The results of the study reveal that long-term injectable cabotegravir as PrEP is very effective in preventing the acquisition of HIV in women

A study by the HIV Prevention Network (HPTN 084) on the safety and efficacy of the long-acting injectable antiretroviral drug cabotegravir (CAB LA) for pre-exposure prevention (PrEP) in HIV-uninfected women was stopped early by a study by the Safety Oversight Board (DSMB) because the results showed that CAB LA is very effective in preventing the acquisition of HIV.

Study design

HPTN 084 enrolled 3,223 women aged 18 to 45 who were at risk of HIV infection in 20 locations in seven sub-Saharan African countries (Botswana, Kenya, Malawi, South Africa, eSwatini, Uganda and Zimbabwe).

The study randomized participants into one of two groups:

• Arm 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

Thirty-eight women in the study acquired HIV. Four were randomized to the long-acting arm of cabotegravir, and 34 were randomized to the daily, oral FTC / TDF group. This translated into an HIV incidence rate of 0.21% (95% CI 0.06% – 0.54%) in the group receiving cabotegravir and 1.79% (95% CI 1.24% -2, 51%) in the FTC / TDF group. Although both methods were very effective in preventing HIV acquisition, long-acting cabotegravir was 89% (95% CI 68-96%) more effective than FTC / TDF. These results indicate that CAB LA is significantly more effective in preventing the acquisition of HIV than oral PrEP in the treatment-intent analysis of this study.

CAB LA and oral FTC / TDF were well tolerated, and most side effects were mild to moderate in severity and generally balanced between both treatment groups. Injection site reactions were low in both groups, although higher in the CAB LA group, and gastrointestinal disturbances and nausea were more common in the FTC / TDF group. There was no discontinuation of treatment due to injection site reactions or injection intolerance in either arm of the study.

Implications of results

Women in the countries surveyed and across East and South Africa continue to have a high incidence of HIV. More effective and acceptable ways of preventing HIV for women are needed. Although oral PrEP is very effective in preventing HIV in women when taken as prescribed, it is difficult for some women to take a daily pill, and inconsistent administration of oral PrEP reduces the effect of prevention. The long-acting formulation for injection may improve the preventive effect without relying on adherence to the daily oral PrEP regimen and increase the possibility of prevention and acceptability among women.

The long-acting PrEP product could offer a better choice for women at significant risk of HIV who either do not want to take or struggle with taking daily pills. These results do not contradict the evidence showing that consistent administration of oral PrEP is very effective, as shown in several studies. However, adherence to a daily dosing schedule is important. Even brief failures in taking oral PrEP can reduce protection against acquiring HIV.

Availability of CAB LA

Now that the women’s trial has been stopped, participants will be notified of the test results and CAB LA will be available to them. Participants who have been in the FTC / TDF arm will be offered CAB LA, and participants in CAB LA will still be able to receive it. Participants who do not wish to receive CAB LA will be offered an FTC / TDF until the originally planned completion of the study.

Before CAB LA becomes available to people outside the HPTN 084 study, the test results will need to be fully reviewed and submitted to the strict regulatory body for approval. CAB LA and production capacity will have to be developed. There are other safety and application issues that need to be considered before wider introduction. Safety studies in adolescents and among pregnant and lactating women will be required, and open enlargement studies (OLEs) should be considered to understand the most effective and acceptable approaches to implementation.

Unresolved issues

• CAB LA for adolescent girls
  As all study participants were 18 years of age or older, a bridging study (HPTN084 / 01) began enrolling adolescent girls. This will assess safety and acceptability in 50 adolescent girls <18 years of age in three locations. Additional information on delivery approaches and ways to support acceptance and follow-up can be obtained through OLE studies.
• Safety during pregnancy and lactation
  When information was available in May 2018 on Dolutegravir (DTG), which is an integrase inhibitor in the same class of drug as cabotegravir, that there was a possible association with fetal neural tube defects (NTD) when taken perconceptually, the protocol change was modified. a requirement that all women enrolled in HPTN 084 also take long-acting reversible contraceptives. Since this safety signal was raised in May 2018, recent data has recorded a decline in risk. As of July 2020, data show a negligible difference in the risk of NTDs with DTG at conception exposure compared to other ARVs.^I However, due to the protocol change, very few women in HPTN 084 became pregnant while taking CAB-LA. Monitoring of adverse fetal outcomes and pregnancy will need to be performed during OLE.
• 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 all need to be assessed and considered. Other implementation evaluations are planned or ongoing.
• Pharmacokinetic tail – will this be a significant risk for drug resistance?
  Cabotegravir for injections has a long half-life, which is why it provides long-term protection (8 weeks). It also has a long pharmacokinetic tail, meaning there is a recognizable drug that stays in the body for months after the injection. These 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 at that time. Previously reported in a phase II study (HPTN 077)ⁱⁱ that the median time to undetected cabotegravir was longer in women at 66.3 weeks (range 17.7 to 182) compared with 42.7 weeks (range 20.4 to 134) in men. It is not yet understood whether this long pharmacokinetic tail will have any significant effect on drug resistance.
  The current recommendation for HPTN 084 trial participants discontinuing CAB LA is to take FTC / TDF to “cover” this tail with an oral regimen. This may not be feasible, desirable, or necessary in actual settings. The importance of covering the tail with oral PrEP and the risk of subsequent drug resistance to HIV are issues that will need to be considered and closely monitored in future OLE studies.

A similar study (HPTN 083) on HIV-uninfected cisgender men who have sex with men and transgender women who have sex with men also stopped her DSMB early in May 2020, after also showing that CAB LA was very effective in prevention Acquisition of HIV in this group. Final analysis showed the superiority of CAB LA compared to FTC / TDF for PrEP in the study population of HPTN 083. The results from HPTN 084 now mean that CAB-LA has been shown to be very effective in all populations.

Key messages:

It is encouraging to learn that the long-term injection option PrEP has been shown to be very effective in women. CAB LA can increase choice and overcome some of the barriers associated with adhering to the long-term use of biomedical HIV prevention.

But it is also important to lower expectations – there are still some important safety and enforcement issues. It will probably be more than a year before CAB LA will be more widely available. However, now that these results are available that show its effectiveness in women, along with results for men who have sex with men and transgender women, plans for regulatory approval will move forward.

Planning open extension studies is a priority for understanding open security issues and implementation approaches for populations in urgent need of effective preventive choices.

Oral daily PrEP remains an effective prevention option for all people at significant risk of HIV, and has been recommended by the WHO since 2015.ⁱⁱⁱ The WHO has developed implementation tools that support safe, effective and acceptable implementation.^iv

^I Zash R et al. Update on neural tube defects with antiretroviral exposure in the Tsepamo study, Botswana. AIDS 2020 virtual. July 6 – 10, 2020 Summary of the OAXLB0102 Oral Switch. https://cattendee.abstractsonline.com/meeting/9289/presentation/3500

ⁱⁱ Landovitz RJ, Li S, Eron JJ, Greenstein B, Dawood H, Albert Y Liu et al. Safety in the tail phase, tolerability and pharmacokinetics of long-term injectable cabotegravir in non-HIV-infected adults: a secondary analysis of the HPTN 077 trial on July 2020; 7 (7): e472-e481

ⁱⁱⁱ 2015 guidelines on when to start antiretroviral therapy and on HIV prevention before exposure

^iv WHO, 2017. A WHO implementation tool for prevention before exposure to HIV infection