Antiretrovirals Protect Partners of HIV-Infected Patients

Treating HIV-infected People with Antiretrovirals Protects Partners from Infection. Findings Result from NIH-funded International Study

Large-scale clinical study (phase 3 clinical trial) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The clinical trial, known as HPTN 052, was slated to end in 2015 but the findings are being released early as the result of a scheduled interim review of the study data by an independent data and safety monitoring board (DSMB).

The DSMB concluded that it was clear that use of antiretrovirals by HIV-infected individuals with relatively healthier immune systems substantially reduced transmission to their partners.

The results are the first from a major randomized clinical trial to indicate that treating an HIV-infected individual can reduce the risk of sexual transmission of HIV to an uninfected partner.

HPTN 052 Study

Study Objective:

Primary goal: To evaluate whether ARV use by the HIV-infected individual reduced HIV transmission to the uninfected partner and potentially benefited the HIV-infected individual as well.

Secondary goal: To evaluate the optimal time for a person infected with HIV to initiate antiretrovirals in order to reduce HIV-related sickness and death.

Study Period: Began in April 2005; run until 2015

Number of subjects: Enrolled 1,763 couples

Study Population:

1. All at least 18 years of age.
2. The vast majority of the couples were heterosexual(97%).
3. Precludes any definitive conclusions about effectiveness in MSM.
4. At the time of enrollment, the HIV-infected partners (890 men, 873 women) had CD4+ T-cell levels—a key measure of immune system health—between 350 and 550 cells per cubic millimeter (mm³) within 60 days of entering the study.
5. The HIV-uninfected partners had tested negative for the virus within 14 days of entering the study.
6. The sex of the infected partner was close to a 50-50 split between men and women.
7. At the onset of the trial, all the infected partners had CD4 cell counts that did not warrant HIV treatment for their health.

Study Sites:

The study was conducted at 13 sites in Botswana, Brazil, India, Kenya, Malawi, South Africa, Thailand, the United States and Zimbabwe. The U.S. site collected only limited data because of difficulties enrolling participants into the study.

Study Protocol:

1. The investigators randomly assigned the couples to either one of two study groups.
2. In the first group, the HIV-infected partner immediately began taking a combination of three antiretroviral drugs (combination of 3 oral antiretroviral drugs).
3. In the second group (the deferred group / delayed ART), the HIV-infected partners began antiretroviral therapy when their CD4 counts fell below 250 cells/mm³ or an AIDS-related event, such as Pneumocystis pneumonia, occurred.
4. A trigger point set by the World Health Organization that the organization raised to 350 cells/mm3 in the middle of the study.
5. Throughout the study, both groups received HIV-related care that included counseling on safe sex practices, free condoms, treatment for sexually transmitted infections, regular HIV testing, and frequent evaluation and treatment for any complications related to HIV infection.
6. Each group received the same amount of care and counseling.
7. Individuals who became HIV-infected during the course of the study were referred to local services for appropriate medical care and treatment.
8. HIV-infected participants in the deferred treatment group will be offered antiretroviral therapy.
9. The study investigators will continue following the study participants for at least one year.

Study Sponsor:

The study was conducted by the HIV Prevention Trials Network, which is largely funded by NIAID with additional funding from the National Institute on Drug Abuse and the National Institute of Mental Health, both part of the NIH.

Additional support was provided by the NIAID-funded AIDS Clinical Trials Group.

The antiretroviral drugs used in the study were made available by Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/Viiv Healthcare and Merck & Co., Inc.

Background of the study:

Clinicians have long suspected that antiretrovirals that benefit HIV-infected patients also could benefit their partners, but no clinical trial has proven that beyond a reasonable doubt.

Previous data about the potential value of antiretrovirals in making HIV-infected individuals less infectious to their sexual partners came largely from observational and epidemiological studies.

This new finding convincingly demonstrates that treating the infected individual—and doing so sooner rather than later—can have a major impact on reducing HIV transmission.

Starting HIV-infected patients immediately after diagnosis on oral antiretroviral therapy (ART) while their immune systems are still relatively healthy is highly effective in protecting their partners from infection.

HPTN findings provide "a powerful policy argument" to encourage widespread testing of individuals to identify those with HIV and get them started right away on ART, not only for their sake but also for their partners.

Results:

The 11 HIV drugs that were used in various combinations included the following:
•Atazanavir (300 mg once daily)
•Didanosine (400 mg once daily)
•Efavirenz (600 mg once daily)
•Emtricitabine/tenofovir disoproxil fumarate (200 mg emtricitabine/300 mg tenofovir disoproxil fumarate once daily)
•Lamivudine (300 mg once daily)
•Lopinavir/ritonavir 800/200 mg once daily (QD) or lopinavir/ritonavir 400/100 mg twice daily (BID)
•Nevirapine (200 mg taken once daily for 14 days followed by 200 mg taken twice daily)
•Ritonavir (100 mg once daily, used only to boost atazanavir)
•Stavudine (weight-dependent dosage)
•Tenofovir disoproxil fumarate (300 mg once daily)
•Zidovudine/lamivudine (150 mg lamivudine/300 mg zidovudine taken orally twice daily)

In its review, the DSMB found a total of 39 cases of HIV infection among the previously uninfected partners.

Of those, 28 were linked through genetic analysis to the HIV-infected partner as the source of infection. 7 infections were not linked to the HIV-infected partner, and 4 infections are still undergoing analysis.

Of the 28 linked infections, 27 infections occurred among the 877 couples in which the HIV-infected partner did not begin antiretroviral therapy immediately.

Only one case of HIV infection occurred among those couples where the HIV-infected partner began immediate antiretroviral therapy.

This finding was statistically significant and means that earlier initiation of antiretrovirals led to a 96% reduction in HIV transmission to the HIV-uninfected partner. The infections were confirmed by genetic analysis of viruses from both partners.

Additionally, 17 cases of extrapulmonary tuberculosis occurredin the HIV-infected partners in the deferred treatment arm compared with 3 cases in the immediate treatment arm, a statistically significant difference.

There were also 23 deaths during the study. 10 occurred in the immediate treatment group and 13 in the deferred treatment group, a difference that did not reach statistical significance.

Discussions:

The timing of ART gets debated,

With the adverse effects and expense of the therapy prompting some to advocate waiting until a patient's immune system takes a turn toward the worse.

Study results were promising but were not conclusive when it comes to choosing immediate over delayed treatment.Of the 23 deaths among study participants, 13 occurred in the delayed-treatment group compared with 10 in the other group. Some of the deaths were not related to HIV.

When all morbidity and mortality events were tallied, "there was a trend towards benefit" with immediate ART, "but it did not reach the 20% difference between study arms required for statistical significance."

In an ongoing international clinical study called Strategic Timing of Antiretroviral Therapy, NIAID is examining the optimal time for asymptomatic HIV-infected individuals to begin antiretrovirals.

Conclusion:

96% Reduction in HIV Transmission With Immediate ART

The efficacy of ART in preventing HIV transmission should not prompt serodiscordant couples to abandon other safe-sex practices such as condom use.