On-demand† PrEP involves taking two tablets of TD*/FTC 2–24 hours before a potential sexual exposure to HIV, followed by a third tablet 24 hours after the first dose and a fourth tablet 48 hours after the first dose. If sex continues beyond one day, a user of on-demand† PrEP can stay protected by continuing to take a pill every 24 hours for each day that sex occurs. A PrEP pill should be taken each day for the two days following the last day that sex occurred.
The World Health Organization (WHO) recently released a technical brief recommending the use of on-demand† PrEP for cis-gender men who have sex with men (MSM) (6). The 2021 ASHM PrEP Guidelines Panel endorses WHO’s recommendation that on-demand† PrEP should be offered to cis-gender MSM. On-demand† PrEP is recommended only for cis-gender MSM because its efficacy is yet to be determined in all other populations at risk of HIV infection. The ASHM PrEP guidelines panel recommends that caution be used in recommending on-demand† versus daily PrEP to adolescent MSM because there have been no trials of on-demand† PrEP in adolescent MSM and because adherence rates to daily PrEP have been consistently low in studies of adolescent MSM (7, 8). Of note, on-demand† PrEP is contraindicated in people with chronic hepatitis B infection.
Evidence in support of on-demand† PrEP dosing
Data on the efficacy of non-daily PrEP dosing are available for cis-gender MSM. Very few transgender women have been evaluated in randomised controlled trials of on-demand† PrEP (9-11); nor have such trials been undertaken in cis-gender women or cis-or transgender men, or in people whose principal HIV exposure risk is injecting drug use. Pharmacological studies in cis-gender women suggest that on-demand† PrEP does not provide adequate tissue levels of PrEP to provide high levels of HIV protection and on-demand† PrEP should not be recommended for cis-gender women.
Data on how efficacious on-demand† PrEP is for MSM in reducing HIV transmission came initially from the randomised, placebo-controlled trial, IPERGAY (Intervention Préventive de l’Exposition aux Risques avec et pour les Gays) (12). This study evaluated the efficacy of on-demand† PrEP comprising two tablets of TDF/ FTC (versus placebo) taken 2–24 hours before potential sexual exposure to HIV, followed by a third tablet 24 hours after the first dose and a fourth tablet 48 hours after the first dose. If multiple episodes of sex occurred, the participants were advised to continue to take one tablet daily until the last sex act then take the two final doses, 24 hours apart. If sexual activity was resumed within a week, a single, rather than a double dose before sex was recommended. If sexual activity resumed more than a week later, the loading dose schedule (two tablets) was recommenced. The incidence of HIV was high in the placebo group (6.6 per 100 person-years) and a risk reduction in the TDF-FTC group of 86% [95% confidence interval (CI), 40 to 98; p = 0.002] was observed (12).
Demonstration studies have been undertaken to determine how effective on-demand† PrEP is when used in community settings. In an open-label extension study of the IPERGAY study, an HIV risk reduction of 97% (95% CI, 81–100) with on-demand† PrEP was reported in 361 participants with a median follow-up of 18 months (10). In a study of 1,069 people commencing PrEP in a single clinic in France, four HIV infections were diagnosed over 486 years of person follow-up (9). In the French Prévenir study, an interim analysis presented in July 2019 at the IAS conference on HIV science showed that of 2,143 participants, 47% took daily PrEP and 52% took on-demand† PrEP (11). The median number of partners in the 3 months before PrEP commencement was 15 (IQR: 7-25) in the daily group and 10 (IQR 5-15) in the on-demand† group (p < 0.001). The median number of condomless sex events in the previous 4 weeks was 2 (0 to 8) and 2 (0 to 4), in the daily and on-demand† participants, respectively (p = 0.04). Follow-up in the daily and on-demand† groups was 744 and 830 person-years, respectively. The HIV-1 incidence was 0 (95% CI: 0-0.5) and 0 (95% CI: 0-0.4) per 100 person-years in the daily and on-demand† groups, respectively (11).
The efficacy of on-demand† PrEP in people who use it infrequently
To address the question of whether on-demand† PrEP is efficacious for people using it infrequently, the IPERGAY study team undertook a post-hoc analysis of IPERGAY study participants who reported relatively infrequent sex (13). Overall, IPERGAY participants reported using a median of 15 PrEP tablets per month (interquartile range (IQR 9–21). The post-hoc study looked at the follow-up time between two consecutive visits during which participants in the placebo and active study arms used ≤ 15 tablets per month and reported they used PrEP ‘systematically or often’ and not ‘from time to time or never”. During these periods of lower PrEP use, participants had a median of five episodes of sex per month (IQR 2-10) and used a median of 9.5 tablets per month (IQR 6-13). Six HIV infections occurred in the placebo arm (incidence: 9.3 per 100 person-years, total follow-up time: 64.8 person-years) and 0 in the TDF/FTC arm (incidence: 0 per 100 person-years, total follow-up time: 68.9 person years, p = 0.013). The relative reduction of HIV incidence in the treatment group was 100% (95% CI, 20-100). The study investigators concluded that an on-demand† PrEP strategy remains highly effective in MSM even when they have infrequent sex (13).
Notably, of concern to the ASHM PrEP Guidelines Panel were the wide 95% confidence intervals of the relative risk reduction in this group of IPERGAY participants practising infrequent sex. However, the recently updated data from the Prévenir study (11) are reassuring in terms of the efficacy of less frequent use of on-demand† PrEP. These updated data show that the median number of partners in the previous 3 months for participants using on-demand† PrEP was 10 (IQR 5-15) and the median number of condomless sex events in the previous 4 weeks was 2 (0 to 4) (p = 0.04) with an associated HIV incidence in the on-demand† participants of 0 (95% CI: 0-0.4) (11).
Toxicity and on-demand† PrEP
There are few data available to determine whether on-demand† PrEP offers less toxicity. In the IPERGAY study, no significant decline in the mean slope of estimated glomerular filtration rate (eGFR) in the TD*/ FTC versus placebo arms was observed over a median of 9.3 months follow-up (14). In the HIV Prevention Trials Network (HPTN) study 067, the Alternative Dosing to Augment PrEP Pill Taking (ADAPT) study, 9% of 178 participants at one study site had creatinine elevation, but this was not significantly different between participants in the daily, time-driven and on-demand† PrEP study arms (p = 0.05) (15).
Preference for on-demand† versus daily PrEP
In the ongoing French Prévenir study, in which MSM are offered the choice of daily or on-demand† PrEP, approximately half of the participants opt for each regimen (11). In the AM PrEP (the Netherlands) and Be PrEPared (Belgium) implementation studies, approximately one-third of men opted to take PrEP on-demand† (16). In a report from the PRELUDE study from New South Wales, one third of participants enrolling in the study expressed a preference for non-daily PrEP (17). Recent data from previous participants of the Victorian PrEPX study showed that 48% would be interested in participating in an on-demand† PrEP study (18) and this interest was most strongly associated with having sex infrequently and concerns about long-term toxicity) (18).
† The Therapeutic Goods Administration (TGA) has not approved this regimen in Australia.