This type of analysis makes it possible to estimate the expected incidence of HIV in the event that a placebo control group had been included in a trial
The use of cabotegravir as pre-exposure prophylaxis (PrEP) against HIV administered in injections every two months would be highly effective in women. This effectiveness could be even greater than suggested in previous analyzes. This is the main conclusion of a study whose results were announced at the XI Conference of the International AIDS Society on the Science of HIV (IAS 2021), held last week virtually due to the COVID-19 pandemic
Long-acting injectable cabotegravir (Vocabria®) is a new integrase inhibitor that has been licensed as a treatment for HIV infection and is administered monthly or bi-monthly together with long-acting injectable rilpivirine (Rekambys®). Cabotegravir has also been developed for the prevention of HIV although its use as PrEP has not yet been licensed.
The HPTN 084 study compared the safety and efficacy of cabotegravir as bimonthly injectable PrEP with daily oral PrEP based on tenofovir disoproxil fumarate / emtricitabine (TDF / FTC; Truvada® or Generic Pharmaceutical Equivalent [EFG]). This trial included more than 3,000 cis women between the ages of 18 and 45 from seven sub-Saharan African countries who were at risk of acquiring HIV.
In November 2020, the blind phase of the study was stopped when an 89% lower risk of acquiring HIV was found among women who received injectable cabotegravir than among participants who took daily oral PrEP. Of the 38 infections that were recorded in the study, only four occurred in the cabotegravir arm and the remainder in the oral PrEP arm, which would translate into an annual HIV incidence of 0.21% and 1.79%, respectively. This result would show up as the highest efficacy ever seen in PrEP research in women.
In parallel, the HPTN 083 study found that for gay, bisexual and other men who have sex with men (GBHSH) and trans women, injectable cabotegravir was 66% more effective than daily oral PrEP. However, while daily oral PrEP has had excellent results in GBHSH men, studies have found it to be less effective in women, largely due to the difficulty women have in maintaining optimal adherence, so there is room for improvement.
During the IAS conference, a group of South African researchers presented the results of an analysis of the 40 HIV cases that were recorded during the HPTN 084 study, 4 in the cabotegravir group and 36 in the PrEP group oral.
Of the four women who acquired HIV in the cabotegravir group, two never received any injections. The first was because, after completing the induction period with oral cabotegravir, he did not show up at the first scheduled visit to receive the injection. The other case was that of a woman who, upon becoming pregnant, switched to oral PrEP before she received her first scheduled injection. The third case was that of a woman who missed or delayed several injections and who had not received an injection during the 16 weeks prior to being diagnosed with HIV at 73 weeks after entry into the study. She showed no evidence of mutations conferring resistance to integrase inhibitors and was successfully linked to care and treatment.
The fourth case was that of a woman who tested positive for HIV after completing the induction phase with oral cabotegravir and receiving five injections with appropriate concentrations of the drug. However, after retrospective analysis, it was shown that she already had HIV when she enrolled in the study. The investigators indicated that cabotegravir exposure is associated with a decrease or delay in the expression of antibodies to HIV and, consequently, the diagnosis of this infection. This phenomenon could also be observed among the men participating in the HPTN 083 study. The woman also did not develop resistance mutations to integrase inhibitors.
On the other hand, of the HIV-positive women in the oral PrEP group, tablet counts and tenofovir levels around the time they tested positive for HIV showed that all but one had poor or poor adherence. inconsistent. This caused a delay in the detection of HIV in eight cases and several developed resistance mutations to the antiretroviral drugs included in oral PrEP.
Once the data were updated and the woman who already had HIV was reclassified at the time of study entry, an HIV incidence of 0.15% was found for the cabotegravir group and 1.85% for the group. oral PrEP group, resulting in a 92% reduction in HIV risk.
For ethical reasons, the research on biomedical HIV prevention tools compares the products under investigation with the standard of PrEP available, which for women would currently be the daily use of TDF / FTC by mouth. However, mathematical models can be used to compare efficacy against a control group with a hypothetical placebo derived from previous studies to estimate the expected incidence of new HIV infections if no biomedical prevention method is used.
Using these mathematical models, researchers at the Fred Hutchinson Cancer Research Center in Seattle (USA) compared new HIV infections in women using injectable cabotegravir as PrEP in HPTN 084 versus a hypothetical placebo, the incidence of which came from the group who received placebo in the VOICE trial, a study that evaluated the efficacy of PrEP using three different options: oral tenofovir, oral tenofovir / emtricitabine, and the use of a vaginal microbicidal gel with tenofovir.
The researchers also adjusted the risk estimates using responses from a risk survey developed for VOICE and matched with the one used in the HPTN 084 trial by selecting a cohort at increased risk of contracting HIV. This questionnaire asked about age, marital status, financial support from the main partner, sexually transmitted infections, and alcohol consumption. In order to fine-tune women's risk of acquiring HIV, HIV rates and viral suppression among men with HIV in the trial site communities were also taken into account.
At the end of the study, and to give it even more validity, the same method was applied to the placebo control groups of different studies carried out in sub-Saharan Africa between 2005 and 2019: HPTN 035 (which evaluated a vaginal microbicide), FEM -PrEP (which evaluated the use of TDF / FTC), ASPIRE (which evaluated a vaginal ring) and ECHO (which evaluated whether contraceptives affect the acquisition of HIV).
Overall, the researchers projected a hypothetical placebo HIV incidence of 2.2% for the HPTN 084 study cohort. Comparing this to the 0.2% incidence rate recorded in the cabotegravir arm (they did not use revised incidence), estimated that injectable cabotegravir would be 91% effective in preventing HIV versus placebo. In contrast, given the 1.85% HIV incidence rate in the TDF / FTC group, this suggests that daily PrEP tablets are only 15% more effective than a placebo in women.
In their conclusions, the researchers celebrate the good results obtained and propose to employ new and various hypothetical placebo approaches to further refine their initial estimates.
Source: Aidsmap / Elaboración propia (gTt-VIH).
References: Marzinke M et al (Delany-Moretlwe S presenting). Long-acting injectable PrEP in women: laboratory analysis of HIV infections in HPTN 084. 11th IAS Conference on HIV Science, abstract PECLB25, 2021.
Moore M et al. Estimated long-acting PrEP effectiveness in the HPTN 084 cohort using a model-based HIV incidence in the absence of PrEP. 11th IAS Conference on HIV Science, abstract OAC0105, 2021.