cotte), and later in Montreal in Quebec (CHUM Hôpital Hôtel Dieu, Dr Cécile Tremblay). The trial will include 300 volunteers in the pilot phase and ultimately 1900 in total.

ANRS IPERGAY will involve men who have sex with men and seronegative trans men who have anal sex with men without routine use of condoms, with at least two different sexual partners in the six months prior to trial participation. Participation will last for between 12 (minimum) and 48 (maximum) months.

The trial will compare two groups of participants, one given Truvada®, the other a placebo, taken in both cases during the period of sexual activity, starting before sexual relations and ending afterwards.
All participants, irrespective of group, will be offered various means of prevention: free condoms, regular HIV screening, regular screening for and treatment of sexually transmitted diseases, vaccination against hepatitis A and B. Participants can ask for personalized prevention advice, if they wish.

An important part of the trial will involve a social sciences study of the profiles of participants and analysis of their sexual behavior, in particular regarding condom use, and will determine whether or not they take the medication as intended.

Participants will be invited to the hospital every two months or so for an interview and for clinical examinations, including screening tests.

The ANRS will sponsor and fund the trial, and Gilead will supply the medication.

The HIV community-based association Aides helped draw up the protocol, is a scientific and operations partner in the trial, and is a member of the scientific board. It will coordinate recruitment in the field and provide volunteers with prevention support.

ANRS press contact:Marie-Christine Simon – Tel :  +33 (0) 1 53 94 60 30  marie-christine.simon@anrs.fr


[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position.]

Apparent declining efficacy in randomized trials: examples of the Thai RV144 HIV vaccine and South African CAPRISA 004 microbicide trials

via AIDS, by O’Hagan, Justin J.; Hernán, Miguel A.; Walensky, Rochelle P.; Lipsitch, Marca

Recent HIV prevention trials have given hope that a suite of interventions that effectively reduce individuals’ risk of HIV infection will soon be widely available. In two studies, the RV144 and CAPRISA 004 trials, the relative risk of infection increased toward the null value of one over time. The RV144 and CAPRISA investigators interpreted these trends as evidence that the interventions’ effects declined over the study period and suggested that their respective findings may be explained by waning vaccine efficacy and decreasing adherence. Here, we discuss these trends in the trials’ results and note that, in addition to the possible mechanisms cited by the investigators, their apparent waning efficacy may be explained in part by selection bias due to heterogeneity in infection risk, an explanation that has not been considered previously. This bias arises when study participants vary in their susceptibility to infection, for example, because of differences in immune systems or exposure to infection. This can lead to increasing differences in the composition of the study population in each trial arm over time as those at highest risk become infected, and can occur despite comparability between arms at baseline. This issue is termed ‘frailty’ in statistics and demography, in which a large body of literature addresses the matter. We also discuss several methods that can improve understanding of the effects of infectious disease interventions and risk factors by assessing the impact of frailty on results.

Variation in frailty among study participants likely creates trends in the incidence of infection over the course of a study. To understand this phenomenon, consider a theoretical placebo-controlled randomized trial, in which the risk of infection varies among participants. The highest risk individuals in such a trial are expected to become infected earlier, leaving a pool of lower risk individuals at later time points. If the intervention being tested is effective, the decline in the incidence of infection over time will be larger in the placebo arm because these individuals experience no direct protection from the intervention, and so those at high-risk will be quickly depleted, thereby lowering the infection rate over follow-up. However, high-risk individuals in the active arm may remain uninfected due to the protection conferred by the intervention, so the active arm's infection rate will be less affected. Consequently, the time-specific rate ratio for treatment vs. placebo will increase over time from a value of less than one initially to a value that may exceed one later. This phenomenon has also been termed ‘survivor bias’, ‘survivor cohort effect’, ‘crossing of hazards’ and ‘depletion of susceptibles’, and is observed in both chronic and infectious disease research.

Read the rest.


[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position.]

Gilead has submitted application for FDA approval of PrEP

via Bay Area Reporter, by Liz Highleyman

The company, which made the announcement December 15, has asked for priority review, meaning a decision could come as early as June. Clinicians can currently prescribe drugs "off label" as they see fit, but official approval of Truvada PrEP would have implications for public health programs and insurance coverage.

"The data from clinical trials clearly show that taking Truvada every day and using condoms can be very effective in preventing HIV for people at highest risk for infection," said Project Inform Executive Director Dana Van Gorder. "We believe in the right of HIV-negative people to choose the evidence-based prevention methods that best support their efforts to remain negative, and we urge quick FDA approval of Truvada for prevention."

PrEP trial results

Gilead's request is based on findings from a series of large international trials of oral PrEP using Truvada or the medications it contains, tenofovir (sold separately as Viread) and emtricitabine (Emtriva). Overall, results have been promising but several questions remain unanswered.

The large iPrEX trial, which enrolled nearly 2,500 gay and bisexual men and transgender women in six countries (including San Francisco and Boston in the U.S.), found that daily Truvada reduced the risk of acquiring HIV by 44 percent overall, with 36 new infections among men receiving PrEP compared with 64 among men taking a placebo pill.

Further data presented at the International AIDS Society conference this summer in Rome showed that risk reduction exceeded 90 percent for participants who had detectable drug levels in their blood, indicating good adherence.

"With 2.6 million new HIV infections occurring each year, and fewer than half of people with HIV receiving treatment, the world needs new and effective HIV prevention strategies," said iPrEx protocol chair Dr. Robert Grant from the Gladstone Institutes and UCSF. "Men who have sex with men have borne an enormous burden in this epidemic, and have also been consistently at the head of efforts to help reverse it."

Two other trials discussed in Rome – Partners PrEP and TDF2 – showed that the drugs in Truvada reduced the risk of HIV infection among heterosexual men and women in Africa by 60 percent to 75 percent.

In contrast, however, two studies of heterosexual African women have not seen a similar effect. The Fem-PrEP study of daily Truvada was halted earlier this year due to lack of effectiveness, as was an arm of the VOICE trial testing oral tenofovir alone (the tenofovir/emtricitabine combination is still being evaluated.)

Read the rest.


[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position.]

Five hundred twenty-five thousand six hundred minutes: How do you measure a year?

Original content from the Mapping Pathways blog team

Another year winds down, and it is time to take stock, to reflect on all the moments that have made 2011 an important year for the HIV prevention community – and for all those of us who hope for and work toward the end of the HIV/AIDS epidemic.

The year began on a high note: the extremely encouraging results from the IPrEx and CAPRISA trials, announced in 2010, had us “jumping up and down” as Jim Pickett (Director of Prevention Advocacy and Gay Men's Health at the AIDS Foundation of Chicago, chair of International Rectal Microbicide Advocates [IRMA], and a member of the Mapping Pathways team) says in his memorable interview, Success! Now What? These results were the long-awaited proof of concept for new prevention technologies – the “first real ‘win’” after many years of hard work.

The first bump in the road was the discontinuation of the FEM-PrEP trial in April due to futility, when the trial’s Independent Data Monitoring Committee concluded that the study would be highly unlikely to prove the effectiveness of Truvada in preventing HIV infection among the study population, i.e., HIV-negative women who are at risk of infection through sexual transmission.

The unexpected development had everyone expressing their opinions and wondering about the implications – after all, what does “futility” mean exactly? Dr. Linda-Gail Bekker (an expert in the field of biomedical trials and research) cautioned against knee-jerk reactions to the trial closure in her interview with Mapping Pathways: “Wait for the evidence, I think that is the message. Extrapolate at your peril. We know only what we know, and we need to just work within that.”

Then came the HPTN 052 results – and we were jumping with excitement again! The study demonstrated that initiation of ART by HIV-infected individuals substantially protected their HIV-uninfected sexual partners from acquiring HIV infection, with a 96 percent reduction in risk of HIV transmission. In an interview with Mapping Pathways, microbicides expert Joe Romano captured the overall sentiment, saying, “The level of efficacy seen in the HPTN052 study is stunning, and is extremely important on several fronts.”

There was good news for India (a Mapping Pathways target country) too: a UNAIDS report stated that the rate of new HIV infections fell by more than 50% in India between 2001 and 2009, double of the average decline in the world. The PrEP debate in India continued through the year. “There is a lot of concern in the country, especially with global funding not available right now,” explains Anjali Gopalan (Executive Director of NAZ India, a Mapping Pathways partner organization), in Notes from India: Concerns and Challenges Around PrEP. Mapping Pathways also published a short post on what we’ve been hearing in India so far.

Soon after the HPTN 052 results, the FACTS 001 trial was announced in South Africa – a follow-up study to confirm the effectiveness of tenofovir and to verify the CAPRISA 004 results in “larger, more diverse populations.”

Around this time, Mark Chataway (co-chairman of Baird’s CMC, a Mapping Pathways partner organization) was in South Africa (a Mapping Pathways target country). “My visit to the country once again brought into sharp focus for me just how significant South Africa and the rest of the southern African region are in the context of HIV treatment and prevention strategies,” writes Mark in his insightful post about South Africa and the HIV epidemic.

July brought bad news: the drought in the Horn of Africa began, bringing the region into international focus as an estimated 11.6 million people struggled for basic nutrition and sanitation in the humanitarian crisis – experts have warned that this situation could have a serious effect on the health of people undergoing HIV treatment.

Prevention trials continued to stay in the news. The Partners PrEP study and the TDF2 Botswana study both showed that taking antiretrovirals can reduce the risk of HIV infection through sexual intercourse by 62-73 percent among heterosexual individuals and heterosexual couples.

As heartening news continued to pour in, the UK’s House of Lords Select Committee on HIV & AIDS gave us another reason to celebrate as they called for greater emphasis and funding toward prevention. “Prevention must be the key policy,” remarked Lord Fowler, chairman of the committee.

In the US, dollars-and-cents issues remained a key factor. “The entire HIV prevention and treatment landscape overall is also in a state of flux in the US … When we get to the end of the day, there are good ideas, and then there are good ideas that are fully funded,” explains Julie Davids (Director of National Advocacy and Mobilization at AIDS Foundation of Chicago, a Mapping Pathways partner organization) in The Economic Effect: HIV/AIDS in the US.

October brought news that rekindled an old debate: the Lancet published the results of a study conducted in Africa, which seemed to suggest that hormonal methods of contraception could lead to increased risk of HIV infection. “Now whether this is a disaster or not, that needs to be considered very carefully in context. There are huge benefits, particularly in the African region, of avoiding an unwanted pregnancy, not only for the morbidity issues but also for mortality reasons … Firstly, we need to work out whether this result is true or not,” points out Dr. Tim Farley (an expert in HIV and sexual and reproductive health) in Hormonal Contraceptives and HIV Prevention: The Grey Area.

Recently, the VOICE trial hit a speed bump: the oral tenofovir arm and the tenofovir vaginal gel arm were dropped from the study. Both decisions were based on reviews of study data, which concluded that they would not be able to demonstrate effectiveness in preventing HIV among the women in the trial (although both products were found to be safe). The reasons for this are still unclear and will be fully investigated when the trial concludes in the middle of 20112. The study continues to examine the oral Truvada tablet to determine whether it’s effective in preventing HIV in the trial population.

A recent highlight was US Secretary of State Hillary Clinton’s speech on HIV/AIDS – one that earned her both bouquets and brickbats from the HIV prevention community. On the upside, Secretary Clinton focused on scientific evidence and called for immediate action to take advantage of the “historic opportunity” to create an “AIDS-free generation.” Unfortunately, she completely omitted any reference to PrEP and rectal microbicides. The speech also failed to mention gay and MSM populations, two groups that are experiencing catastrophic rates of HIV globally.

The year wound up with IRMA’s rectal microbicide African strategy meeting and the big ICASA conference in Addis Ababa, Ethiopia in December. (Click here and here to read about some of the important developments at these events.)

All in all, 2011 has been a dynamic year: lots of excellent news as well as some troubling developments. From the Mapping Pathways blog team, here’s to celebrating our achievements, learning from our failures, and working to address the challenges.

Happy New Year!

[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position.]