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CROI 2011: Researchers Report Further Findings from iPrEx PrEP Trial

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Investigators presented further details of findings from the ground-breaking iPrEx trial this week at the 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011) in Boston. With longer follow-up, pre-exposure prophylaxis (PrEP) using tenofovir/emtricitabine (Truvada) continued to have a protective effect against HIV acquisition, but signs of mild bone loss raise potential concerns about safety.

An estimated 2.6 million new HIV infections occurred worldwide in 2009, 41% of them in people between 15-24 years old. There is thus a pressing need for new and more effective prevention methods.

One such method that has garnering a great deal of attention is pre-exposure prophylaxis, which refers to HIV negative people taking antiretroviral drugs in an effort to prevent infection.

In an oral presentation at CROI 2011, Robert Grant from the Gladstone Institute of Virology and Immunology in San Francisco presented 144 week extended phase results from the iPrEx study. This study is among the first to evaluate the safety and efficacy of PrEP in men who have sex with men (MSM) and transgender women.

The trial was funded by the U.S. National Institutes of Health and the Bill and Melinda Gates Foundation, and study drugs were provided by Gilead Sciences (Gilead had no role in designing the study or collecting or analyzing data).

Earlier results from this study have been presented at other meetings, and the primary analysis was published late last year in the New England Journal of Medicine.

The iPrEx trial enrolled 2499 HIV negative people at 11 sites worldwide, including the U.S. (San Francisco and Boston), South America, Africa, and Asia. Participants were randomly assigned to take either tenofovir/emtricitabine or a placebo once-daily.

Study participants had an average age of 25 years. They were sexually active and considered to be at high risk of HIV infection. In addition to receiving the study drug or placebo, participants were provided regular safe sex counseling and monthly HIV testing.

In addition to evaluating the rates of new HIV infection, researchers looked at rates of adverse events, levels of adherence, drug resistance, number of sexual partners, amount of high-risk sexual activity, and viral load among people who did become infected during the trial.

Results

There were 131 new HIV infections during the trial: 48 among people taking tenofovir/emtricitabine and 83 among those taking placebo.

The researchers calculated that 35 possible new infections were avoided by using PrEP.

The overall efficacy of tenofovir/emtricitabine PrEP was 44%.

Efficacy was observed in all sub-group analyses, including breakdowns by age, ethnicity, region, level of schooling, alcohol use, and circumcision status.

The greatest benefit was seen in people with the highest risk -- those who engage in unprotected receptive anal intercourse. PrEP was 56% effective in this group.

These findings indicate both a high level of non-adherence throughout the study, as well as a strong relationship between detectable drug levels and the likelihood of becoming infected.

Detectable drug levels were found in 51% of people who remained uninfected and 9% of those who became infected.

PrEP conferred 92%-95% protection if the drugs were detectable in blood

No new HIV infections occurred among people who had drug levels consistent with daily dosing.

The benefit of tenofovir/emtricitabine was greatest among people with the highest level of adherence.

Those who reported taking over 90% of their doses saw a 68% reduction in new HIV infections.

People who reported less than 50% adherence saw only a 16% reduction in new infections.

Adverse effects were similar between the PrEP and placebo groups.

Nausea and weight loss were more common in the tenofovir/emtricitabine arm; these effects were uncommon, occurring in less than 5% of participants.

There was a low incidence of elevated creatinine, a possible indicator of kidney impairment: 2% in the tenofovir/emtricitabine arm vs 1% in the placebo.

No new drug resistance emerged during the extended phase of trial.

All drug resistance occurred in people who were later found to be already HIV-infected at the start of the trial.

The reported number of sexual partners decreased throughout the study.

At the start of the trial, the average number of sexual partners reported in the previous 12 weeks was 18 in both arms.

This number trended downward in both groups, and by the end of the study the average in both arms was 6.

Reported unprotected receptive anal intercourse also declined in both arms throughout the course of study.

A related iPrEx sub-study, reported by Kathleen Mulligan from the University of California at San Francisco, added a cautionary note, however.

About one-fifth of iPrEx participants in 5 cities underwent DEXA bone scans of the hip and spine. People randomly assigned to the tenofovir/emtricitabine arm experienced a small but statistically significant decline in bone density at week 24 weeks. Bone loss is a known potential risk of tenofovir.

Mulligan explained that it is not yet known whether the observed 0.5% to 1.0% decrease is clinically significant, or whether it would worsen, stay the same, or improve with longer use of PrEP.

Overall, the results from the extended phase of the iPrEx study confirm what was reported previously. While concerns about adherence and side effects remain, PrEP was shown to be effective and safe when used by men who have sex with men and transgender women in this study.

These results are promising. As Grant put it, "Finding new ways to block the spread of HIV is critically important for getting ahead of the epidemic."

"The key issue is adherence," he emphasized at a press conference following his presentation. The iPreX regimen "was protective when used, and not protective when not used."

Investigator affiliations: Abstract 92: Gladstone Institute of Virology and Immunology, San Francisco, CA; Investigaciones Medicas en Salud, Lima, Peru; Univ of California, San Francisco, CA.

Abstract 94LB: Univ of California, San Francisco, San Francisco, CA; Investigaciones Medicas en Salud, Lima, Peru; Assn Civil Impacta Salud y Ed, Lima, Peru; San Francisco Dept of Public Health, San Francisco, CA; Chiang Mai Univ, Chiang Mai, Thailand; Desmond Tutu HIV Foundation, Cape Town, South Africa; Federal Univ of Rio de Janeiro, Brazil; Gladstone Institute of Virology and Immunology, San Francisco, CA.

3/4/11

References

R Grant, J Lama, D Glidden and others. Pre-exposure Chemoprophylaxis for Prevention of HIV among Trans-women and MSM: iPrEx Study. 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27-March 2, 2011. Abstract 92.

K Mulligan, D Glidden, P Gonzales, and others. Effects of FTC/TDF on Bone Mineral Density in Seronegative Men from 4 Continents: DEXA Results of the Global iPrEx Study. 18th Conference on Retroviruses and Opportunistic Infections. Boston. February 27-March 2, 2011. Abstract 94LB.

Other Source

Gladstone Institute of Virology and Immunology. New Data Show the Protective Benefit of Pre-Exposure Prophylaxis to Prevent HIV Infection Is Durable at 144 Weeks. Press release. March 1, 2011.