BioWorld Today Contributing Writer

Interim review of a Phase III trial by the National Institute of Allergy and Infectious Diseases (NIAID) showed a striking benefit of the use of antiretroviral therapy for the partners of HIV-infected individuals. An independent data and safety monitoring board (DSMB) released the results ahead of the trial's scheduled 2015 end date because the results were so clear.

"This is the first randomized clinical trial, and therefore strongest evidence possible. There were prior observational studies large ones in the U.S. This confirms what they had indicated," David Burns, chief of the Prevention Research Branch, told BioWorld Today.

A total of 1,763 serodiscordant couples were enrolled in the trial and randomized to either begin antiretroviral therapy immediately, or waited until the disease course progressed to the point that antiretroviral therapy is normally recommended. The trial, designated HPTN 052, documented 28 cases of transmission to the originally HIV-negative partner, and of those, only one occurred in the test group.

At the beginning of the trial, HIV-infected participants had CD4+ T-cell (CD4) levels between 350 and 550 cells per cubic millimeter, and their partners tested negative for the virus. A healthy, uninfected person would have CD4 counts around 750 per cubic millimeter.

HIV-positive participants in the control group began antiretroviral therapy when their counts fell below 250 per cubic millimeter, or when they had an AIDS-related medical event, like Pneumocystis pneumonia.

HIV-positive participants in the test group began antiretroviral therapy immediately. Participants in both groups equally received safe sex counseling, free condoms, regular HIV testing and treatment for sexually transmitted diseases.

The NIAID is offering antiretroviral drugs to all enrolled participants, who will be followed for at least one year.

"It's important to say the study is not stopping at the moment," Sheryl Zwerski, acting director, Prevention Sciences Program for the NIAID, told BioWorld Today.

Since the overwhelming majority of couples (97 percent) were heterosexual, the NIAID said that it could not draw conclusions about the effectiveness of the regimen for couples in which both partners are male.

Is a new study on the horizon to replicate those benefits in the gay male population? Not necessarily, Zwerski said. "It's going to be very difficult given the very strongly positive result to have people not receiving therapy immediately."

The trial was carried out at 13 sites around the world, including Botswana, Brazil, India, Kenya, Malawi, South Africa, Thailand, Zimbabwe and the U.S.

For the 28 cases of transmission between partners, the study used genetic analysis to confirm the origin of the virus. The DSMB concluded that there was a 96 percent reduction in HIV transmission to the uninfected partner.

The analysis also turned up unexpected benefits for the HIV-positive participants. Cases of extrapulmonary tuberculosis were greatly reduced in the immediate treatment arm of the study. Among deferred treatment participants, there were 17 cases of extrapulmonary tuberculosis, while the immediate treatment arm had only three cases. That difference was statistically significant.

There were slightly fewer deaths in the immediate treatment group, but that difference was not statistically significant.

The six-year study faced a number of challenges, including poor enrollment in the U.S., and shifting WHO guidelines for HIV treatment. When the trial began in April 2005, its protocol was consistent with WHO treatment guidelines at the time, which recommended that antiretroviral therapy be given to anyone with advanced disease or whose CD4+ T-cell counts fell below 200.

A series of revisions to the WHO guidelines put HPTN 059's control group out of step with the standard of care. Finally, in November 2009, WHO recommended that antiretroviral therapy be initiated in anyone whose CD4 count fell below 350, regardless of symptoms.

NIAID initially adjusted by changing the protocol so that the criterion for the delayed treatment arm went from less than 200 to between 200 and 250, and raising the entry criteria from between 300 and 500 to between 350 and 550. Those changes retained the integrity of the study design.

However, the 2009 WHO revision was problematic because some of the countries in the study lacked a sufficient drug supply. The study protocol was not changed at that time.

Instead, participants were informed of the WHO recommendation and that they were free to leave the study at any time to begin antiretroviral therapy through their local health system.

Although the trial results would seem to be a slam dunk for drug makers, resulting in a big increase in prescribing and sales of antiretrovirals, the picture is not that clear. U.S. treatment guidelines already call for antiretroviral therapy for anyone whose CD4 counts have fallen below 500, which washes out the distinction made in the study between immediate-treatment and delayed-treatment groups. In the U.S. almost all of those patients would be immediate-treatment based on the established standard of care.

On the other hand, the strength and clarity of the treatment results could well affect conversations between doctors and patients, influencing reluctant patients to initiate treatment, or doctors to work harder to persuade patients to get into treatment.

A bigger factor in the fortunes of manufacturers of antiretroviral therapies may be evolving treatment guidelines that call for ART at CD4 levels above 500. The NIAID is running another trial to sort out the optimal timing for beginning therapy.

The Phase IV trial, called Strategic Timing of Antiretroviral Therapy (START) began in March, and will enroll 4,000 HIV-infected men and women, comparing initiation of therapy at CD4 counts above 500 to waiting until CD4 counts fall below 350.