Progress with PrEP

PrEP--pre-exposure prophylaxis with antiretrovirals--has the potential to dramatically reduce the number of new infections of HIV worldwide. Unfortunately, that potential has not been observed in a number of large “field” trials of PrEP.^1,2 The main reason for the failure to demonstrate a benefit at the population level is lack of adherence to, typically, daily tenofovir-based oral regimens. Even in successful trials³ of PrEP, adherence has been shown to wane substantially after 1 to 2 years.

Recently, a number of promising results of trials with PrEP have been reported, including trials of injectable long-acting antiretrovirals. Dr. Martin Markowitz, from the Aaron Diamond AIDS Research Center in New York City, reported on the results of the ÉCLAIR study at the recently-completed 2016 Conference on Retroviruses and Opportunistic Infections (CROI).⁴ He and his colleagues randomized 127 men who have sex with men (MSMs) 5:1 to every 12-week injections of cabotegravir versus placebo. Those randomized were deemed, by study design, to be at “low-risk” for HIV infection. Cabotegravir, an integrase strand transfer inhibitor similar to dolutegravir, is being developed as both an oral tablet and a nanosuspension for intramuscular injection. Cabotegravir is anticipated to be available for treatment of HIV and, possibly, PrEP in the near-future. One person in each arm of the 41-week trial acquired HIV. The individual who acquired HIV in the cabotegravir arm was found to have low serum cabotegravir levels, such that an every 8-week schedule is being contemplated. The injections in the study were painful, but satisfaction surveys found that participants preferred the injections to daily oral medications.

A somewhat-related article⁵, using computer simulations, looked at the cost-effectiveness and clinical value of 3 different strategies:

• No PrEP
• Standard PrEP (effectiveness 62%; cost per participant US$150 per year)
• Long-acting PrEP (75% effectiveness; cost per participant US$220 per year) in South African women at high-risk for HIV infection.

In South Africa, the incidence of HIV-infection in young women between the ages of 14 and 24 is estimated at 5% per year. While both PrEP regimens were found to be cost effective compared to no PrEP, long-acting PrEP was very cost effective: US$150 per life-year saved. The total 5-year cost of providing long-acting PrEP to 50% of eligible South African women was estimated to be US$1.6 billion.

Also presented at the 2016 CROI was a study of maraviroc versus placebo for PrEP. Maraviroc is a CCR5 antagonist. The study randomized 406 men with a history of recent condomless anal sex to maraviroc alone versus maraviroc plus emtricitabine versus maraviroc plus tenofovir versus tenofovir plus emtricitabine (“standard” PrEP). There were 5 new HIV infections in the 48-week trial, of which 4 occurred in the maraviroc only arm. Only one of the 5 individuals who seroconverted had serum levels of maraviroc deemed high enough to be effective, again demonstrating the importance of adherence with any PrEP regimen.

SUMMARY

Interest in PrEP remains high, although it remains to be determined how acceptable any of the regimens will be in the long-term. In high risk populations, PrEP is likely to be cost-effective, regardless of which regimen, or which route, is used. Also ongoing are studies of various rectal gels (eg, tenofovir, tenofovir/emtricitabine), either for daily use or for before-sex (“on demand”) use. However, it seems unlikely to me that adherence will be any better with these products than has been seen previously with oral therapies. In that regard, long-acting regimens, requiring injections every 8 to 12 weeks, ultimately may be shown to have greater long-term efficacy than either daily oral/rectal gel-based regimens or “on demand” oral/rectal gel-based regimens.

References:

1. Marrazzo JM, Ramjee G, Richardson BA, et al. Tenofovir-based preexposure prophylaxis among African women. N Engl J Med. 2015;372:509-518.
2. Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367:411-422.
3. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:2587-2599.
4. Markowitz M, Frank I, Grant R, et al. ECLAIR: Phase 2A safety and PK study of cabotegravir LA in HIV-uninfected men. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 106.
5. Walensky RP, Jacobsen MM, Bekker L-G, et al. Potential clinical and economic value of long-acting preexposure prophylaxis for South African women at high-risk for HIV infection. J Infect Dis. 2016;213:1523-1531.