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Now we’ll review the different PrEP options, eligibility for each option by population, and the data to support the use of each option in the populations studied.
Before continuing, please take a moment to answer the following questions.
Oral FTC/TDF PrEP is approved by the FDA and recommended in US, Canadian, and WHO PrEP guidelines for use in broad populations, that is, MSM, TGW, heterosexual men and women, transgender men, and people who inject drugs (PWID).4,7-10
On-demand PrEP is the name for an alternative dosing strategy for oral FTC/TDF PrEP, where doses are taken before and after sex rather than daily. This approach has been in use primarily within Europe but has become more popular in the United States. It is an off-label strategy, although guidelines from the International Antiviral Society–USA panel and the WHO recommend on-demand oral FTC/TDF PrEP as an option for MSM, but not for other populations.
Daily oral FTC/TAF is approved by the FDA in people at risk of HIV from sexual acquisition, but not those at risk from receptive vaginal sex.11 PrEP guidelines recommend oral FTC/TAF in MSM, TGW, and heterosexual men. Off-label use in those at HIV risk from receptive vaginal sex is not recommended but is under investigation.
As noted, LA injectable CAB is approved by the FDA for use as PrEP in persons at risk of sexual acquisition of HIV.12 This includes a broad population of MSM, TGW, heterosexual men, heterosexual women, and transgender men.
Of note, CAB is not indicated in pregnancy. There have been some data from those who have become pregnant while receiving CAB in clinical trials, but data are limited to date.13
The dapivirine vaginal ring is an HIV prevention device intended for cisgender women and transgender men. It is not currently available in the United States. In Europe, it has received a positive opinion from the European Medicines Agency for use as an HIV prevention tool in women in high-burden settings,14 and it is recommended by the WHO as a choice to be offered to women at substantial risk of HIV infection.15
The efficacy of once-daily oral TDF-based PrEP has been evaluated in several large, randomized trials and numerus open-label extension studies and demonstration projects. In iPrEx, a blinded, placebo-controlled phase III trial conducted in MSM, the efficacy of FTC/TDF for reducing HIV incidence was 44.0% (P = .005).16
Partners PrEP was a placebo-controlled phase III study evaluating FTC/TDF in serodiscordant heterosexual couples.17 Efficacy in this study was 75.0% (P <.001). TDF2 was a similar phase II/III study conducted in the same population that reported 62.2% efficacy with FTC/TDF compared with placebo (P = .03).18
Finally, the Bangkok Tenofovir Study was a phase II/III trial of TDF monotherapy vs placebo in PWID.19 This study found 48.9% efficacy in reducing HIV acquisition (P = .01), increasing to 73.5% in individuals with detectable TDF (indicative of medication adherence).
The iPrEx open-label extension reported a 49% reduction in HIV incidence in MSM receiving FTC/TDF PrEP after adjusting for sexual practices.20 The PROUD study was a pilot study conducted in UK sexual health clinics that was terminated early after observing an 86% reduction in HIV incidence with immediate FTC/TDF PrEP vs initiation deferred for 12 months in MSM.21
Finally, a community-based PrEP demonstration project involving 557 MSM and TGW reported 2 HIV infections, equating to an HIV incidence rate of 0.43 (95% CI: 0.05-1.54) infections per 100 person-years.22 Both occurred in individuals who were not receiving PrEP daily based on dried blood spot testing of tenofovir diphosphate levels. Taken together, these studies provide compelling evidence of the “real-world” efficacy of FTC/TDF PrEP.
Dosing of the on-demand FTC/TDF PrEP strategy involves taking 2 pills 2-24 hours before sex, followed by 1 pill 24 hours after the first 2 pills, and then 1 further pill 48 hours after the first 2 pills.4 The efficacy of this “2-1-1” regimen was demonstrated in the IPERGAY trial, which reported an 86% risk reduction in MSM in the placebo-controlled phase of the trial (P = .002).23 A subsequent open-label extension phase, conducted in MSM and TGW who have sex with men, reported a 97% risk reduction with on-demand PrEP compared with the HIV incidence observed in the placebo arm of the randomized study.24
On-demand FTC/TDF PrEP is not an approved indication in the United States and has been rigorously studied only in MSM. It is not indicated or recommended as a PrEP option in other populations. On-demand dosing should not be used by MSM with hepatitis B infection, who should instead take any tenofovir-based PrEP regimen daily. This strategy may be better suited to those with infrequent sexual exposures and less appropriate for those who have difficulty adhering to complex dosing regimens, such as adolescents or people who are actively using substances. Daily PrEP is likely to provide the most effective protection in these groups.
The DISCOVER trial compared FTC/TAF with FTC/TDF PrEP in MSM and TGW.25 There were very few breakthrough HIV infections—7 in the TAF arm and 15 in the TDF arm at Week 48, giving a 47% incidence rate reduction with FTC/TAF. Noninferiority of the FTC/TAF regimen was maintained through 96 weeks, for a 54% reduction in HIV incidence.26
Use of the TAF regimen was associated with more favorable bone and renal safety at Week 96 compared with FTC/TDF.26 By contrast, median body weight increased with FTC/TAF. There was no statistical difference in weight gain between regimens within the first year, but by Week 96, there was significantly more weight gain with FTC/TAF than FTC/TDF (median 1.7 kg vs 0.5 kg; P <.001). There was a small increase in BMI from a median of 25.3 at baseline to 25.9 at Week 96 in the FTC/TAF arm, compared with stable BMI in the FTC/TDF arm. Although this difference was statistically significant, it may not be clinically significant, given the small increase observed.
HPTN 083 and 084 were large, international, randomized, double-blind phase IIb/III (083) and III (084) trials in which LA CAB given intramuscularly every 8 weeks was compared with daily oral FTC/TDF in MSM and TGW (083) or cisgender women (084).27,28 In both studies, CAB met criteria for superiority in preventing HIV infection vs daily oral FTC/TDF.
In HPTN 083, which recruited 4566 participants, there were 12 incident HIV infections in people receiving CAB, including 4 in people receiving on-time injections in the initial analysis. (A later analysis found that there have been 7 infections with on-time injections to date.)29 At present, there is no clear explanation for why these breakthrough infections occurred.
In HPTN 084, which recruited 3224 cisgender women, there were 4 incident HIV infections on CAB, including 1 breakthrough infection with on-time injections and 1 person who was later determined to have been infected at baseline. (A later analysis found an additional 3 infections in the CAB arm, but all were associated with poor/absent product use and no additional breakthrough infections with on-time injections.)28
Superior risk reduction with CAB was demonstrated in HPTN 083 with an HR of 0.34 (95% CI: 0.18-0.62) and in HPTN 084 with an HR of 0.12 (95% CI: 0.05-0.31). Again, these are compelling data supporting this new modality for effective protection against HIV infection.
I think it is probably the case that the superiority of CAB here is due not only to its potency as an integrase inhibitor, but also to the likelihood that a scheduled injection every 2 months results in higher adherence rates vs daily oral PrEP, at least in the context of a clinical trial. In HPTN 083 and 084, CAB was given as directly observed therapy, so in addition to having a higher likelihood of adherence, adherence could be precisely measured in the CAB arms and only estimated for the FTC/TDF arms. In HPTN 083, adherence to FTC/TDF was noted to be inadequate in approximately one third (38.7%) of people randomly selected for pharmacokinetic analysis of tenofovir exposure.27
Injection-site reactions (ISRs) were reported in 81.4% of people receiving CAB in HPTN 083 compared with 31.3% of those assigned to FTC/TDF in this placebo-controlled trial.27 However, this resulted in few permanent discontinuations (2.4%) in the CAB arm. In HPTN 084, 38% of patients receiving CAB had an ISR vs 10.8% in the FTC/TDF arm.28 There were no discontinuations due to ISRs in this study.
In HPTN 083, there was initial weight gain with CAB during the first 40 weeks and weight loss with FTC/TDF.27 After this, weight changes were similar across study arms. In HPTN 084, overall weight gain on CAB was similar to that seen with FTC/TDF, with mean annual increases of 2.4 kg and 2.1 kg, respectively.28
The overall impression, at present, is that FTC/TDF appears to have a neutral or even suppressive effect on weight, whereas FTC/TAF and CAB may result in some weight gain.
Available PrEP options differ in their impact on renal, bone, and body weight outcomes. In the iPrEx study conducted in MSM and TGW, there was a decrease in CrCl and bone mineral density at the hips and spine with daily FTC/TDF PrEP vs placebo.30,31 Weight gain was reduced with FTC/TDF PrEP vs placebo, and there was no evidence of altered fat distribution or lipodystrophy.32 For patients with concern about weight gain, or those already in a higher BMI category, FTC/TDF may be preferred over other agents.
On-demand FTC/TDF PrEP was compared with placebo in MSM in the IPERGAY study, which reported a small decrease in the estimated glomerular filtration rate and no new proteinuria or glucosuria in patients receiving active treatment.33 There are no published data on the bone effects or weight changes associated with this strategy.
Daily FTC/TAF was compared with daily FTC/TDF in MSM and TGW in the DISCOVER trial. There were improvements in proximal tubular renal function with FTC/TAF and small increases in bone mineral density at the hip and spine through 96 weeks.34 Use of FTC/TAF was associated with increased weight gain compared with FTC/TDF.26 Again, this suggests that for people with concern about weight gain, FTC/TDF may be preferred over FTC/TAF.
Finally, LA CAB has been compared with FTC/TDF in MSM and TGW in HPTN 083 and in cisgender women in HPTN 084.27,28 These studies have not yet reported the changes in renal values over time but have reported similar rates of renal adverse events between groups. Data on bone outcomes with CAB have not yet been reported.
In HPTN 083, there was a slight increase in weight gain with CAB for the first 40 weeks and then similar overall weight change across the 2 regimens later in the trial. In HPTN 084, women receiving CAB experienced an initial increase in weight, but overall, mean weight was increased in both groups.
In addition to the PrEP renal outcomes just reviewed, we also have extensive clinical experience with use of TDF in HIV treatment regimens. The totality of evidence has shown that TDF is associated with mild decreases in renal function and rare cases of renal failure.4 For this reason, FTC/TDF PrEP is reserved for patients with a CrCl ≥60 mL/min. Oral FTC/TAF PrEP can be used in patients with CrCl ≥30 mL/min. CAB is not renally excreted and can be considered for use at any level of CrCl.