Can Treatment End AIDS?

Results of a Phase III trial show earlier treatment reduces HIV transmission in serodiscordant couples by an astounding 96%, leading some to ask whether this is a way to end AIDS

By Regina McEnery and Kristen Jill Kresge

Recent results from a large, international efficacy trial linking earlier initiation of antiretroviral (ARV) therapy with sharp drops in HIV transmission have provoked discussion of the role ARVs might play in curbing, or even eliminating, the AIDS pandemic.

The new findings, which come from the Phase III HPTN052 trial, show that earlier initiation of ARV treatment reduced the risk of HIV transmission by 96% in a cohort of 1,763 serodiscordant couples enrolled at 13 clinical trial sites on four continents (see HPTN052 in Detail, below). This finding was so convincing that the trial’s independent Data and Safety Monitoring Board recommended the study, which started in April 2005, stop several years ahead of its scheduled end date in 2015.

Because viral load is considered the principal predictor of HIV transmission risk, clinicians and researchers have suspected for years that HIV transmission rates would be dramatically lower when HIV-infected individuals are taking ARVs that effectively suppress their viral loads. But HPTN052 is the first randomized, controlled clinical trial to investigate whether earlier initiation of ARVs actually reduces the risk of heterosexual transmission of HIV.

Additionally, the HPTN052 study showed that individuals who started treatment earlier also had a lower incidence of extrapulmonary tuberculosis (a statistically significant difference compared to those in the delayed treatment group), slightly fewer deaths (though not statistically significant), and a remarkably high level of adherence to the daily treatment, which consisted of a combination of three or four ARVs from a formulary of 11 drugs.

These findings sent ripples through the HIV prevention community, inspiring many activists and advocates to argue for earlier treatment of HIV-infected individuals, not only because of its benefits to the HIV-infected person that have been widely recognized among clinicians, but because it could also substantially reduce HIV transmission rates. An open letter was circulated by New York City-based advocacy groups AVAC and the Treatment Action Group with the title “We CAN End the AIDS Epidemic.” The letter, which to date has been signed by more than 330 scientists and activists, urged funders to allocate future HIV prevention dollars toward evidence-based strategies, with ARVs as a cornerstone of this effort. The letter said every person living with a CD4+ T-cell count less than 500 cells/µl who is not offered ARV treatment is a missed opportunity to avert AIDS-defining illnesses and to prevent new infections.

The HPTN052 findings also reignited discussion of the test-and-treat strategy, which calls for universal HIV testing and immediate treatment of all HIV-infected individuals as a way to control the virus’ spread. This strategy was initially promulgated by researchers at the World Health Organization (WHO), who published results from a mathematical model in 2009 that suggested test and treat could end the AIDS pandemic (see Test and Treat on Trial, IAVI Report, July-Aug. 2009). The feasibility of this approach is now being assessed in a pilot study, funded by the US National Institute of Allergy and Infectious Diseases (NIAID), in New York City and Washington, D.C. 

HPTN052 in Detail

In the Phase III HPTN052 study, 1,763 serodiscordant couples were randomized to an early treatment arm, in which HIV-infected partners began antiretroviral (ARV) therapy immediately, or a delayed treatment arm, in which therapy was initiated once their CD4+ T-cell counts dropped below 250 cells per µl of blood or they developed an AIDS-related illness. All infected partners had to have CD4+ T-cell counts between 350 and 550 up to 60 days post-enrollment. The median CD4+ T-cell count of the infected partners was 436 cells/µl at time of enrollment. Below are some additional details about the trial. Background: 97% of the couples were heterosexual. The infections at baseline were evenly split between men and women. The study’s original “deferred treatment” threshold was changed from a CD4 count of 200 to 250 to reflect the recommendation made by the World Health Organization (WHO), which altered its treatment guidelines in 2006. However, the study protocol was not changed in 2009 when the WHO guidelines were revised again, recommending treatment be initiated at 350 CD4+ T cells, because the amended guidelines were not immediately adopted by all of the countries participating in the study, primarily due to lack of drugs. The study was conducted at 13 clinical trial centers in Botswana, Brazil, India, Kenya, Malawi, South Africa, the US, Thailand, and Zimbabwe. The US National Institute of Allergy and Infectious Diseases largely funded the US$73 million trial. Results: 39 new HIV infections occurred through April 28, 2011, when the trial’s independent data and safety monitoring board reviewed the data. Of these, 27 occurred in the delayed treatment arm, and one occurred in the immediate treatment arm. 17 of the 27 infections in the delayed treatment arm occurred when the index partner’s CD4+ T-cell count was greater than 350. There were seven unlinked infections that couldn’t be genetically traced to the infected partner—four in the delayed treatment arm, three in the immediate treatment arm. Samples from another four individuals who were newly infected are still being analyzed. The median viral load for transmitting partners at the visit prior to seroconversion was 4.91 log copies of viral RNA/ml blood. There were 105 morbidity and mortality events—65 in delayed treatment arm and 40 in immediate treatment arm, which was not a statistically significant difference.

There were 20 cases of extrapulmonary tuberculosis—17 in delayed treatment arm and 3 in immediate treatment arm, which was a statistically significant difference.

There were 23 deaths—13 in delayed treatment arm, 10 in immediate treatment arm, which was not a statistically significant difference.
 

Myron Cohen, a researcher from the University of North Carolina who led the HPTN052 study, acknowledged the complex questions the study results have raised for public health authorities when he presented a keynote address at the New York Academy of Science’s May 16 symposium “Cracking the Safe: Advances in HIV/AIDS Prevention and Treatment,” several days after the results were announced. “We don’t claim we will treat our way out of the epidemic,” said Cohen. “But the horse is out of the barn. There is now a big wind behind this strategy, and the public health use of this strategy carries some real challenges. We need to handle the tool responsibly.”

One important caveat underscored by Cohen is how difficult it is in a real-world setting to identify individuals with acute HIV infections—the period of a few months immediately after seroconversion when the likelihood of HIV transmission is greatest. “It is impossible to find them all,” said Cohen. And even when HIV-infected individuals are discovered earlier, Cohen noted that it is sometimes challenging to get them into treatment programs, even in the US. This means that the actual reduction in HIV transmission rates at the population level would likely be lower than what was observed in HPTN052.

Anthony Fauci, director of NIAID, described HPTN052 as a “slam-dunk study” during a June 9 panel discussion held in conjunction with the United Nations’ (UN) 2011 High Level Meeting on AIDS in New York City. But at a time of increasingly constrained resources, is there enough money to consider earlier treatment of HIV? Fauci said the added expense of earlier treatment would still likely be cheaper over the long run. “Either you are going to pay a lot now or an awful lot later on.”

According to estimates from the Joint United Nations Programme on HIV/AIDS (UNAIDS), only about a third of the 15 million people who are eligible to receive antiretroviral therapy in developing countries are currently receiving it, based on current guidelines that call for treating HIV-infected individuals when their CD4 counts dip to 350. UNAIDS also noted that overall AIDS spending in low- and middle-income countries has been flat since 2008, at around US$16 billion.

The US government is discussing the implications of HPTN052 with its partners in the countries now receiving foreign aid through the President’s Emergency Program for AIDS Relief (a $32 billion initiative in 30 countries), and the Global Fund to Fight AIDS, Malaria and Tuberculosis.

Meanwhile, the WHO, which raised the minimum threshold for initiation of treatment two years ago—it went from 200 to 350 CD4+ T cells—is poised to issue new guidelines in July that are specifically aimed at preventing HIV transmission among serodiscordant couples. While the guidelines have been in the works for a while, the findings from HPTN052 could put pressure on the WHO to call for all HIV-infected partners in serodiscordant couples with CD4+ T-cell counts between 350 and 500 to qualify for treatment as a way of curbing HIV transmission within this population.

“This breakthrough is a serious game-changer and will drive the prevention revolution forward,” said Michel Sidibé, executive director of UNAIDS, in a statement following release of the HPTN052 study results. “Now we need to make sure that couples have the option to choose treatment for prevention and have access to it.”

Julio Montaner, former president of the International AIDS Society, who has been studying whether earlier treatment helps lower community viral load and HIV incidence in Vancouver, British Columbia, said the HPTN052 study “ends the argument” over whether early ARV treatment should be offered to serodiscordant couples.

“We’ve been steadily moving in this direction and the 052 study was the cherry on the top,” said Montaner, adding that he hopes the WHO guidelines will be clear and inclusive. “The most draconian approach, I feel, would be to leave treatment preferentially to married couples who are serodiscordant. I would say it should be liberally offered to anyone who is HIV infected and who is sexually active.”