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The guidelines are aimed at clinical professionals directly involved in, and responsible for, HIV prevention, and at community advocates and organisations responsible for supporting HIV prevention strategies in those at risk of HIV acquisition. A detailed review of the evidence base is included in Section 4. Sections 5–7 are intended to offer practical guidance in risk assessment, starting PrEP, ongoing management while on PrEP and stopping PrEP. We recognise the importance of these guidelines being inclusive and relevant to all, regardless of sexuality or gender identity or expression. For the sake of brevity in the main text of the guidelines, phrases such as "men who have sex with men" refer to cis-gender or non-binary or gender-queer men who have sex with men and "heterosexual men and women" refer to cis-gender or non-binary or gender-queer men and women who have heterosexual sex. Where sections are specifically relevant to trans people, we identify this using the terms trans people, trans men or trans women. The multidisciplinary guideline writing group developed the guidelines based on the process outlined in the BHIVA Guidelines Development Manual 1. All members of the group underwent GRADE training. We undertook a comprehensive literature review on PrEP and HIV prevention using the PICO question shown below. The recommendations are the result of a series of face-to-face and virtual meetings of the writing group and a meeting of community activists and organisations who commented on a draft of the guidelines in May 2017. The writing group also reviewed and incorporated input from the public consultation process. The literature review search was from January 2004 to May 2016. Medline, Embase and Cochrane databases were searched. Only papers in English were included and animal studies were excluded. In addition, although the formal literature review was not repeated, subsequent evidence published between May 2016 and July 2017 that the writing group felt was relevant has been included. A Grade 1 recommendation is a strong recommendation to do (or not do) something, where benefits clearly outweigh risks (or vice versa) for most, if not all, patients. Most clinicians and patients would want to follow a strong recommendation unless there is a clear rationale for an alternative approach. A strong recommendation usually starts with the standard wording "We recommend". A Grade 2 recommendation is a weaker or conditional recommendation, where the risks and benefits are more closely balanced or are more uncertain. Alternative approaches or strategies may be reasonable depending on the individual patient's circumstances, preferences and values. A weaker or conditional recommendation usually starts with the standard wording "We suggest". The strength of a recommendation is determined not only by the quality of evidence for defined outcomes, but also the balance between desirable and undesirable effects of a treatment or intervention, differences in values and preferences, and where appropriate, resource use. Each recommendation concerns a defined target population and is actionable. In addition to graded recommendations, the writing group has also included good practice points (GPPs). GPPs are recommendations based on the clinical judgement and experience of the working group and feedback from community and public consultation. GPPs emphasise an area of important clinical practice for which there is not, nor is there likely to be, any significant research evidence. They address an aspect of treatment and care that is regarded as such sound clinical practice that healthcare professionals are unlikely to question it, and where the alternative recommendation is deemed unacceptable. It must be emphasised that GPPs are not an alternative to evidence-based recommendations. The guideline writing group included representation from Terrence Higgins Trust and NAZ. In order to widen the stakeholder involvement, a meeting of community activists and organisations was held in May 2017, when feedback was sought on the content of the draft guidelines and recommendations prior to wider public consultation. We acknowledge the following for their helpful contributions: Yusef Azad (NAT), Takudzwa Mukiwa (THT), Will Nutland (Prepster), Greg Owen (I Want PrEP Now), Michelle Ross (CliniQ), Sophie Strachan (Sophia Forum), Marc Thompson (Prepster/Black Out UK) and George Valiotis (HIV Scotland). The guideline writing group recognises that although the PrEP trials used tenofovir disoproxil fumarate (TDF), increasingly other salts of tenofovir disoproxil (including maleate, succinate and phosphate) will be used in generic formulations. We have therefore used the acronym TDF-FTC where Truvada was used in a trial and TD-FTC to denote all other (generic) forms of tenofovir disoproxil and emtricitabine. The iPrEx study 1 was a Phase 3, randomised, double blind, placebo-controlled, multi-centre trial conducted among 2499 MSM and trans male-to-female adults (n = 339) in Peru, Ecuador, Brazil, Thailand, South Africa and the United States. Participants were randomly assigned to either a daily dose of TDF-FTC (1251 participants) or placebo (1248 participants). Primary outcome was HIV infection with a total of 3324 person-years of follow-up. Over the course of the study, 100 participants became infected with HIV; 36 in the TDF-FTC group and 64 in the placebo group, representing a 44% (95% confidence interval [CI] 15–63) reduction in HIV incidence using a modified intention-to-treat (ITT) analysis, excluding those confirmed HIV positive at randomisation. Efficacy was higher in the per-protocol analysis; at visits where adherence was >50% by self-report and pill count/dispensing, efficacy was 50% (95% CI 18–70). The PROUD study was a Phase 3, randomised, open-label, multi-centre trial conducted in 544 MSM at 13 sexual health clinics in England 2. Participants were randomly assigned to a daily dose of TDF-FTC immediately (275 participants), or after a deferral period of 12 months (269 participants). Primary outcomes were time to accrual of 500 participants and retention at 12 and 24 months; HIV infection was a secondary outcome. At interim review, the DSMB recommended that all study participants should be offered study drug. A total of 23 participants became infected with HIV over the course of the study: three in the daily TDF-FTC group and 20 in the deferred (no-PrEP) group, representing a rate difference in HIV infection of 7.8 per 100 person-years (90% CI 4.3–11.3) The relative risk reduction was 86% (90% CI 64–96%) and the number needed to treat over 1 year to prevent one HIV infection was 13 (90% CI 9–23). The IPERGAY study was a Phase 3 double-blind, randomised, multi-centre trial conducted among 414 MSM in France and Canada 3. Participants were randomly assigned to either receiving an on-demand regimen of TDF-FTC (206 participants) or placebo (206 participants). The on-demand regimen involved taking a double dose of TDF-FTC 2–24 h before sex, and a daily dose during periods of sexual risk and for 48 h (two doses) after ceasing sexual risk. Participants were followed up every 8 weeks for HIV testing and risk-reduction advice, and every 6 months for sexually transmitted infection (STI) testing for a total of 431 person-years of follow-up. Primary endpoint was HIV infection. At interim review, the placebo group was discontinued and all study participants were offered study drug. Over the course of the study, 16 people became infected with HIV: two in the TDF-FTC group and 14 in the placebo group, representing a relative risk reduction of 86% (95% CI 40–98%) in the ITT analysis. One Phase 2 safety trial, the CDC MSM Safety Trial 4, compared tenofovir (TDF) to placebo in a randomised, double-blind, placebo-controlled, wait-listed design among 400 HIV-negative MSM. Participants were randomly assigned in a 1:1:1:1 design to receive TDF or placebo immediately or after 9 months. Main endpoints were safety and behavioural outcomes. There were no infections among those taking active drug. Seven participants seroconverted: four in the placebo arm and three among delayed-arm participants who were not on the study drug. An eighth participant was HIV positive at enrolment. Two further smaller studies include a pilot feasibility and acceptability study, Project PrEPare, which recruited 58 young MSM aged 18–22 years in the United States. Participants were randomly allocated to receive a behavioural intervention alone, the behavioural intervention and PrEP (TDF-FTC) or the behavioural intervention and placebo. There were no seroconversions among the 58 participants 5. The IAVI Kenya Study was a small safety and adherence study conducted among Kenyan MSM and female commercial sex workers (CSWs). Sixty-seven MSM and five female CSWs were randomly assigned to daily TDF-FTC or placebo, or intermittent (Monday, Friday and within 2 h after sex) TDF-FTC or placebo in a 2:1:2:1 ratio. There was one seroconversion in the placebo arm 6. The iPrEx Open-label Extension (iPrEx-OLE) 7 enrolled 1603 HIV-negative men and 339 (14%) trans women who have sex with men who were previously part of PrEP studies (iPrEx, ATN082/Project PrEPare and CDC MSM Safety Trial). Participants were offered daily TDF-FTC and were followed up for 72 weeks after enrolment. Uptake was high at 76%, and this was higher among those reporting condomless receptive anal intercourse and those who were herpes simplex-2 virus (HSV-2) seropositive, suggesting use during periods of risk. HIV incidence was 1.8 infections per 100 person-years, compared with 2.6 infections per 100 person-years in those who concurrently did not choose PrEP (hazard ratio [HR] 0.51, 95% CI 0.26–1.01, adjusted for sexual behaviours) 7. Examination of drug levels by dried blood spot testing was extrapolated to pill taking and compared to HIV incidence each quarter. No seroconversions were seen when drug levels were compatible with taking four or more pills per week. The IPERGAY Open-label Extension (IPERGAY-OLE) enrolled 362 individuals to take on-demand TDF-FTC and followed them for a median of 11.7 months, of whom 299 (83%) completed follow-up with a single HIV infection (0.19 per 100 person-years, 95% CI 0.01–1.08) 8. A community-based clinic in San Francisco screened 1249 MSM (and three trans men) and offered PrEP with TDF-FTC with 95.5% uptake. Condomless sex was reported by 93% at enrolment. After a maximum of 16 months' follow-up there were no new HIV infections in the men enrolled in the programme 9. At the time of writing there have been three case reports of HIV transmissions in MSM taking PrEP despite apparent confirmed adherence. Two individuals were infected with resistant virus and, in one case, transmission occurred with wild-type virus sensitive to both tenofovir and emtricitabine 10. Efficacy of PrEP is highly dependent on adherence, with a meta-analysis of PrEP studies 12 demonstrating that adherence is a significant moderator of PrEP effectiveness. The higher the levels of adherence to oral PrEP in the study population, as measured by detectable drug, the greater the efficacy. In the iPrEX study, adherence was monitored using pill count and self-reported adherence. Pharmacokinetic plasma and intracellular drug-level sampling was conducted in a pre-specified subgroup analysis where subjects with HIV infection were matched with two controls selected from seronegative subjects. In those who had detectable drug levels of TDF-FTC, the reduction in HIV incidence was 92% (95% CI 40–99%) compared to those who had no drug detected 1, suggesting that a high level of adherence is associated with a high level of efficacy. In the PROUD study, adherence was monitored using prescription data, self-reported adherence and drug levels in a convenience sample of study participants. Overall, sufficient study drug was prescribed for 88% of the total follow-up time and tenofovir was detected in all samples taken from 52 participants who reported taking study drug within the preceding 3 days 2. In the IPERGAY study, adherence was monitored using pill counts, self-reported adherence and drug levels in a subset of 113 participants. Of participants in the active treatment group who had drug levels measured, protective drug levels of tenofovir were detected in 86%. However, computer-assisted interview (CASI) data collected in 319 participants in the randomised phase suggested that only 43% of people took study drug correctly during last sexual intercourse, 29% took a suboptimal dose and 28% did not take the study drug at all 3. In the open-label phase, adherence in 362 men completing 1617 CASI returns reported 50% of men taking study drug correctly during last sexual encounter, 24% taking a suboptimal dose and 26% taking no study drug at all 8. Comparison of adherence to different regimens of TDF-FTC PrEP has been investigated in MSM in the HPTN 067 (ADAPT) study. The study recruited MSM and trans women in Harlem (New York, USA) and Thailand and heterosexual women in South Africa. Following a 4-week phase of daily dosing, participants were randomly assigned 1:1:1 to one of three regimens: daily dosing ("daily") or one tablet twice a week and one tablet post sex ("time driven") or one tablet 24–48 h before sex and one tablet within 2 h after sex ("event-based"). Results from 178 Thai MSM showed that coverage (defined as taking more than one pill in the 4 days before sex and more than one pill in the 24 h afterwards) was significantly higher in the daily (85% of events covered) and time-driven (84%) arms than in the event-driven arm (74%). Two seroconversions occurred in the 4 week pre-randomisation phase 13. In 179 MSM in Harlem, figures were 66%, 47% and 52%, respectively, with one seroconversion in the pre-randomisation phase and one in the randomised phase 14. Adherence was higher in the daily-dose arms: in Thailand, 85% of daily doses, 79% of twice-weekly doses, and 65% of event-driven doses were taken as prescribed. In Harlem, the respective figures were 65%, 46% and 41%. Although these represent two diverse populations of MSM in different settings, the study demonstrated similar coverage of sex acts for daily and non-daily regimens with both groups demonstrating lower adherence and coverage rates for the event-driven approach. Higher coverage of events in the Thai MSM was associated with older age and higher level of education. Use of stimulant drugs and higher sexual frequency was associated with lower coverage 15. To date, studies of TDF-FTC PrEP suggest short-term safety. A meta-analysis of PrEP studies 12 demonstrated no difference in the proportions of adverse events comparing PrEP to placebo across 10 placebo-controlled RCTs (odds ratio [OR] 1.01, 95% CI 0.99–1.03, P = 0.27) with no differences seen in subgroup analysis that included mode of acquisition, adherence, sex, drug regimen, dosing or age. No differences were seen in grade 3 or 4 adverse events comparing PrEP and placebo groups across 11 placebo-controlled RCTs (risk ratio [RR] 1.02, 95% CI 0.92–1.13, P = 0.76). Results were not presented by subgroup. In the iPrEx study, there was no difference in reported adverse events between the two study arms: 867/1251 (67%) of participants in the TDF-FTC arm reported any adverse event, compared to 877/1248 (70%) in the control arm. Both arms reported similar rates of grade 3 and 4 adverse events: 151/1251 (12%) of TDF-FTC participants compared to 164/1248 (13%) of control-arm participants 1. There was no difference in permanent or temporary discontinuation of study drug between the two arms: 25/1251 (2%) permanent discontinuations in the intervention arm compared to 27/1248 (2%) in the placebo arm and a total of 79/1251 (6%) permanent or temporary discontinuations in the intervention arm compared to 72/1248 (6%) in the placebo arm. However, nausea was more common among those taking TDF-FTC compared to placebo in the first month (95% vs. 5%). Depression-related adverse events were the most common severe or life-threatening adverse events reported in iPrEx, but were not associated with being randomly assigned to TDF-FTC (OR 0.66, 95% CI 0.35–1.25) 16. In the PROUD study, 21/275 participants (8%) interrupted or missed study drug doses because of adverse events, the commonest of which were headache and nausea 2. In IPERGAY, drug-related gastrointestinal adverse events were reported more commonly in the TDF-FTC group compared to the placebo group (14% vs. 5%, P = 0.002), but there was no difference in the frequency of grade 3 or 4 adverse events 3. PrEP trials have shown modest, but statistically significant declines in renal function with administration of daily TDF-FTC, but the incidence of serious renal events was very low and mostly reversible. In PROUD, three participants interrupted drug due to elevated creatinine concentrations (two were classed as mild elevation, defined as 1.1–1.3 times the upper limit of normal [ULN], and one as moderate, 1.4–1.8 ULN), although the most likely explanation in one man was recreational drug use and the other two men were older with comorbidities 2. In the IPERGAY study, 18% of active drug participants experienced elevated creatinine levels compared to 10% of placebo group (P = 0.03). All, but one were mild and transient and none led to discontinuation of study drug 3. In the iPrEx study, use of TDF-FTC was associated with a mild non-progressive decrease in estimated creatinine clearance (CrCl) of 2.4% from baseline, which was reversible 14. Creatinine elevations of >1.1 ULN were similar between active and placebo arms, occurring in 32 (2.6%) in the active arm and 24 in the placebo arm 95% CI Most creatinine elevations in the active arm of the study follow-up 72 occurred at weeks and all occurred at by was detected but there was no difference in the of participants positive for placebo vs. P = In addition, the positive of in a confirmed creatinine was at 14. In the of to at over the first year on PrEP was but was more likely when participants PrEP at older or with a starting 15. For participants years of the in over the of the study 72 was and no patients experienced a to in those with adherence to daily dosing, that of renal function in this group should be However, being aged years or with a lower creatinine clearance at of PrEP were associated with a risk of to with daily that more renal on PrEP may be in older PrEP and in those with renal function at baseline, if there are no other risk for renal In an iPrEx of 500 participants who underwent to a small decrease in of was seen among those randomly assigned to TDF-FTC (n = compared to placebo (n = after 24 weeks in both and total There are no data on health for people on TDF-FTC PrEP. In the CDC MSM study, in analysis, was associated with use of TDF and also a small decrease in among a subset of men in the San Francisco However, TDF use was not associated with In the iPrEx trial, drug developed in two participants who had HIV infection at individuals had a before starting PrEP, but In the PROUD study, two of the three participants with a positive HIV at or the 4-week had drug no was detected in participants who HIV 2. In IPERGAY, none of the HIV infections demonstrated to study drug 3. In a reviewed from trials that reported of or TDF drug using Although the only study of MSM included in this analysis was iPrEx, the risk associated with of drug will be similar in MSM and people who have heterosexual sex. The risk of an among those infected with HIV at was significantly higher in the group randomly allocated to receive TDF-FTC compared to placebo (risk ratio 95% CI P = The risk of a was not statistically different between PrEP and placebo, regardless of PrEP regimen, among those infected at enrolment. (2%) or infections occurred among 544 HIV five in PrEP groups and one in a placebo were small to a relative risk. has been measured using outcomes use and sexual The most relevant outcome is not because the other two are self-reported and, as to reporting In the placebo-controlled one of the placebo is to control for and is not to on the of PrEP on as participants do not if are on active drug. However, is to the of the risk-reduction to all and there were benefits in iPrEx, the CDC MSM Safety but not the IAVI Kenya study. In the iPrEx study, both PrEP and placebo groups reported use over the course of the study and reported use did not between the arms (P = 1. The number of reported receptive sexual intercourse in both arms also over the course of the study, with no significant difference in the number of reported in each group at each time (P = 1. The reduction in risk may the that the of iPrEx participants from populations with to risk-reduction In IPERGAY, there were no significant differences between TDF-FTC and placebo groups in the of condomless receptive anal sex (P = and (P = There was a but significant decrease in the number of sexual in the 2 months in the placebo group compared to the TDF-FTC group vs. P = 3, In the CDC MSM Safety Trial number of sexual in the 3 months and the reporting condomless anal sex over 24 months of follow-up. The IAVI Kenya study, which included was the only trial to an in study from to but may have been at 6. In the open-label PROUD study, in which participants were taking PrEP and that was at there was no difference between the and deferred (no-PrEP) groups in the total number of sexual (P = in the 3 months prior to the but a greater of the group reported receptive anal sex a with 10 or more compared to the deferred group vs. P = 0.03). There was no difference in the frequency of during the randomised phase (P = 2. In the study, both groups reported in reported condomless receptive anal intercourse from to P = among those PrEP and from to P = in the group who PrEP. in there was a higher rate and a significant in reported condomless sex at last receptive anal intercourse from at to 86% at months (P = for 8. Examination of three different of use and and four of PrEP use over time in that in the of declines in use were by on-demand PrEP but in a of men this was not the by using on-demand PrEP was lower in men for all three In a study of MSM PrEP in a community-based clinic in San self-reported use for different of men taking PrEP for periods of months was in in and in 9. Both the PROUD and IPERGAY studies high levels of in MSM the course of follow-up. IPERGAY, participants were screened at and every 6 months during follow-up for and and 10. Of participants receiving TDF-FTC, a new during compared to in the placebo most were and 10% a new infection 3. were within the PROUD study where to was offered and the proportions with a were 50% and of men with an respectively, in the deferred and treatment arms of the study (P = to IPERGAY, 10% of individuals in PROUD a new infection 2. In iPrEx the incidence of was similar in both although higher among PrEP person-years compared to person-years in 95% CI In IPERGAY, incidence rate of first was per 100 person-years in the phase, and per 100 person-years in the open-label phase 3. has also been reported in clinical trials and PrEP In HIV-negative MSM who enrolled in the PrEP had higher virus at than HIV-negative MSM in the clinic at suggested that in HIV-negative men starting PrEP were similar to those in MSM. In the PROUD study, participants who had on one or more for had infection There were three infections in the arm and two in the deferred arm 2. In IPERGAY, there were five infections 3 suggesting that HIV-negative men on PrEP are at risk of infection and should testing for while on PrEP. Two RCTs have demonstrated the efficacy of daily oral PrEP in HIV among heterosexual One Phase 3 PrEP 1, the efficacy of daily oral TDF vs. TDF-FTC vs. placebo in heterosexual in Africa and one Phase 3 TDF-FTC vs. placebo in sexually active heterosexual adults at high risk of HIV in No studies have the efficacy of an on-demand PrEP regimen in and to there have been no RCTs in heterosexual men and women in Although there is no to the efficacy would be the of RCTs in in to the of high PrEP efficacy from these two trials in Africa to the because HIV incidence is and no group of with high HIV incidence be in there are likely to be differences in and that adherence and efficacy and further any of the Two RCTs 3 and both in heterosexual women in reported low efficacy rates of daily oral PrEP. In both the studies were conducted and the and of the when compared to and PrEP, are to low adherence using drug to the study drug in the intervention arm. was a double-blind, placebo-controlled Phase 3 following heterosexual comparing single and PrEP vs. with placebo conducted from to 1. Participants were sexually active heterosexual in and HIV-negative participants were aged between and sexually active with an of intercourse with in the 3 with no infection. HIV-negative women who were or to were from the study. The study also HIV-negative participants with or ongoing with and a of not to sexual were years sexually with no of and not using The HIV incidence in the control arm was per 100 Overall, the study the efficacy of PrEP using TDF was