March 06, 2019
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Discover trial: TAF noninferior to TDF for HIV PrEP
SEATTLE — After several years of study, an HIV pre-exposure prophylaxis regimen containing tenofovir alafenamide was found to be noninferior to the traditional regimen with tenofovir disoproxil fumarate.
In 2016, the FDA approved emtricitabine plus tenofovir alafenamide (F/TAF) — marketed as Descovy (Gilead Sciences) — for the treatment of HIV. Studies have shown that TAF has a better safety profile than tenofovir disoproxil fumarate (TDF), the original formulation of tenofovir, and it can be administered at a lower dose.
Charles B. Hare, MD, an infectious disease specialist at the University of California, San Francisco, presented results from the phase 3 Discover study, which included more than 5,300 cisgender men who have sex with men and transgender women in North America and Europe. Researchers evaluated the two drugs for HIV pre-exposure prophylaxis (PrEP). Considered at “very high risk” for HIV, the participants were randomly assigned 1:1 to a daily regimen of F/TAF (200 mg/25 mg) or F/TDF (200 mg/300 mg), Hare said. Participants were followed for up to 96 weeks, and their adherence to the regimens were measured through pill counts and how much of the drug was detected in their blood.
Among the F/TAF arm, seven HIV infections were identified — an incidence rate ratio of 0.16 per 100 person-years. Among those in the F/TDF arm, 15 infections were found, translating to an incidence rate ratio of 0.34 per 100 person-years. This led researchers to conclude that F/TAF was noninferior to F/TDF.
“Both drugs actually performed quite well,” Hare said.
The safety of the two drugs were “comparable,” according to Hare. Discontinuation rates due to adverse events were 1.3% in the F/TAF arm and 1.8% in the F/TDF arm. The most common of these included anal chlamydia, oropharyngeal gonorrhea and rectal gonorrhea.
One pre-specified secondary analysis in a subset of patients showed an improvement in bone safety in patients taking F/TAF, according to Hare, and another pre-specified analysis showed “small but statistically significant differences that favored” F/TAF in terms of renal safety.
Hare said the overall rate of STIs was high in the study, with 57% of participants having at least one. High rates of rectal gonorrhea, chlamydia and syphilis were “persistent and maintained throughout the study,” suggesting that these “were the right participants to be enrolled in the study,” he added.
Notably, less than 10% of the study population was black, a limitation that Hare acknowledged.
“It would have been nice to have seen more African Americans in the study,” he said. – by John Schoen
Reference:
Hare CB, et al. Abstract 104LB. Presented at: Conference on Retroviruses and Opportunistic Infections; March 4-7, 2019; Seattle.
Disclosure: Hare reports no relevant financial disclosures.
Perspective
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Stephen M. Smith, MD
F/TDF, or Truvada, has limited efficacy in preventing HIV infections in high-risk individuals, including MSM, who have sex with multiple partners in a year. TDF has well-known adverse effects of bone loss and kidney damage. Using F/TDF for HIV PrEP puts an individual at risk for these side effects for a modest (44%-62%) reduction in HIV infections. The Discover trial established that TAF is as good, or bad, as TDF in PrEP, and that TAF is associated fewer side effects than TDF. Discover’s results were expected, given the plethora of data on TAF vs. TDF for HIV treatment.
Regardless, Discover is a welcome step toward doing the right thing. Going forward, those on PrEP with TAF will not be at increased risk for bone loss and kidney injury. People on TDF for PrEP experience these side effects at similar rates as those on TDF for treatment. Further, Discover’s data may show that TAF is better than TDF in preventing HIV infections; the investigators did not discuss this possibility. By conditional maximum likelihood, the chance that the TAF and TDF incidences are the same is less than 5%.
Because Discover did not have a placebo group, the efficacy of F/TAF or F/TDF in preventing HIV transmission cannot be discerned. The only valid evaluation is the comparison of F/TAF to F/TDF. The investigators included data on HIV incidences in so-called similar populations. These data are irrelevant; inferences of absolute efficacy are invalid. The data on HIV incidence rates from other studies should not be included in the presentation of Discover’s data.
An unintended consequence of HIV chemoprophylaxis is an increase in “unsafe” sex practices, and a commensurable increase in the rates of other STDs. Although the extant data are somewhat inconsistent, most observational PrEP studies show an increase in high-risk behavior and/or the incidence of STDs. In Discover, the STD rate was 99.5 per 100 person-years, meaning that nearly every trial participant acquired one STD per year, and 57% of trial participants had at least one STD. The STD rates in Discover are much higher than in other PrEP trials and in the MSM population studied. This issue needs to be addressed.
Once again, the choice of using two active anti-HIV drugs for PrEP is arbitrary. Obviously, the key to eliminating transmission is to have all HIV-positive people with undetectable viral loads. PrEP is offered in lieu of that goal. Still, why only two active agents and not three? Why not use an integrase or protease inhibitor along with F/TAF for HIV PrEP? That debate should be had.
References:
Grant RM, et al. N Engl J Med. 2010;doi:10.1056/NEJMoa1011205.
Thigpen MC, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1110711.
Stephen M. Smith, MD
Infectious Disease News Editorial Board member
Founder and medical director, Smith Center for Infectious Diseases and Urban Health
East Orange, N.J.
Disclosures: Smith reports no relevant financial disclosures.
