Exciting new results from a long-term PrEP study show that it is effective in preventing the acquisition of HIV in men who have sex with men and transgender women.

HIV Trial Network (HPTN 083) on the safety and efficacy of the long-acting injectable antiretroviral drug kabotegravir (CAB LA), for the prophylactic exposure to prophylaxis (PrEP) in cisgender men who are not infected with HIV and have sex with men and transgender people
Women who have sex with men were stopped early by the Data Monitoring and Security Committee (DSMB) because the results showed that CAB LA very effective in preventing HIV infection.

Study design

The study included about 4,600 HIV-free non-infectious men who have sex with men and transgender women at risk of getting HIV, aged 18 and older, in places in Argentina, Brazil, Peru, South Africa, Thailand, the United States and Vietnam. Vulnerability
HIV has been shown 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 the study participants were under the age of 30, and 12% were transgender women. One half
participants in the U.S. identified as black or African American. The study randomized participants into one of two arms:

• Hand A – CAB LA (as an intramuscular injection every 8 weeks) and daily oral TDF / FTC placebo.
• Hand B – daily oral TDF / FTC and intramuscular CAB LA placebo every 8 weeks.

the results

Fifty people became infected with HIV (total incidence 0.79 per 100 person-years). There were 38 infections (1.21 per 100 person-years) and 12 infections in the CAB LA group (0.38 per 100 person-years) in the daily oral TDF / FTC arm. These results showed
that CAB LA is as effective in preventing HIV infection as oral PrEP, and that both are very effective prevention options for men who have sex with men and transgender women who are at significant risk of HIV.

Safety was similar in the two groups. Eighty percent of participants in the CAB LA arm reported pain or tenderness at the injection site, compared with only 31% of those in the TDF / FTC group who received placebo injections. Discontinuation due to injection
site reaction or injection intolerance in the CAB LA group was 2% and there were no discontinuations due to TDF / FTC injection site reactions.

Implications of results

Although oral PrEP is very effective in preventing HIV, some people find it difficult to take a daily pill, and inconsistent use of oral PrEP reduces the effect of prevention. The long-acting injection formulation can be improved on prevention
performance without reliance on adherence to daily or event oral PREP regimen, increasing choice of prevention and acceptability among users.

A long-acting PrEP product could offer a choice to people at high risk for HIV who either don’t want to take it or are struggling to take a daily pill. For people using oral PrEP, these results do not contradict the evidence showing that oral PrEP is very high
effective. This has been proven in several trials, but it is important to adhere to a dosing schedule, whether it is daily or on demand. Even short failures when taking oral PrEP can reduce protection against HIV.

Consequences for women

Another similarly designed CAB LA trial, HPTN 084, began a year after HPTN 083. The study will involve about 3,200 women, from 18 to 45 years, with a high risk of HIV. .
South Africa, Eswatini, Uganda and Zimbabwe). The DSMB also reviewed the data from HPTN 084 and recommended that they proceed as planned. The next review of the DSMB will be later in 2020; results are expected in 2021.

Availability of CAB LA

Now that the trial of men who have sex with men and transgender women has been stopped, participants will be notified of the test results and CAB LA will be available to them. Participants who were in the TDF / FTC will be offered CAB LA and
participants in the CAB LA section will continue to receive it. Participants who do not wish to receive CAB LA will be offered a TDF / FTC by the end of the originally planned study.

However, before CAB LA becomes available to individuals outside the HPTN 083 study, the test results must be fully reviewed and submitted to the strict regulatory body for approval. Currently, the production of CAB LA is limited and limited
it will have to evolve. There are other security and enforcement issues that must be considered before widespread implementation. Adolescent safety studies are planned and open label spread (OLE) is being considered.

Unresolved issues

CAB LA for adolescents

As all study participants were 18 years of age or older, bridging studies are planned to assess safety in the younger population. Additional information on acceptability and feasibility can be obtained through open extension studies.

Real-world implementation issues

Where and how CAB LA can be delivered – which requires an injection every eight weeks – implementation adjustments that may be needed in HIV prevention programs and health systems and eligibility issues will need to be assessed and considered:
other implementation evaluations are planned or underway.

Pharmacokinetic tail – will this be a significant risk for drug resistance?

Injectable cabotegravir has a long half-life, which provides long-term protection (8 weeks). It also has a long pharmacokinetic tail which means there is a detectable drug that stays in the body for months after the injection. It
small amounts of the drug may not be sufficient to protect against HIV infection and may result in the development of drug-resistant HIV after exposure during that time. It was previously reported that the pharmacokinetic tail lasted for at least 42 weeks
in approximately half of the men included in the phase II study (HPTN 077). The results presented do not provide a drug resistance report, but an analysis of these data is ongoing.

The current recommendation for HPTN 083 study participants discontinuing CAB LA is to take oral TDF / FTC for 12 months to cover the “tail” with the oral regimen. This may not be feasible, desirable or necessary in the actual settings.
The importance of covering the tail with oral PrEP and the risk of subsequent resistance to HIV drugs are issues that will need to be carefully considered and monitored in future open-label studies.

Key messages

Oral daily PrEP remains an effective prevention option for all those at significant risk of HIV, and has been recommended by the WHO since 2015.^I The 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 regime, often called 2 + 1 + 1.ⁱⁱⁱ

The exciting news is that the long-acting prEP option has proven to be effective and it has the potential to increase choice and overcome some of the barriers associated with adhering to and long-term use of HIV prevention strategies. While
Who is very encouraged by these results, it is also important to ease expectations – as there are still some important issues to be addressed, and it will probably be many months before CAB LA is widely available to men who have sex with men,
transgender women and, hopefully, for women, if HPTN 084 can provide similar positive results.

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^I: WHO, 2015 Guidance on when to start antiretroviral therapy and on preventive exposure to HIV

ⁱⁱ: WHO, 2017. WHO implementation tool for preventive exposure to HIV prophylaxis

ⁱⁱⁱ: WHO, 2019. What is 2 + 1 + 1? Event-oriented oral pre-exposure prophylaxis for men who have sex with men: Update the WHO recommendation on oral PrEP