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Department of Infectious Diseases
Rush University Medical Center
Department of Infectious Diseases
Cook County Health
Gregory Huhn, MD, MPH, has disclosed that he has received funds for research support from Gilead Sciences, Janssen, Lilly, Proteus, and ViiV; has received consulting fees from Janssen and Lilly; and has served on advisory boards or panels for Gilead Sciences, Janssen, and ViiV.
Toward the goal of ending the HIV epidemic in the United States, one of the most critical pillars of the nationwide public health initiative is to expand access and uptake of pre-exposure prophylaxis (PrEP). Specifically, the goal is to increase PrEP use in at-risk populations at least 50% by 2025. As we approach the halfway point for this 10-year goal, what has been our progress to date?
Currently, among the 1.2 million Americans who are eligible for and likely to benefit from PrEP, only 18% are receiving it. Moreover, although Black and Hispanic individuals account for 69% of new HIV infections in the United States, those initiating first-time PrEP are largely White (66%). So, we have underrepresented populations among new PrEP starts, underscoring the need for HIV prevention programs to focus on locally tailored, link-and-treat prophylaxis strategies to engage those populations at high risk for HIV transmission as a necessary step to achieve the national goals in Ending the HIV Epidemic in the United States.
DISCOVER: FTC/TAF vs FTC/TDF
We now have the latest data and the latest indication for tenofovir-based PrEP with emtricitabine (FTC)/tenofovir alafenamide (TAF), which was licensed in October 2019 based on data from the phase III DISCOVER trial.
The DISCOVER trial is an international, randomized, double-blind, head-to-head comparison of FTC/TAF vs FTC/tenofovir disoproxil fumarate (TDF) for HIV prevention in cisgender men who have sex with men (MSM) and transgender women at high risk for HIV infection. The study leveraged the favorable attributes of TAF, including reduced off-target effects for bone and renal safety, as well as more efficient uptake for achieving steady state levels of active diphosphorylated tenofovir (approximately 6-fold higher with FTC/TAF vs FTC/TDF). FTC/TAF also boasts more rapid kinetics vs FTC/TDF, reaching an effective concentration above the target threshold of 90% within 1-2 hours vs 3-4 daily doses with FTC/TDF.
In the most recent analysis of DISCOVER, the noninferiority of FTC/TAF was maintained at Week 96. The noninferiority margin was set at 1.62, which preserves 50% of the FTC/TDF effect from the 3 previous randomized-controlled trials in MSM. At 96 weeks, 7 HIV infections occurred in the FTC/TAF arm vs 15 in the FTC/TDF arm. Excluding 5 suspected baseline infections, the incidence rate ratio (IRR) was 0.54 in favor of FTC/TAF, which was within the noninferiority criteria and comparable to the 0.55 IRR at the Week 48 primary analysis. Most of these breakthrough infections were due to low adherence (fewer than 2 doses per week).
These updated data further solidify that FTC/TAF is a highly effective strategy for HIV prevention, particularly for persons at higher risk for renal dysfunction or decreased bone mineral density, and those with current renal or bone conditions. However, it is important to note that the DISCOVER trial population was 84% White and 9% Black and therefore not representative of the demographics comprising new HIV infections in the United States. Moreover, I would say that FTC/TDF remains the standard of care for HIV prevention in most populations, including those without renal and bone safety concerns, as well as—of importance—cisgender women. We do not yet have efficacy data for FTC/TAF in cisgender women, but multiple studies are currently underway.
By contrast to daily PrEP, on-demand PrEP targets prophylactic dosing around infrequent incidents of high-risk sexual exposure. Individuals take 2 FTC/TDF pills 2-24 hours previous to sexual intercourse followed by 1 pill 24 hours afterward, and a final pill 48 hours afterward. On-demand PrEP is primarily recommended by advisory boards outside of the United States and is not fully endorsed by the DHHS. This approach offers an expanded HIV prevention tool kit for MSM with infrequent sexual encounters and those who are able to plan sex. Indeed, both the International Antiviral Society-USA and WHO endorse this strategy in those circumstances. I should emphasize that on-demand PrEP should not be used for HIV prevention by high-risk heterosexual men and women, transgender men and women, persons who use drugs, or people with hepatitis B infection, because we do not have data in these populations.
HPTN 083: Long-Acting Injectable CAB vs Daily Oral FTC/TDF
Daily oral PrEP is remarkably effective if taken with a certain degree of adherence—at least 4 pills per week. However, as we seek to develop new innovations for PrEP, one goal is to limit the requirements for near-daily adherence. To this end, the integrase inhibitor cabotegravir (CAB) has been in development as a long-acting injectable therapy and is also under evaluation for prevention of infection.
The international randomized double-blind phase IIb/III HPTN 083 study compared long-acting CAB injections vs daily oral FTC/TDF for HIV prevention in MSM and transgender women at high risk of infection.
Of importance, the HPTN 083 investigators made an effort to recruit populations who have been previously underrepresented in clinical trials for oral PrEP agents. For example, the enrollment targets for both Black participants in the United States and persons younger than 30 years of age was 50% or greater. This is a very important consideration, because, as I learned during my training at the CDC, epidemiology is information for action. Once we understand the burden of disease among communities, then we can explore the effectiveness, safety, and implementation of interventions aimed at addressing the disparities for those at higher risk. Indeed, those prespecified enrollment goals were achieved in HPTN 083, with Black participants comprising 49.7% of the US enrollment and a median age of 26 years.
At the interim analysis, when 25% of the endpoints had accrued, the Data and Safety Monitoring Board (DSMB) recommended terminating the study due to crossing the pre-specified stopping bound. In the CAB arm, there was a 66% reduction in new HIV infections relative to the FTC/TDF arm (13 vs 39 infections), with CAB demonstrating statistically significant superiority.
We are awaiting further analysis of the breakthrough infections in the CAB arm. We know that 2 occurred at baseline, and 5 were associated with poor adherence. Among the remaining breakthrough infections, which occurred in the context of good adherence to the study regimen, it is not yet clear if they were associated with resistance, host factors, etc. Data are still forthcoming, due to COVID-related reporting delays, that will address these outstanding questions.
However, in perspective, 13 infections out of more than 2200 participants in the CAB arm is extremely important. This trial overwhelmingly fulfilled its objectives, and it was exciting to see the DSMB unblind the study and open up the CAB arm to all enrolled participants.
HPTN 084: Long-Acting CAB in Cisgender Women
Continuing the story of long-acting injectable CAB as HIV prevention, the phase III HPTN 084 study is evaluating long-acting CAB vs daily oral FTC/TDF in cisgender women in Sub-Saharan Africa. The trial is now fully enrolled following a pause due to COVID-19 in March through June.
In May, the DSMB examined the data to date and recommended continuing the study, and informing all of the participants of the outcome of HPTN 083, to encourage their continued participation. We look forward to the findings from this trial to understand if long-acting CAB will prevent HIV infection in cisgender women. We cannot extrapolate the data from HPTN 083, as there are different routes of HIV acquisition in women and potential differences in pharmacokinetics. Moreover, this trial will gather safety data in cisgender women of childbearing potential and likely some pharmacokinetic data in women who become pregnant while participating in the study.
Long-Acting CAB in Adolescents
Finally, there are 2 ongoing studies of long-acting CAB as HIV prevention in adolescents. The HPTN 083-01 and HPTN 084-01 studies are enrolling adolescents younger than 18 years of age who are not currently receiving PrEP at 3 sites in the United States (Chicago, Boston, and Memphis), as well as 3 international sites (Johannesburg, Harare, and Kampala). Together with the HPTN 084 study, we look forward to more information on this prevention regimen in 2021.
To summarize, we have made encouraging progress toward expanding PrEP use through the development of new PrEP regimens. There is a great need for these innovations, as we will be challenged to reach our expanded use goals with daily oral PrEP alone. Indeed, among providers who treat persons at high risk for HIV and see patients who seek out PrEP, 70% say that approximately 25% to 50% of their patients would be in favor of long-acting formulations.
Do you anticipate incorporating long-acting CAB into your HIV prevention practice? Answer the polling question and join the discussion by posting a comment. For more discussion of HIV prevention, treatment, and COVID-19–related issues, download the slides and watch the videos from our recent HIV Annual Update symposium.