Long-acting cabotegravir injections are effective as HIV PrEP in gay men and transgender women: results from HPTN 083
Two oral presentations at AIDS 2020 provided headline news from the HPTN 083 study about a new formulation of PrEP that uses two-monthly injections compared to a daily oral pill. [1, 2]
Although top-line results from the HPTN 083 had been released a month earlier [3, 4] the new results included more details on incident infections and also showed how effectively important populations were successfully enrolled in the research.
HPTN 083 is an international, double-blind, active control study that randomised 4566 gay men and transgender women who have sex with men to either cabotegravir injections (CAB-LA) or daily oral TDF/FTC PrEP plus matching placebo. Cabotegravir was given by intramuscular injection every eight weeks, after an initial five-weeks using placebo-controlled oral formulations of both drugs.
Pre-specified minimum demographics included that overall 50% of participants would be younger than 30 years old, 10% would be transgender women (TGW) and more than 50% of US participants would be black/African-American. The study included 43 sites in the US, Latin America (Argentina, Brazil, Peru), South-East Asia (Thailand, Vietnam) and South Africa.
Overall baseline characteristics included: median age: 26 years (IQR: 22 to 32); 12%TGW (n=567); and that 50% of US participants were black (n=844). Retention was high with 91%, 87%, and 74% at 6, 12, and 24 months, respectively.
For the primary endpoint, 52 participants became HIV positive over 6389 person-years: 13 in the CAB-LA arm vs 39 randomised to oral TDF/FTC. This produced an overall incidence rate of 0.81% (95%CI 0.61 to 1.07); with 0.41% (95% CI: 0.22% to 0.69%) vs 1.22% (95% CI: 0.87% to 1.67%) in the cabotegravir vs TDF/FTC groups respectively in favour of CAB-LA.
This showed CAB-LA to be superior to TDF/FTC based on the primary endpoint of reducing new infections (HR: 0.34; 95%CI: 0.18 to 0.62, p=0.0005). However, both arms were highly effective given background incidence before the study was estimated at approximately 4.5%.
The most important new information was on the incident infections in the CAB-LA arm. This is because the greater adherence assumed with CAB-LA was expected to drive the differences compared to TDF/FTC. However, given the TDF/FTC in the context of good adherence generates 100% efficacy, any infections on CAB-LA (when adherent) might technically favour oral PrEP.
Of the 13 HIV infections on CAB-LA, two were now known to already be HIV positive at baseline, three who became positive during the oral phase, and five who become HIV positive after an extended time without having an injection (two who never returned after the oral dosing phase, two who already switched to oral TDF/FTC and one who had missed an injection visit for 31 weeks).
This left 5/13 participants who became positive despite continuous cover on CAB-LA (effectively during confirmed 100% adherence). However, further essential details on these cases are not yet available due to complications in sampling and testing linked to COVID-19. These analyses might show, for example, whether these cases can be explained by infection with drug-resistant HIV or low drugs levels (linked to either low individual absorption or faster clearance, for example at the end of the dosing cycle).
Of the 39 infections in the TDF/FTC group, 3 became positive during the lead-in phase, 6 after not returning for prescriptions and 30 who were still routinely in the study. Further information on drugs levels, adherence and drug resistance are still needed to explain these cases.
Tolerability was good in both arms, but injection site reactions (ISRs) were significantly more common in CAB participants – as was fever (5.6% vs 2.4%, p<0.001) and increased glucose (9.0 vs 5.1, p<0.001). Nausea was significantly more common in TDF/FTC participants. Injection intolerance led to discontinuation in 46 (2.2%) active CAB-LA recipients and was associated with the severity of the intolerance/reaction.
In the second presentation, Beatriz Grinsztejn, from the Oswald Cruz Foundation (FIOCRUZ), Brazil, presented more detail on the populations enrolled in HPTN 083, including breakdowns for key demographics and results by region and age.
This included that median age in the four regions varied from 23 to 27 with 61 to 80% being <30 years and 7% to 30% were TGW.
By the same categorisation, of the 52 incident HIV infections, 44 were <30 years old (11 vs 33; HR: 0.32; 95%CI: 0.16 to 0.63), 9 were TGW (2 vs 7; HR 0.29; 95% CI: 0.06 to 1.41) and 19 were black (4 vs 15; HR 0.28, 95%CI: 0.10 to 0.83), all CAB-LA vs TDF/FTC respectively.
Across regions, the HR ranged from 0.19 (95% CI: 0.07 to 0.56) in the US to 0.54 (95% CI: 0.20 to 1.46) in Latin America for CAB-LA vs TDF/FTC respectively.
CAB-LA was also significantly more effective than TDF/FTC in gay men (HR 0.34; 95%CI: 0.17 t0.67) and US region (HR: 0.19; 95%CI: 0.07 to 0.56).
The presentation also reported by sub-populations on retention at 12 months (overall 86%, similar across groups), side effects (generally injection site reactions, slightly higher in African-Americans) and new sexually transmitted infections (generally slightly higher in younger participants). For more details please see webcast and slides.
Further information is available form the HPTN website, including a community webinar with 30-minute Q&A sessions. [5, 6]
These results are important in providing clear data to support a new option for PrEP in gay men and that included 12% transgender women.
They show high acceptability within a research setting to include and retain people from groups who are at high risk of HIV but often underrepresented in studies, including a high proportion who were younger and black.
Overall, CAB-LA was superior to oral TDF/FTC, with the better results likely due to suboptimal adherence to oral TDF/FTC. However, in the context of perfect adherence, TDF/FTC is already effectively 100%, so further analyses are needed on drug resistance and drug levels to understand cause of the five infections linked to CAB-LA. Either way, these are tiny numbers in a study this size.
Results from the related HPTN 084 study are expected within a year. This study with a similar design is being run in women at 20 sites in 7 high-incidence countries: South Africa, Botswana, Uganda, Kenya, Malawi, Eswatini, and Zimbabwe. Although it started a year later, the results are needed for regulatory submission to include women. 
A late-breaker poster at AIDS2020 from ViiV looked at implementation barriers among health workers for injectable ART. 
Results from a macaque study reporting on penile protection from cabotegravir were also just published in JID (1 August 2020). 
- Landovitz R et al. HPTN083 interim results: Pre-exposure prophylaxis (PrEP) containing long-acting injectable cabotegravir (CAB-LA) is safe and highly effective for cisgender men and transgender women who have sex with men (MSM, TGW). Late breaker oral abstract OAXLB0101.
- Grinsztejn B et al. HPTN 083 interim results: Efficacy of pre-exposure prophylaxis (PrEP) containing long-acting injectable cabotegravir (CAB-LA) is maintained across regions and key populations. AIDS2020, Late breaker oral abstract OACLB0101.
- Cabotegravir long-acting injections prevent HIV as PrEP. HTB (1 June 2020).
- 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).
- HPTN website.
- HPTN 083. Post-AIDS2020 webinar, includes 30 minutes Q&A.
- HPTN 084. A Phase 3 double blind safety and efficacy study of long-acting injectable cabotegravir compared to daily oral TDF/FTC for pre-exposure prophylaxis in HIV-uninfected women.
https://www.hptn.org/research/studies/hptn084 (HTPN website)
- CzarnogorskiM et al. Perceived implementation barriers decrease during initial stages of the first implementation science hybrid III study (CUSTOMIZE) of cabotegravir and rilpivirine long-acting (CAB+RPV LA) in US healthcare settings: Healthcare team perspective. AIDS2020, late breaker poster abstract LBPEE42.
- Dobard C et al. Long-acting cabotegravir protects macaques against repeated penile simian-human immunodeficiency virus exposures. Journal of Infectious Diseases222(3):391–395. DOI: 10.1093/infdis/jiaa095. (1 August 2020).