PrEP updates and new products at IAS 2021

A large amount of important research on PrEP were presented at the 11th IAS Conference on HIV Science.

Exciting and encouraging results were presented on the laboratory analysis of HIV infections in the HIV Prevention Trial Network (HPTN) 084 study on long-acting injectable cabotegravir (CAB-LA) PrEP for cisgender women. In HPTN 084, , four participants who were allocated to receive CAB-LA were found to be HIV positive, but post-hoc analysis found that one of these participants was infected prior to enrollment to the study and so was re-classified as a prevalent infection. Two participants with incident infection received no CAB injections and had no recent CAB exposure. The third incident infection occurred during the injection phase of the study in a participant with delayed injection visits. In the comparison group of people taking daily oral PrEP, there were 36 incident infections. This means that the risk of becoming infected with HIV was 92% lower among people in the CAB-LA arm of the study compared to those in the oral PrEP arm (unadjusted hazard ratio for CAB vs. TDF/FTC:0.08 (95% confidence interval: 0.03, 0.27)).

A modelling analysis presented compared CAB-LA to a hypothetical control group that did not use PrEP similarly suggested a 91% effectiveness of CAB-LA at preventing HIV acquisition. In the oral PrEP arm of the HPTN 084 study, 35 out of the 36 infections occurred in women with poor or inconsistent adherence which was equivalent to participants taking less than 4 pills per week. This reinforces the message that, although oral daily PrEP is highly effective at preventing HIV for women, consistent use is needed to achieve high levels of protection.

Detection of HIV infection may be delayed when people who take PrEP use tests for HIV with diagnostic assays that are currently available in low- and middle-income countries, particularly when long-acting products like CAB-LA are used that are highly potent at suppressing HIV. It is a concern that this delayed diagnosis of HIV infection among people on long-acting PrEP could induce drug resistance, particularly against HIV treatments of the integrase strand transfer inhibitor (INSTI) class. The emergence of drug resistance is of particular concern given that dolutegravir (DTG), an INSTI HIV treatment drug, is recommended by WHO as the preferred first-line treatment for all populations. However, in the HPTN 084 trial, no major INSTI mutations were observed in the CAB-LA arm. This will be continued to be observed in open-label extensions of the study.

Drug resistance to antiretroviral drugs, which are also used for treatment, raises anxiety and requires ongoing monitoring. The Global Evaluation of Microbicide Sensitivity (GEMS) project implemented resistance monitoring resistance monitoring in oral PrEP users diagnosed with HIV, while participating in the national PrEP programs in Kenya, Zimbabwe and Eswatini and rollout projects in South Africa. Of the estimated 104,000 PrEP users, 229 individuals were reported to have acquired HIV, 208 provided a sample for the study, and 104 samples were successfully genotyped. Out of these 118 samples, (52) 44% had had at least one HIV drug resistance mutation, with 25 cases of resistance mutations unrelated to PrEP use as they likely originated from the antiretroviral therapy of the partner from whom HIV was acquired. However, there were 27 samples with mutations associated with PrEP drugs, most (23 of 27 cases) associated with emtricitabine (FTC) mutation (referred to as M184I/V). There were only four cases of tenofovir-resistant HIV. Recent studies have shown that HIV with the M1841/V mutations and/or tenofovir-associated mutations can be effectively treated with widely available combinations of antiretroviral drugs, which allays concern. Research by WHO presented at IAS 2021 documented large global increases in global increases in oral PrEP use, and the overall message is that the benefit of PrEP in preventing HIV outweighs the risk of drug resistance. However, continued monitoring for drug resistance with PrEP rollout, and for all PrEP products, will be important for the long-term success of both treatment and prevention programmes.

Further research was presented at IAS 2021 on Islatravir, a nucleoside reverse transcriptase translocation inhibitor with a long half-life, which offers the possibility of a single monthly oral dose. It is in development for both treatment and prevention of HIV. The safety and safety and pharmacokinetics (PK) during the first 24 weeks in a phase 2a trial. Oral monthly Islatravir 60mg and 120mg were well-tolerated and achieved the pre-specified PK threshold for HIV prevention. These results pave the way for two phase 3 clinical trials (IMPOWER-002 among cisgender women and IMPOWER-024 among men and transgender women who have sex with men) and highlight the exciting pipeline of HIV prevention products that will offer more choices to people at risk of HIV infection.

The dapivirine vaginal ring was recommended by WHO in January 2021 to be offered as an additional prevention option for women at substantial risk of HIV and WHO released its new consolidated HIV guidelines (2021), which includes this new recommendation and further guidance. Although two randomized controlled trials showed that the ring did prevent HIV infection in women, they failed to demonstrate efficacy in adolescent girls and young women – likely due to low adherence. This has also been a feature of some of the earlier oral PrEP trials that showed less effective use by young women. The interim results from the REACH study however were able to show higher adherence among young women in a more real-world setting to both oral PrEP and the dapivirine ring. Both products were well-tolerated and highly acceptable. REACH suggests that the dapivirine ring can be a viable, promising new HIV prevention method, and adherence to the ring and oral PrEP can be achieved with the right support strategies. Planning and designing PrEP programmes must include a focus on young women’s choices and understand ways that promote and support effective use.

Public Release. More on this here.