Debate over Treatment for Prevention Continues

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The ongoing debate about whether to start antiretroviral therapy with a CD4 cell count above 500 cells/mm3 for HIV positive people, as well as the widespread use of treatment for prevention in HIV negative people, has been inflamed by results from the HPTN 052 trial.

HPTN 052 was a randomized controlled trial looking at the effectiveness of antiretroviral drugs to prevent HIV transmission within serodiscordant couples. HIV positive partners in one group received treatment immediately regardless of CD4 cell level, while the other group deferred treatment until their CD4 count reached 250.

Out of 39 previously uninfected individuals who tested positive during the study, 29 infections were linked to a stable positive partner. Of these infections, 27 occurred in the group that waited to start antiretroviral treatment. This study -- the first randomized controlled trial to look at HIV transmission within serodiscordant heterosexual couples --confirmed several observational studies that reached similar conclusions. It is still not definitively known whether the same reduction in transmission would be seen in gay men or bisexuals, as these populations were not studied in HPTN 052.

One dispute surrounds the individual benefits and risks of treatment versus the public health advantage of reducing HIV transmission in the wider community. Community-based organizations, provider groups, the National Institute of Allergy and Infectious Diseases (NIAID), and the AIDS blogosphere have all weighed in on the discussion, but it is still unclear how best to use antiretroviral drugs for early treatment or prevention.

Proponents of early therapy have used evidence from HPTN 052 to urge prompt treatment regardless of CD4 cell count, before the evidence of risks and benefits for treated individuals is definitive. Some have even suggested placing HIV negative long-term partners on antiretroviral medications for pre-exposure prophylaxis, or PrEP.

Opponents have expressed concern about casting such a wide net when antiretroviral drugs are not universally accessible for HIV positive people. They also worry about long-term toxicities and are concerned that drug resistance could develop if seroconversion occurs in a person taking antiretrovirals for prevention.

The individual benefit of early HIV treatment is still unclear, and there is not consensus even among national and international guideline panels that weigh evidence and expert opinion. The U.S. DHHS guidelines recommend starting treatment at 500 cells/mm3 (though half the panel members favor starting above this level), while World Health Organization (WHO) recommendations advise beginning treatment at 350 cells/mm3. Guidelines panels also do not agree on the strength of the available evidence, illustrating the need for further randomized clinical trials to clear up the debate once and for all.

The START trial -- conducted by the INSIGHT Clinical Trials Network and funded by NIAID -- is the best case for waiting to find out how harmful or beneficial early treatment would be. The goal of this large trial is to determine whether asymptomatic individuals who start treatment above 500 cells/mm3 would have less chance of developing AIDS or other serious illness compared to those who defer ART until their CD4 count is 350 cells/mm3.

The trial, which is currently enrolling and will not be completed until 2015, has butted up against the HPTN 052 results, which have excited public health experts and led some to propose very early treatment as one route to end the epidemic. Some now feel it is more important to promptly initiate treatment-as-prevention programs for everyone who tests HIV positive, rather than waiting until the START trial is completed and gives more definitive data.

The START study released a memo to investigators this past May explaining that the trial would address a different population, and also ask a different question, than HPTN 052. START participants enroll with a baseline CD4 count above 500 cells/mm3.

The trial is not designed to collect data about the partners of participants, including their HIV status. The critical difference is that the primary goal of START is to look at the health of the enrolled positive participants themselves, asking whether HIV-infected people with CD4 counts above 500 cells/mm3 will ultimately benefit from earlier initiation of treatment.

"We believe that the findings from HPTN 052 underscore the need and relevance of the START study. If the use of ART is to be promoted to prevent HIV transmission, it is critical to reliably assess the impact of initiation of ART on the individual HIV-infected person," the trial organizers wrote. "START will quantify the benefits and risks of early treatment initiation and provide important data on serious AIDS and non-AIDS morbidity and mortality, including drug toxicity and drug resistance. START will provide clearer guidance to clinicians and HIV- infected persons regarding the timing of ART initiation."

Everyone agrees that widespread antiretroviral treatment will help control a stalled AIDS epidemic. But as a person living on HIV medications for almost 20 years, I remain concerned about the unknowns of starting treatment early for HIV positive people. While I have been fortunate to have few side effects with my own treatment, many people have low tolerance for these effects, leading them to switch to less effective regimens. Also, in a world of great inequity, the very real issue of treatment access cannot be dismissed.

I am concerned about offering treatment too early without more definitive information about health outcomes from randomized clinical trials. I worry that for the sake of the larger community, people with HIV may suffer and not get real benefit from early treatment, and some may actually be harmed. I worry that people will be coerced to start treatment or made to feel guilty unless they do so. I worry that doctors may offer their patients incomplete information about starting treatment without evidence from randomized trials. And until antiretroviral treatment is universally available for HIV positive people globally, discussion of such widespread use of these drugs before resources are committed can be problematic.

People starting treatment should have autonomy in any healthcare decision. With less vocal HIV/AIDS advocates today, the concerns of people living with HIV are often outweighed by fears of an exploding epidemic from the public health machine. The debate continues regarding which approach is most ethical; until we have more definitive answers from trials like START, the debate will continue.

7/15/11