Cabotegravir long-acting injections prevent HIV as PrEP

Simon Collins, HIV i-Base

On 18 May 2020, the international phase 2b/3 HPTN 083 study reported that cabotegravir injections were effective at reducing the risk of HIV transmission. Compared to participants using daily oral PrEP (TDF/FTC) fewer participants using the injections became HIV positive. [1, 2]

However, because some participants did become HIV positive when using cabotegravir, explaining the full results might show that in the context of perfect adherence that oral TDF/FTC is technically more effective. When adherence is not good, the benefit is likely to come from using long-acting injections.

All participants in HPTN 083 will now be offered the option to change to cabotegravir injections, for the last two years of the study. If approved, which seems likely, this will lead to a new way to prevent HIV infection, but the detailed results from this study will also be just as important as the headline news.

HTPN 083 randomised 4570 gay men and transgender women who have sex with men to either cabotegravir injections (intramuscular, every eight weeks, after intial four-week dose) or daily oral TDF/FTC PrEP plus matching placebo. The first five weeks was placebo-controlled oral formulations of both drugs. The study is being run in 43 sites in Argentina, Brazil, Peru, Thailand, the US, Vietnam, and South Africa. [3]

The study started in December 2018 and was due to finish in March 2022 but travel restrictions due to COVID-19 led to an early assessment of results by the independent data and safety monitoring board (DSMB). Although HPTN 083 was originally to test whether cabotegravir long acting (LA) was superior to TDF/FTC, the DSMB reported that changing to a non-inferior design would provide sufficient differences to show that cabotegravir LA is significantly more effective than oral TDF/ FTC. This led to a DSMB recommendation to discontinue the TDT/FTC arm early and offer cabotegravir injections to all participants.

The top-line results – all that have so far been released – reported that injectable PrEP was 69% more effective compared to oral PrEP. Overall, 50 participants became HIV positive: 12 in the cabotegravir arm vs 38 randomised to oral TDF/FTC. This produced an HIV incidence rate of 0.38% (95% CI: 0.20% to 0.66%) vs 1.21% (95% CI: 0.86% to 1.66%) in the cabotegravir vs TDF/FTC groups respectively. HPTN 083 was planned with the expectation that 172 incident infections occur.

The limited baseline demographics include that regionally 37% of participants are in the US, 43% are in Latin America, 16.5% in Asia and 3.5% in Africa. Mean age is 28 years old, with 40% less than 25 and 66% less than 30. It is significant that transgender women make up 12% of participants and that half of the participants in the United States identified as black or African American.

In an online press conference to present these results, tolerability and safety were also reported as generally good. Injections site reactions were more common in people receiving active injections – 80% vs 31% – with discontinuations at 2.2% vs 0, respectively.

A similar study that started a year later – HPTN 084 – is being run in 3200 cisgender women in Botswana, Kenya, Malawi, South Africa, Eswatini, Uganda and Zimbabwe. This study is almost recruited and already has 25% of follow-up. The same DSMB has recommended that this study should continue as planned. [4]

Both studies are a collaboration funded by the US NIAID with support from ViiV Healthcare and Gilead Sciences.

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Results from HPTN 083 will be used as part of the regulatory submission for cabotegravir LA as PrEP to both the FDA and EMA, although the timeline for this was not announced.

These results are important as many people at high risk of HIV do not find oral PrEP an easy or acceptable option, but the results also need to be interpreted cautiously until the full analysis are presented and published.

Although in this study cabotegravir LA was more effective than oral PrEP this is likely to be explained by different levels of adherence in the two arms. Cabotegravir adherence should by definition have been 100% because it was given at study visits, whereas oral PrEP would depend on individual participants remembering to take a daily pill.

Although the press statements include that in a pharmacokinetic sub-study of HPTN-83, drug levels were generally good in the oral PrEP arm, the infections that did occur on oral PrEP are likely to be in people who missed doses. Other studies have reported true efficacy of oral PrEP in the context of good adherence is effectively 100%.

Strictly speaking, in the context of 100% adherence, cabotegravir injections appear to be less effective than oral PrEP. Further details to explain the new infections in the cabotegravir group, possibly because of early infections at the start of the study, lower drug levels at some timepoints and in some people, or development of drug resistance, will be important in the presentation of the full results.

For someone who is strictly adherent to oral PrEP, switching to cabotegravir LA injections now might therefore reduce their current level of protection against HIV. In someone where adherence is a difficult problem, the advantages of long-acting injections are likely to be better.

This article was first posted online on 20 May 2020.

References

HPTN press release. Long-acting injectable cabotegravir is highly effective for the prevention of HIV infection in cisgender men and transgender women who have sex with men. (18 May 2020).
https://www.hptn.org/news-and-events/press-releases/long-acting-injectable-cabotegravir-highly-effective-prevention-hiv
ViiV press release. Global HIV prevention study to stop early after ViiV Healthcare’s long-acting injectable formulation of cabotegravir dosed every two months shows higher efficacy than daily oral PrEP. (18 May 2020).
https://viivhealthcare.com/en-gb/media/press-releases/2020/may/global-hiv-prevention-study-to-stop-early-after-viiv-healthcares
clinicaltrials.gov. Safety and efficacy study of injectable cabotegravir compared to daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), for pre-exposure prophylaxis in hiv-uninfected cisgender men and transgender women who have sex with men.
https://clinicaltrials.gov/ct2/show/NCT02720094
clinicaltrials.gov.evaluating the safety and efficacy of long-acting injectable cabotegravir compared to daily oral TDF/FTC for pre-exposure prophylaxis in hiv-uninfected women.
https://clinicaltrials.gov/ct2/show/NCT03164564.