Wednesday, November 24, 2010

"I have not cried this hard in years" - Mayer reflects on iPrEx and the future of HIV prevention

HIV Chemoprophylaxis:
New Optimism and New Challenges

by Ken Mayer, Fenway Community Health, IRMA steering committee member

Friday night, on the last leg of a trip from Geneva, heading home to Boston, I started crying, which is not my usual response to reviewing medical literature.

The tear-producing document was shared with the world on Tuesday morning in the New England Journal of Medicine (see IRMA post). It shows that taking a daily antiretroviral pill can protect HIV-uninfected men who have sex with men from becoming infected.

I have not cried this hard in years.

I cannot help but to think about Ira Gold whom I met when I was a medical student in 1975; Ducan Erley, another friend from the Chicago days; Nick Rango, who went on to head the New York State AIDS Program;  Fred Mandel, one of the first men I met in Boston,  whose picture is on my office wall at Fenway Health (one of the sites involved in the new study). Fred is leaning over then-Mayor Ray Flynn so that he glad hand Dr. Everett Koop’s (he was a gregarious human rights lawyer), during one of the first AIDS walks in the mid-1980’s; less than 10 years later, he died a horrible death before he was 40, like the other mentioned friends.

In my reverie, I recall the women and men I have cared for in Providence (the inconsolable sobs of a police chief father with his wasted daughter in his arms, blindness and dementia in a university professor and other nightmares), and the disenfranchised patients receiving world class treatment at YRGCARE, a community-based organization in Chennai, India. 

Along with so many others, they remain constant reminders of the ineffable toll. Too many, too young, and why?  Many years after their passing, and millions of needless deaths later, lots to think about now.

It is always sobering to recall where you were at a key moment in history. I heard that JFK was shot during shop class in 7th grade, and remember the sad weekends after the Challenger disaster and the death of Princess Diana. As the decades increase, so do the memories.

The  results of the iPrEx study, the first trial to prove that a pill can protect against HIV, are now being shared with the world. Over the past few years, data  from primates  that supported the rationale for chemoprophylaxis, plus the increased tolerability of newer anti-HIV medications, and the expectation that developing a highly effective preventive vaccine will take some time, led the National Institutes of Health and the Bill and Melinda Gates Foundation to  support this study in 11 sites, 6 countries and 4 continents. The dedication of almost 2500 participants and the study staff enabled the research team to evaluate this approach among people with enhanced risk for HIV.

Now that the data are public, after having undergone peer review (i.e. a group of researchers who had no association with the work have deemed it worthy of publication in a high profile medical journal), the results are exciting and challenging. The main conclusion is that using pills for prevention works, if people take the medication, in conjunction with a comprehensive package of counseling and other services. 

Before starting the trial, participants had to be educated about risks and benefits, and indicate that they knew what they were doing. The informed consent document that spelled out their rights and risks indicated that they had a 50-50 chance of getting a placebo, and the researchers did not know if the medication would work.  

Using the most rigorous analytical methods, men who were assigned to take the active medication were 43.8% less likely to become HIV-infected, whether they actually adhered to the regimen or not.  Among men who reported taking at least half their pills, the risk of becoming HIV-infected decreased by more than half.  More impressively, if drug was detected in samples from men assigned to take medication, the protective effect exceeded 90%.

The medicine was protective when taken, but many men did not routinely adhere to the regimen. So, what next?

Now that we have proof that oral medication can partially protect against HIV, the first question is whether we can do better?  Will men who are now informed that the medication works become more adherent , since previously the protective effect was only a theoretical possibility? What about women, heterosexual men, people at risk of becoming HIV-infected through unsterile syringes? 

Fortunately, there are multiple studies underway, looking at different populations, dosing strategies, modes of drug delivery. A topical gel containing tenofovir, one of the drugs used in the iPrEx study, was shown to decrease HIV transmission in South African women this summer. This was the first proof in humans that using antiviral medication before exposure to HIV is protective.

Other studies of vaginal and rectal gels are underway, as well as study in African women to see whether a gel or a pill is more protective. Very soon, there will be about 20,000 men and women involved in studies of chemoprophylaxis. 

The short term difference between the approaches is that there is no FDA-approved gel yet, while the medication used in iPrEx is prescribable now.  Some have raised the concern that using the same drugs for treatment as prevention could promote the spread of resistant strains, so other trials are evaluating  different drugs, which might be able to be solely used for chemoprophylaxis.  However, many of the question will take time to answer; the promising data revealed this week are  only part of  a long journey that could take many years.

Most prevention researchers and public health officials hope that the use of antiretroviral drugs for prevention will be a stopgap, which could prevent millions of infections on the road to an effective AIDS vaccine. For antiretroviral chemoprophylaxis to be effective, sufficient drug has to be concentrated in the relevant tissues at the right time. This will present some operational challenges, given that for each of more than 35 million HIV-infected persons, many more are at risk for becoming infected, and the majority of them are unaware when they are being exposed.

Rolling out chemoprophylaxis has the potential to strain underfunded and underdeveloped treatment systems, many have only recently  been strengthened by the U.S. President’s Emergency Fund (PEPFAR), the  multi-donor Global Fund, and other philanthropies.

On the other hand, since chemoprophylaxis involves medications that are familiar to clinicians who treat HIV, and many of their infected patients have uninfected partners or at risk friends, hese  experts should be engaged to help roll out chemoprophylaxis. This begs the issue of who will pay, since even generic antiretroviral medications may be relatively expensive in resource-constrained environments. 

Although  the iPrEx  study found the pill to be safe, long term monitoring will be necessary to anticipate later stage infrequent toxicities. Some of the newest studies underway are trying to establish what is the least amount of pre and post-exposure medication needed to prevent the maximal number of infections. Chemoprophylaxis raises questions of equity of access to preventive health care services, and major donors must think creatively of ways to offer comparable standards of prevention across the globe.

Chemoprophylaxis is a work in progress, and iPrEx suggests that this approach will only be effective if it is part of a comprehensive prevention package that continues to promote condoms and safer sex (some of the men who took more than 50% of their pills still became infected), medication adherence, diagnosis and treatment of other sexually transmitted infections, and ongoing behavioral counseling.

This is clearly not an approach for the general population in most countries, even among those at increased risk. The shorter the duration, the more cost effective PrEP will be. The more comfortable clinicians are in assessing risks and in encouraging HIV testing, antiretroviral drugs will be used most strategically. 

Unfortunately, most of the people living with HIV on this planet are unaware of their infection. Even in the US, several hundred thousand Americans are unaware of their infection and/or not linked into care. Testing and HIV status determination remain the cornerstone of any effective prevention strategy.

Chemoprophylaxis is not a panacea, nor a substitute for providers becoming comfortable assessing sexual and other risk behaviors. Newly diagnosed HIV-infected patients can be offered treatment for their health, and to decrease their infectiousness to others; those at risk who are not infected may benefit from chemoprophylaxis, after careful risk assessment and counseling.

In the wake of a global recession, many donor countries, foundations, and transnational bodies may not be keen to bear the costs of rolling out chemoprophylaxis. More refinements are needed, but  this cannot be a substitution for inaction. HIV-infected people must still have universal access to care. But, the iPrEx results suggest that a pill that is already FDA-approved can help protect people from contracting an incurable infection . 

Maybe It is an upcoming decennial birthday, maybe it is the musings after so much loss, but I hope the world will quickly understand that we have a new tool to arrest the ongoing epidemic, which should not be ignored.

After more than 60 million infections and more than 25 million deaths, it is time for the global community to wrestle with how to use these drugs most expeditiously to prevent unnecessary deaths and new infections.

In the halcyon days of youth, I could not anticipate a global pandemic with its personal and broad-reaching toll, and now, I hope that the chastened World will not ignore new hope.

No one said it would be easy.

[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.]


Sam said...

Thank you, Ken, for this piece and for all your writing and work over the years. These iPrex results are a milestone, and for me as well, they resonate all the way to those first emotional foundations of this work - how do I keep from losing the ones I love and how do I get better options to stay uninfected. We get new answers every decade, and now more is on the horizon. - Sam

Mark S. King said...

What a moving article, and a clear overview of this historic study. This piece taught me, and choked me up!


BostonSarav said...

Thank you Ken for all you do. Tireless researchers and leaders like you make this fight very personal and meaningful.
Sarav Chidambaram

Anonymous said...

You're an inspiration to us all Ken. I am proud and honored to be your staff. God bless you and MABUHAY!

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