VOICE Lesson: It's Unfair to be Non-Adherent

This post by IRMA's Jim Pickett first appeared on the blog of the HIV Prevention Justice Alliance.


The VOICE results are extremely important to the field of new prevention technology research. I hope current/future/much-needed discussions about VOICE don’t get drowned out by the HYPE (yes, all caps HYPE) surrounding the “baby cure” story which has dominated coverage out of CROI so far.

If there is one VOICE lesson to focus on, it is adherence. Or in this case, the upsetting lack thereof. It is absolutely important to fully understand why so many of the women in the trial didn’t apply the gel, or take the pill. And it is critically important for scientists to develop things people actually WANT to use, and DESIRE. Perhaps a daily gel, or a daily pill, is simply not desirable for a lot of folks. Makes sense to me.

But here’s the rub. The field can’t move forward with product development when people don’t actually test-drive the product being investigated. Products can’t be improved without data from people who actually used the product. Sure, a daily gel or a daily pill may not be everyone’s idea of a good time… but the only way those ideas get translated from the clunky Model T Ford to a slick 2013 BMW is through a long, iterative process. Which requires trial participants to APPLY THE GEL and/or TAKE THE PILL.

I get that people join trials for all kinds of reasons, and that for many; it is their only access to healthcare. So, they may have no interest in actually participating in test driving anything, but are very excited about regular HIV and STD screening, counseling, access to condoms and lube, referrals to other services, etc. Can’t be mad at them for wanting those things. Right?

It’s a crime, really, or at the very least an outrage, that clinical trials end up being the only healthcare access point for too many folks. That needs to be addressed, on its own.

But…we simply can’t afford enrolling thousands of people into complicated and costly clinical trials to have them just forgo what they SIGNED UP to do. Let’s be brutally honest here, joining a trial to get health screenings and condoms is great for the individual – but it does NADA, NOTHING, NOOTCH for the community/communities fighting HIV who are desperate for new tools to prevent HIV.

Being in a clinical trial is a commitment to following the protocol as best as possible, and being honest when unable. Clinical trial participation necessitates a strong sense of altruism, a desire to help answer big questions for whole populations. I think it is unfair to everyone, especially highly impacted communities where HIV rates are soaring, and where the crisis is anything but over, for trial participants to sign informed consents and derive individual benefits from trials without fully engaging in the study protocols that would allow for potential population benefits.

There are not unlimited resources. In fact, they are shrinking (Hello Sequester!) We can’t continue to fund expensive, resource-intensive, multi-year trials in which most people only SAY they test drove the product.

Jim Pickett is the Chair of the International Rectal Microbicide Advocates (IRMA). This blogpost is part of our ongoing coverage of the 2013 Conference on Retroviruses & Opportunistic Infections (CROI). To read more perspective and analysis on the VOICE results at CROI, click here.

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  *Join IRMA's robust, highly-active. moderated, global listserv addressing rectal microbicide research and advocacy as well as other interesting new HIV prevention technologies by contacting us at rectalmicro@gmail.com. Joining our listserv automatically makes you a member of IRMA - a network of more than 1,100 advocates, scientists, policy makers and funders from all over the world.

*Please look for us on Facebook: www.facebook.com/InternationalRectalMicrobicideAdvocates, and you can follow us on Twitter: @rectalmicro.

*Also, please note that shared news items from other sources posted on this blog do not necessarily mean IRMA has taken any position on the article's content.

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IRMA Statement on VOICE Results

[Click here for the VOICE press release - "Daily HIV Prevention Approaches Didn’t Work for African Women in the VOICE Study" - from the Microbcide Trials Network]


IRMA, like the rest of new prevention technology researchers and advocates, is disappointed to learn that daily oral Truvada was not found to be an effective HIV intervention among the African women at risk for HIV who participated in the VOICE trial.

We applaud the efforts of the 5,029 women from South Africa, Zimbabwe, and Uganda who volunteered to participate in the VOICE trial. We also commend the Microbicide Trials Network and the National Institutes of Health for successfully executing this extraordinarily ambitious, important trial, and for contributing critical new information to the field.

Today at CROI 2013 we learned that the majority of women in the daily oral Truvada arm of VOICE were not taking their drugs regularly if at all. Rather than a biological explanation, it appears daily oral Truvada was not effective at preventing HIV among the women in the VOICE trial because the drug was not used regularly.

The results of VOICE indicate low adherence to all the drugs/regimens tested in the trial. There was also low adherence in the daily oral tenofovir and daily tenofovir gel arms. Both these arms were closed due to futility in late 2011 after separate reviews by the independent Data Safety and Monitoring Board. VOICE’s daily oral Truvada arm remained open until August 2012.

One of the biggest challenges the field faces is that of adherence. Clinical trials cannot show that a drug works to prevent HIV if trial participants do not take the drug. More must be done to accurately assess adherence during clinical trials in “real time”, and more must be done to develop HIV prevention interventions that people actually want to use, and like to use. But, we won’t be able to refine the drugs, the drug dosing strategies, and/or the drug delivery vehicles to make them more acceptable if trial participants are not adherent along the way.

Science is an iterative process. We are in the “car phone” phase of new prevention technologies - some of the drugs and dosing strategies are perhaps a little clunky. We all want to get to the “i-Phone” phase where we have interventions that are highly acceptable, and desired, but we won’t get there without going through the clunky phase first.

As the field moves forward, issues of recruitment are as important as adherence. Identifying potential trial participants who are most likely to be adherent during the trial is absolutely critical – and very challenging, as the way to achieve this is admittedly not clear.

The MTN-017 trial, a Phase II safety and acceptability study testing a reduced glycerin formulation of tenofovir gel, is getting ready to launch in the coming months. The study will enroll 186 gay men and transgender women at sites in Thailand, South Africa, Peru, and the United States, including Puerto Rico. It will be absolutely essential that MTN-017 volunteers take the study drugs as directed. If adherence is low during this trial, adequate amounts of safety data will not be collected, making it likely that efforts to develop tenofovir gel as a rectal microbicide will be halted permanently. Have no doubt, this would be a huge setback for rectal microbicide research, development, and advocacy efforts in general.

IRMA is very supportive of MTN-017’s inclusion of “real time” monitoring to assess adherence throughout the trial. This will allow investigators to understand and address challenges regarding adherence while the trial is underway, and will help participants make appropriate adjustments in “real time” to improve adherence outcomes. MTN-017 sites should also pay extra special attention to recruitment activities and work to engage and enroll individuals who are most likely to fully participate in the trial, and follow the various regimens being tested as directed.

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*Join IRMA's robust, highly-active. moderated, global listserv addressing rectal microbicide research and advocacy as well as other interesting new HIV prevention technologies by contacting us at rectalmicro@gmail.com. Joining our listserv automatically makes you a member of IRMA - a network of more than 1,100 advocates, scientists, policy makers and funders from all over the world.

*Please look for us on Facebook: www.facebook.com/InternationalRectalMicrobicideAdvocates, and you can follow us on Twitter: @rectalmicro.

*Also, please note that shared news items from other sources posted on this blog do not necessarily mean IRMA has taken any position on the article's content.

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Antiretroviral Prophylaxis for HIV Prevention Reaches a Key Milestone

via Lancet.com, by Salim S Abdool Karim  and Quarraisha Abdool Karim

On May 10, 2012, a US Food and Drug Administration (FDA) advisory committee voted in support of the use of tenofovir-emtricitabine for HIV prevention.1 If the FDA, which is scheduled to make its decision by June 15, adopts the committee's recommendations, tenofovir-emtricitabine will become the first antiretroviral drug to be approved as pre-exposure prophylaxis (PrEP) for the prevention of HIV, paving the way for implementation.

PrEP has a unique advantage in young women in southern Africa, who bear a disproportionate burden of the HIV epidemic. In much of this region, young women are often unable to convince their male partners to use condoms, remain faithful, or have an HIV test. To rely on her HIV- positive discordant male partner to come forward to test, to agree to take antiretroviral therapy (ART), and to take his ART with high adherence, all for her protection, puts a woman's risk of acquiring HIV back in the hands of men, thereby disempowering women and undermining their efforts to control their risk of HIV.

However, there are several criticisms and concerns about PrEP. First, that data on the effectiveness of PrEP, especially in women, are inconsistent. This concern is based on the results of two PrEP studies—the FEM-PrEP2 and VOICE3, 4 trials—which were stopped, at least partly, earlier than planned when they did not show efficacy. To some extent, this concern has been allayed by recent data from the FEM-PrEP trial5 which show that adherence to daily tenofovir-emtricitabine in the trial was too low allow assessment of efficacy. Data to explain the VOICE trial, which still has an ongoing tenofovir-emtricitabine group, are not expected until 2013.

Second, some suggest that antiretroviral drugs should be provided to HIV-negative people only when all eligible HIV-positive patients are receiving ART. Although it is a legitimate concern that eligible HIV-positive patients should be prioritised for ART for their own health and to save their lives, it is spurious to trade off treatment and prevention as if these drugs are being taken away from sick and dying patients to be given to healthy people. Treatment and prevention strategies are a continuum in their use of antiretroviral drugs—both are needed in conjunction with each other to ensure ART provision is sustainable in the long term and to realise the quest to end the HIV epidemic.

Read the Rest.


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*Join IRMA's robust, highly-active. moderated, global listserv addressing rectal microbicide research and advocacy as well as other interesting new HIV prevention technologies by contacting us at rectalmicro@gmail.com. Joining our listserv automatically makes you a member of IRMA - a network of more than 1,100 advocates, scientists, policy makers and funders from all over the world.
 
*Also, please note that shared news items from other sources posted on this blog do not necessarily mean IRMA has taken any position on the article's content.
 
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An Interview with Professor Salim Abdool Karim about VOICE Trial Setbacks

viaAllAfrica, interview with Professor Salim Abdool Karim

Professor Salim Abdool Karim, director of the Centre for the AIDS Program of Research in South Africa (Caprisa) at the University of KwaZulu-Natal and Columbia University in the United States, spoke to AllAfrica's Julie Frederikse about the unexpected halt of a study into tenofovir vaginal gel. This followed a finding that the microbicide failed to prevent HIV transmission, in contrast to the positive result in a previous study conducted by his Caprisa team.

What happened when you heard the findings of the new study that contradicted your results?

We were surprised and very disappointed. We know that science doesn't always give you the answers you want and hope for, but when you look at the totality of the evidence, we know that there's still pretty strong evidence, whether from the laboratory or in monkeys or in humans, that tenofovir gel is effective in preventing HIV. This is rationale for why the Caprisa and Voice (Vaginal and Oral Interventions to Control the Epidemic) studies were conducted in the first instance. So now we need to understand why the Voice trial produced a different result.

Is this a big setback to Caprisa's research?

The Voice trial is an important result. We now need to understand it. It doesn't take us completely off track - it's a temporary setback - and understanding this result would put us in a better position to move forward again. Science grows not only from success, it also grows from failure.

Has the suspension of this study demoralised your team?

That's the nature of science. In a series of studies, it is seldom that every study shows the same thing. But we'll stay on track, and try and understand why the Voice result is different. Whether the women in the study were not using the gel correctly, or there were other underlying problems, we don't know yet. It's too early to tell.

Read the rest.


[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article's content, whether in support or in opposition.]

No time to give up on microbicides

via allAfrica.com, by Julie Frederikse

Africans tracking the worldwide HIV epidemic have not found much to celebrate since Aids began ravaging the continent 30 years ago, but researchers are optimistic that they are learning as much from their failures as their successes.

Sub-Saharan Africa still carries the biggest burden of HIV worldwide, and while there has been a significant improvement in access to antiretroviral treatment in recent years, scientists searching for a gel or vaccine that can prevent HIV infection ride a rollercoaster of hope and disappointment.

Take the case of a husband and wife team from the University of KwaZulu-Natal in South Africa. Professors Salim Karim and Quarraisha Abdool Karim head up a research unit that has been at the forefront of clinical trials to find a safe and effective microbicide to protect women from HIV.

In July 2010, delegates at the last World Aids conference gave the couple a standing ovation when they announced the results of one of the most promising studies on HIV prevention to date. Their team at the Centre for the Aids Program of Research in South Africa (Caprisa), showed that a vaginal gel called tenofovir was able to reduce sexual transmission of the virus by 39 percent overall and 54 percent in women who used it consistently.
But the euphoria over this breakthrough has dissolved into disappointment, with the unexpected finding of a wider sub-Saharan African study that the microbicidal gel, when prescribed daily, does not prevent HIV infections. This has led to the suspension of tenofovir in the Vaginal and Oral Interventions to Control the Epidemic (Voice) trial.

Read the rest.


[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article's content, whether in support or in opposition.]

IRMA Statement on Discontinuation of Gel Arm in VOICE Prevention Trial

25 November, 2011
IRMA Expresses Disappointment; Calls for MTN 017 to Move Forward

International Rectal Microbicide Advocates (IRMA) expresses disappointment regarding today’s announcement that the vaginal tenofovir gel arm in the Microbicide Trial Network’s (MTN) VOICE trial is being discontinued. VOICE has been exploring two ARV-based HIV prevention approaches since it began enrolling women in high incidence areas in South Africa, Uganda and Zimbabwe in 2009.

The MTN announced that the VOICE arm studying daily vaginal application of tenofovir gel was stopping after a regular review of study data conducted by the independent Data Safety Monitoring Board revealed that the gel, while safe, was not effective at preventing HIV infection in women . Less than two months ago, VOICE announced the discontinuation of its study arm testing tenofovir tablets because they also were shown to not be effective at preventing HIV in the trial. VOICE will continue to study the safety and efficacy of Truvada tablets.

“This is tough news to hear, so soon after the tenofovir tablet arm stopped, and we are certainly disappointed,” said Jim Pickett, IRMA chair. “The field has placed a great deal of hope – and resources – in the development of vaginal tenofovir gel and no one is happy about such an outcome.”

The scientific path is a long, challenging and often confounding one. While this wasn’t information anyone wanted to hear, we will learn much about why tenofovir gel did not work in this well-conducted trial. At the moment we do not know whether this was a matter of adherence, biology, or sexual behaviors – or a combination of all three.

“Too often heterosexual transmission is presumed, by default, to be through unprotected vaginal intercourse. It will be interesting to learn how much anal intercourse was being reported in the trial. Unprotected anal intercourse is 10 to 20 times more likely to result in HIV transmission compared to unprotected vaginal intercourse. If even a small portion of VOIC E participants were practicing unprotected anal intercourse, this may have confounded the efficacy of the vaginal gel being tested,” said Pickett.

It is critical that the planned MTN 017 Phase II rectal microbicide trial moves forward. MTN 017 will study a modified formulation of tenofovir gel, to be applied rectally among gay men and other men who have sex with men (MSM) in Thailand, South Africa, Peru and the United States with a proposed launch in mid-2012. While moving forward with MTN 017 is dependent on the MTN 007 study which tested rectal safety and acceptability of this gel, we expect results soon. If the results indicate this modified formulation of tenofovir gel is both safe and acceptable when used rectally, MTN 017 must happen.

“Gay men and other MSM suffer very high prevalence rates in every part of the world, and their primary exposure is from unprotected anal intercourse. It is therefore an imperative we study products for rectal use. The rectum is a more fragile environment than the vagina and has other characteristics that increase the chances for HIV infection to take hold,” said Pickett. “As anal intercourse is a human behavior not confined to gay men and other MSM – we all have rectums after all– developing safe, effective, acceptable and accessible rectal microbicides will be important to the health and well-being of millions of women and men in Africa and throughout the world.”

IRMA is pleased the FACTS 001 study, a Phase III trial in South Africa testing the same regimen of tenofovir gel used in CAPRISA 004, plans to continue. IRMA is also excited about the upcoming Phase III trial testing a vaginal ring containing the ARV dapivirine. Delivery methods such as vaginal rings may improve adherence and drug availability.

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IRMA (www.rectalmicrobicides.org), a project of AIDS Foundation of Chicago (www.aidschicago.org) is a global network of advocates, researchers, policy makers and funders committed to the research and development of safe, effective, acceptable and accessible rectal microbicides for all that need them.

[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article's content, whether in support or in opposition.]