The HIV Prevention Trials Network (HPTN 083) study on the safety and efficacy of the long-acting injectable antiretroviral drug cabotegravir (CAB LA), for pre-exposure prophylaxis (PrEP) in HIV-uninfected cisgender men who have sex with men and transgender women who have sex with men, was stopped early by the trial Data and Safety Monitoring Board (DSMB) as results showed CAB LA to be highly effective in preventing HIV acquisition.
The study enrolled approximately 4600 HIV-uninfected men who have sex with men and transgender women at risk for acquiring HIV infection, aged 18 or older, at sites in Argentina, Brazil, Peru, South Africa, Thailand, the United States and Vietnam. Vulnerability to HIV has been seen to be higher in younger men who have sex with men and in men who have sex with men from ethnic minorities. In this study two-thirds of study participants were under 30 years of age, and 12% were transgender women. Half of the participants in the United States identified as black or African American. The study randomized participants to one of two arms:
- Arm A – CAB LA (as an intramuscular injection every 8 weeks) and daily oral TDF/FTC placebo.
- Arm B – Daily oral TDF/FTC and intramuscular CAB LA placebo every 8 weeks.
Fifty people became infected with HIV (overall incidence of 0.79 per 100 person-years). There were 38 infections in the daily oral TDF/FTC arm (1.21 per 100 person-years) and 12 infections in the CAB LA arm (0.38 per 100 person-years). These results showed that CAB LA is as effective in preventing HIV acquisition as oral PrEP, and that both are highly effective prevention options for men who have sex with men and transgender women who are at substantial HIV risk.
Safety was similar in the two groups. Eighty per cent of participants in the CAB LA arm reported pain or tenderness at the injection site, compared to only 31% of those in the TDF/FTC arm, who received placebo injections. Discontinuation due to injection site reactions or injection intolerance in the CAB LA arm of the study was 2%, and there were no discontinuations due to injection site reactions in the TDF/FTC arm.
Implications of the results
While oral PrEP is highly effective in preventing HIV, some people find it difficult to take a daily tablet and inconsistent use of oral PrEP reduces the prevention effect. A long-acting injectable formulation has the potential to improve on the prevention effect without relying on adherence to a daily or event driven oral PrEP regimen, increasing prevention choices and acceptability among users.
A long-acting PrEP product could offer choice for people at substantial HIV risk who either do not want to take or struggle with taking a daily tablet. For people using oral PrEP these results do not contradict evidence showing that oral PrEP is highly effective. This has been demonstrated in several trials, but adhering to the dosing schedule, whether daily or on-demand use, is important. Even short lapses in taking oral PrEP can reduce the protection from HIV acquisition.
Implications for women
Another similarly designed CAB LA trial, HPTN 084, began a year after HPTN 083. That study will enrol approximately 3200 women, 18 to 45 years old, at high HIV risk, in seven countries in East and southern Africa (Botswana, Kenya, Malawi, South Africa, Eswatini, Uganda and Zimbabwe). The DSMB also reviewed data from HPTN 084 and recommended that it continue as planned. The next DSMB review will be later in 2020; results are anticipated in 2021.
CAB LA availability
Now that the trial in men who have sex with men and transgender women has been stopped, the participants will be informed of the trial results and CAB LA will be made available to them. Participants who were in the TDF/FTC arm will be offered CAB LA and participants in the CAB LA arm will continue to receive it. Participants who do not want to receive CAB LA will be offered TDF/FTC until the end of the originally planned study.
However, before CAB LA becomes available to people outside the HPTN 083 study, the trial results will have to be fully reviewed and submitted to a stringent regulatory authority for approval. At the moment there is limited production of CAB LA and manufacturing capacity will have to be developed. There are also other safety and implementation issues that need to be considered prior to a broad roll-out. Safety studies in adolescents are planned and open-label extension (OLE) studies are being considered.
CAB LA for adolescents
As the study participants were all aged 18 or older, bridging studies are planned to assess safety in younger populations. Additional information on acceptability and feasibility could be gained through open-label extension studies.
Real-world implementation issues
Where and how CAB LA – which requires an injection every eight weeks – could be delivered, implementation adjustments that may be needed in HIV prevention programmes and health systems, and acceptability issues, will all need to be evaluated and considered: other implementation assessments are planned or underway.
The pharmacokinetic tail – will this be a significant risk for drug resistance?
Injectable cabotegravir has a long half-life, which is why it provides long-acting (8 weeks) protection. It also has a long pharmacokinetic tail meaning that there is detectable drug that remains in the body for months after an injection. These small amounts of drug may not be enough to protect against HIV infection and could result in development of drug resistant HIV following exposure during this time. It has been previously reported that the pharmacokinetic tail lasted at least 42 weeks in about half of men involved in a Phase II study (HPTN 077). The results presented do not report on drug resistance, but analysis of these data is underway.
The current recommendation for the HPTN 083 trial participants who discontinue CAB LA is to take oral TDF/FTC for 12 months to ‘cover’ this tail with an oral regimen. This may not be feasible, desired, or necessary in real-world settings. The importance of covering the tail with oral PrEP and the risk subsequent HIV drug resistance are issues that will have to be considered and monitored carefully in future open-label studies.
Oral daily PrEP remains an effective prevention option for anyone at substantial HIV risk, and it has been recommended by WHO since 2015.i WHO has developed implementation tools to support safe, effective, and acceptable implementation.ii Men who have sex with men can also use an event-driven regimen, often called the 2+1+1.iii
It is exciting news that a long-acting injectable PrEP option has been shown to be effective, and this has the potential to increase choice and overcome some of the barriers related to adherence and long-term use of HIV prevention strategies. While WHO is very encouraged by these results, it is also important to temper expectations— as there are still some important issues to address, and it is likely to be many months before CAB LA will be widely available for men who have sex with men, transgender women and, we hope, for women, should HPTN 084 provide similarly positive results.