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HIV Treatment as Prevention: Can Acute Infections Shake Our Faith?

October 8, 2015

Treatment as prevention (TasP) has become a bedrock concept in the quest to eradicate HIV. TasP is the theory that treating infected patients to achieve viral suppression is one of the best ways to prevent new infections. It is now widely accepted as gospel among HIV practitioners, says Myron Cohen, M.D., professor of medicine, microbiology and immunology, as well as epidemiology chief at the University of North Carolina.

Speaking at IDWeek 2015 in San Diego on Oct. 8, Cohen joked about the "religion" of TasP. But he asked the audience, "How did we get to this belief?" and wondered, "Is there anything that could shake our faith?"

Simply put, it is important to know whether TasP works as well as many experts believe it does. The concept is now a vital component of United Nation's "90-90-90" plan to eliminate HIV: The UN set a bold target that by the year 2020, 90% of patients will know their status, 90% will be on treatment and 90% will have achieved virological suppression.

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According to Cohen, there are two main pillars supporting faith in TasP. The first comes from observational studies. Of the 14 relevant studies, 12 supported the idea of treatment as prevention. These 12 studies showed that among couples having unprotected sex, an HIV-infected partner on successful antiretroviral therapy (ART) was unlikely to pass the virus to an HIV-uninfected partner.

The second pillar is randomized clinical trial data. In 1999, Cohen and his colleagues embarked on a clinical trial -- HPTN 052 -- in what would become a 14-year endeavor. Ultimately, this study would show a 96% reduction in HIV transmission among couples in which the positive partner was assigned early ART -- a breakthrough finding.

Yet, there were significant challenges along the way. HPTN 052 recruited mixed-status couples to evaluate the likelihood that an HIV-infected partner treated with ART would pass the virus to an uninfected partner during unprotected sex. But what about infidelity? Researchers had to be sure that any new case of HIV in a previously uninfected person was "linked" to his or her HIV-infected partner. Identifying linked cases required an analysis of the viral strain.

In addition, clinical guidelines around favored ART regimens change quickly and change often. Sure enough, U.S. HIV treatment guidelines changed during the trial, but the rigidity of a trial doesn't allow much flexibility to suddenly switch patients to a new care standard. This challenge, called equipoise, poses a significant risk to the integrity of any trial, but especially a long-term marathon such as HPTN 052. For example, in HPTN 052 patients were given either "immediate" ART or "delayed" ART, but medical consensus on the proper CD4+ count at which to start delayed treatment kept changing.

Despite these challenges, Cohen and his team released preliminary results in 2011, and these results were picked as Science's "breakthrough of the year." Out of the 1,763 couples enrolled in the trial around the world, there were 39 new infections. Of those, 11 were unlinked, meaning that the HIV-uninfected partner contracted the virus from someone other than his or her partner.

Patients were followed for another two years, and by the end of the study 70% of the couples who had originally enrolled were still involved. Among patients who received ART immediately upon diagnosis, there were only three linked transmissions. Among patients who received delayed ART, there were 43 linked transmissions.

Cohen pointed out that four infections were diagnosed soon after the infected partner started ART, meaning that the transmission likely happened either before treatment started or soon afterward. This raises an important question for the medical community: Experts still don't know exactly how many days a person needs to be on ART before the drugs start blocking transmission.

Regardless, the HPTN 052 study data created the second pillar supporting TasP. "This became the belief that this was the end of AIDS; it supports the 90-90-90 idea," Cohen said. "This is good. But now I need to be the voice of reason."

According to Cohen, HPTN 052 still left behind two major obstacles for TasP. The first obstacle -- when to start treatment -- was soundly resolved by the landmark START and TEMPRANO studies. Today, revised World Health Organization guidelines reflect the consensus that ART should be given to all newly diagnosed patients, not only those with a certain CD4+ count threshold.

The second obstacle -- acute infections -- remains hotly debated, Cohen said. When people are first infected with HIV, their viral levels spike within the first few weeks before tapering off to a "set point." In men who have sex with men, 20% to 50% of new cases of HIV are contracted from someone with acute infection. The risk of transmission during these early days of infection is greatly increased, Cohen said.

Cohen believes that acute infection is extremely important, and might require a different treatment approach. However, other groups have published editorials directly refuting Cohen's hypothesis. This debate will only be resolved with large clinical studies, and four such studies are ongoing today, Cohen said. These include HPTN071, CDC Botswana, ANRS Africa Center and SEARCH Uganda.

Ultimately, the UN's 90-90-90 plan is very well grounded in observational studies and large, randomized trials, Cohen said. Still, the next question to tackle is the significance of acute infections.

"We don't know how much damage we're doing by missing acute infection -- a little bit of damage or a lot of damage?" Cohen said. The solution, he said, lies in empirical results.

Sony Salzman is a freelance journalist reporting on health care and medicine, who has won awards in both narrative writing and radio journalism. Follow Salzman on Twitter: @sonysalz.





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