Treatment Is Prevention

After results from several trials illustrated the preventive benefits of antiretrovirals, researchers at the annual International AIDS Society conference declare treatment is prevention

By Kristen Jill Kresge

There is no question that antiretroviral (ARV)-based prevention stole the show at the International AIDS Society’s Sixth International Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2011). “I’ve never seen something explode like this,” said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health.

The fervor surrounding ARVs for prevention was fueled by the results of three recent trials, two showing that pre-exposure prophylaxis (PrEP)—the administration of ARVs to uninfected individuals—was 62%-73% effective in reducing HIV transmission, and the third showing that earlier initiation of ARV therapy for HIV-infected individuals results in an overwhelming 96% reduction in HIV transmission. Together, these studies added substantial evidence to support the notion that ARVs may be an effective means by which to curb the spread of HIV. “We are now on solid scientific ground that even without a vaccine or a cure we could turn around the trajectory of the pandemic,” said Fauci. “That’s huge.” The mood in Rome, where more than 5,000 delegates gathered for the conference from July 17-20, was so ebullient that researchers were comparing it to 1996, the year combination ARV therapy was first shown to be an effective strategy for controlling HIV. “Rome is the watershed for treatment as prevention,” said Stefano Vella, a co-chair of IAS 2011.

But as the dust settled in Rome, many researchers and policymakers began asking how PrEP or early treatment will be implemented when funding is tight (see Snapshot of 2010 Funding). “The next steps are trying to figure out how to implement this,” said Fauci. “With the resources we have, we can’t do everything.” Although policymakers will likely face difficult decisions, HIV prevention advocates were happy to be in the position of having new ways to beat back HIV. “These are the challenges we’ve longed for,” said Mitchell Warren, executive director of the HIV prevention advocacy group AVAC. “For many years we’ve been asking what if. Now we’re asking what now.” Stefano Bertozzi, director of HIV and tuberculosis at the Bill & Melinda Gates Foundation, said the question is how to capitalize on these results to try to re-energize funding.

Snapshot of 2010 Funding

Funding for HIV vaccine research and development declined by 1% in 2010 from the previous year and by 11% from its peak in 2007, according to the annual report by the HIV Vaccines and Microbicides Resource Tracking Working Group. The report, which was compiled by IAVI, the HIV prevention advocacy group AVAC, the International Partnership for Microbicides, and the Joint United Nations Programme on HIV/AIDS, was released at the IAS 2011 conference in Rome (www.hivresourcetracking.org). The funding drop is due in part to the expiration of the two-year economic stimulus package that was passed in 2009 by the US Congress and funneled millions of dollars toward large grant-making institutions like the US National Institutes of Health, some of which went to support HIV-related projects.

Funding for HIV vaccine research totaled US$859 million in 2010, with the bulk of the money—$726 million—coming from the public sector, according to the report. Total investments for research and development of other HIV prevention strategies were as follows: microbicides ($247 million), pre-exposure prophylaxis (PrEP; $58.3 million), adult male circumcision ($21.7 million). For the first time, the report also included an estimated annual investment of $19.6 million for treatment as prevention in HIV-infected individuals. In 2010, funders invested $1.19 billion in research and development for preventive HIV vaccines, microbicides, PrEP, and adult male circumcision, which the report’s authors note approached the previous historical high of $1.23 billion reached in 2007 for these four strategies. —RM

Earlier is better

Because effective ARV therapy can suppress HIV replication, in many cases to levels below detection by all but the most sensitive single copy assays, researchers have long speculated that starting HIV-infected individuals on ARVs earlier would likely have the fringe benefit of making them less infectious. This was borne out in several observational studies, and served as the basis for the controversial test and treat strategy that calls for universal HIV testing and immediate treatment for those found to be infected (see Test and Treat on Trial, IAVI Report, July-Aug. 2009). The most outspoken proponent for test and treat was Julio Montaner, former IAS president, who in Rome was recognized by many researchers for his work in this area.

But until the results from a trial known as HPTN052 were released in May showing that earlier ARV treatment reduced HIV transmission by 96% among a cohort of 1,763 serodiscordant couples, there was never a randomized, controlled clinical trial demonstrating the prevention benefits of starting ARVs earlier. “As we put people on treatment we render them less infectious,” said Myron Cohen, principal investigator of HPTN052. “That’s a given now.” Montaner called treatment as prevention a “double hat trick”—ask a Canadian if you’re not sure what that means—and called for it to be implemented immediately.

The US$73 million Phase III trial, conducted at 13 clinical research centers in Africa, Asia, and North and South America, was launched in April 2005, or as the white-haired Cohen joked, back when he was in high school. In May, the study’s independent data safety monitoring board (DSMB) recommended stopping the delayed treatment arm four years ahead of the study’s scheduled completion date based on the overwhelmingly clear benefit of starting treatment earlier. At IAS 2011, several investigators presented for the first time the full analysis of the trial, which was published simultaneously (1).

The early treatment group in HPTN052 started therapy when their CD4+ T-cell counts were between 350 and 500, while treatment was delayed for the other half of HIV-infected individuals until their CD4+ T-cell counts dropped to 250 or they developed an AIDS-defining illness. Of the 39 new infections that occurred during the trial, phylogenetic analysis of the HIV pol sequence or deep pyrosequencing was used to confirm that 29 of the new infections were genetically linked to the infected partner, seven were unlinked, while three are still being classified. Of the 29 linked transmissions, only one occurred in the early treatment group, and Cohen said data suggests this transmission likely occurred before the individual’s viral load was fully suppressed.

Based on an analysis of 28 linked infections (one was confirmed to be linked just before the conference but not included in the published article), 64% occurred when the infected partner’s CD4+ T-cell count was above 350, the point at which current guidelines from the World Health Organization call for treatment to be initiated. Of note were the regional differences in the new infections: 23 of 28 (82%) of the linked transmissions occurred in sub-Saharan Africa, even though couples there accounted for only 54% of the volunteers enrolled in the trial. Mina Hosseinipour, an HPTN052 site investigator, said differences in baseline viral load might contribute to this difference. And, as the study investigators note in the paper, clade C HIV, the dominant type in southern Africa, may have transmission advantages as well. Hosseinipour also noted that there were “markedly different” behavioral characteristics among the African volunteers, with 9% of volunteers at African sites reporting unprotected sex compared to 4% at the Asian/American sites.

Beatriz Grinsztejn, another HPTN052 investigator, reported earlier treatment in the trial was also associated with a 41% reduction in HIV-related clinical events, suggesting earlier treatment has a clinical as well as a prevention benefit. This difference was largely due to the discrepancy in the number of cases of extrapulmonary tuberculosis in the early and delayed treatment arms (three versus 17 cases respectively).

Based on these results, Cohen concluded “this tool should be applied aggressively in the population we studied.” And although he and his colleagues acknowledge that serodiscordant couples may not be representative of the general population, they say that the HPTN052 results support the use of ARVs as a strategy to reduce the spread of HIV.

Even in serodiscordant couples alone, earlier treatment could have an impact, based on mathematical models developed by John Stover of the Futures Institute. Although earlier initiation of ARV therapy would raise treatment costs by an estimated 6%-9%, Stover said it would be a good investment in the long run. The question, he said, is “are we willing to pay the money now to avert having to pay more in the future?” The World Health Organization (WHO) originally planned to release guidelines on studies involving serodiscordant couples at IAS 2011, but delayed the release based on the influx of new data. Now, the WHO hopes guidelines will be available by the end of the year.

Vaccine Update

With all the pomp surrounding antiretroviral-based prevention at IAS 2011, it was easy for other strategies, including vaccine research, to be overshadowed. But at a satellite symposium before the start of the conference, researchers gathered to discuss progress and prospects in HIV vaccine research and development.

Nelson Michael, director of the US Military HIV Research Program, reported that the eagerly anticipated results of the search for immune correlates of protection from the RV144 vaccine trial, the first to show any efficacy, will be released at the AIDS vaccine meeting in September, though he warned that even if correlates are identified, they may not be at all applicable to other vaccine approaches.

Meanwhile, a promising avenue of pre-clinical research has been the isolation of numerous new broadly neutralizing antibodies from chronically HIV-infected individuals (see Research Briefs). But given that researchers don’t yet know how to elicit these antibodies, many are suggesting other approaches must move forward in the meantime. “We’re still at the point where we don’t know how to make neutralizing antibodies and nobody wants to wait until we’re able to do an efficacy trial with neutralizing antibodies,” said Robin Shattock, professor of mucosal infection and immunity at Imperial College, London. “The presumption is that antibody-based vaccines is the way to go without any proof that it’s a correlate,” he added.

Speaking a few days later at a special session to commemorate 30 years of AIDS, Anthony Fauci, director of the US National Institutes of Allergy and Infectious Diseases, said, “an effective vaccine is going to require multiple immunological components.” —KJK

More positive results on PrEP

The other ARV-based prevention strategy to show efficacy is PrEP. Results from two PrEP studies were released the week before the opening of IAS 2011 and researchers scrambled to pull together data to make it available at the conference. The first trial, known as Partners PrEP, showed that a daily dose of tenofovir (TDF) reduced the risk of HIV infection by 62% in a cohort of 4,758 serodiscordant couples in Kenya and Uganda, while a daily dose of Truvada (the single pill combination of TDF and the ARV emtricitabine, or FTC) reduced HIV infection risk by 73%, a difference that was not statistically significant. “Both drugs work to prevent HIV acquisition,” said Jared Baeten, associate professor of global health at the University of Washington who presented the Partners PrEP results. These results spurred the trial’s DSMB to recommend discontinuation of the placebo arm of the trial 18 months before its scheduled end date. The study, which was funded by the Bill & Melinda Gates Foundation, is the largest PrEP study conducted thus far.

The other PrEP results presented at IAS 2011 were from the TDF2 trial, sponsored by BOTUSA, a partnership of the US Centers for Disease Control and Prevention and the government of Botswana. The study showed that a daily dose of Truvada reduced the risk of HIV infection in a cohort of 1,219 sexually active men and women in Botswana by approximately 63%. If individuals who interrupted PrEP at any point during the study were excluded from the analysis, the efficacy reached 78%.

TDF2 was originally planned as a Phase III efficacy trial but was scaled back to an expanded safety study when investigators concluded they would need to double enrollment in the trial due to a lower than expected HIV incidence in the country. Despite this, the TDF2 study did yield statistically significant results.

Although these trials are not the first to show PrEP is effective (results released last year from the iPrEx trial showed that daily Truvada was 44% effective in preventing HIV among nearly 2,500 men and transgendered women who have sex with men), they are the first trials to indicate this strategy is effective in heterosexuals. Earlier this year, doubts were raised about PrEP efficacy in heterosexuals when the Phase III FEM-PrEP trial, involving 1,951 high-risk heterosexual women in Africa, was stopped early because the DSMB concluded that it was highly unlikely the trial would be able to show efficacy given the HIV infections that had occurred so far were equally split between PrEP and placebo recipients. But given the results from TDF2 and Partners PrEP, these concerns were largely alleviated. “There’s little doubt about the power of ARV-based prevention strategies among heterosexuals,” said Michael Thigpen, a TDF2 study investigator.

However, data from the TDF2 trial do suggest there may be a difference in the protective efficacy in men and women. Although Thigpen did note that the study was not powered to determine efficacy by gender, based on the 33 new HIV infections that occurred during the trial, the protective efficacy among men was 80%, while among women it was 49%. For the Partners PrEP study, Baeten said, “Our results are robust for both women and men,” though he didn’t share the breakdown.

The evidence from these two studies were strong enough for Fauci to suggest the FEM-PrEP trial was likely a fluke, but others like Helen Rees, executive director of the Wits Reproductive Health and HIV Institute at the University of the Witwatersrand in Johannesburg, South Africa, were not fully convinced. She suggested that the field wait until the results of the VOICE study—which is testing oral Truvada and TDF, as well as a TDF microbicide gel in 5,029 women in Uganda, South Africa, and Zimbabwe—before any guidelines about PrEP use are crafted. Results from the VOICE study aren’t expected until early 2013.

1. N. Engl. J. Med. 365, 493, 2011