Key points from the evidence

The content of this evidence summary was up-to-date in October 2016. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

This evidence summary reviewed 4 randomised trials of Truvada (emtricitabine/tenofovir disoproxil 200 mg/245 mg) for pre-exposure prophylaxis (PrEP) of HIV in either HIV-negative men or transgender women who have sex with men, or HIV-negative individuals in a heterosexual partnership with a person already infected with HIV. In these trials, Truvada reduced the relative risk of acquiring HIV infection by between 44% and 86% compared with placebo or no prophylaxis, which is equivalent to approximate numbers needed to treat of between 13 and 68 per year. In all trials, Truvada was given in addition to a comprehensive package of prevention services including HIV testing, risk-reduction counselling, condoms and sexually transmitted infection management. In addition to efficacy, issues relating to uptake, adherence, sexual behaviour, drug resistance, safety, prioritisation for prophylaxis and cost-effectiveness are also important to consider, especially at a population level.

Regulatory status: A licence extension for the use of once-daily Truvada for PrEP was approved by the European Medicines Agency in August 2016. The aim of this evidence summary is to inform forward planning around the use of Truvada for PrEP within local health systems.

Effectiveness

  • In 3 randomised trials of PrEP in men or transgender women who have sex with men, Truvada (emtricitabine/tenofovir disoproxil 200 mg/245 mg) reduced the relative risk of acquiring HIV infection by the following amounts (modified intention to treat [mITT] populations):

    • 44% compared with placebo (iPrEx, n=2441; Truvada given daily; number needed to treat [NNT] 62 per year)

    • 86% compared with no prophylaxis (PROUD, n=523; Truvada given daily; NNT 13 per year)

    • 86% compared with placebo (IPERGAY, n=400; Truvada given 'on demand'; NNT 18 per year).

  • In 1 randomised trial of PrEP in serodiscordant heterosexual couples, once-daily Truvada (emtricitabine/tenofovir disoproxil 200 mg/245 mg) reduced the relative risk of acquiring HIV infection by 75% compared with placebo (Partners PrEP, n=3136, mITT population; NNT 68 per year).

Safety

  • Emtricitabine and tenofovir are primarily excreted by the kidneys. The summary of product characteristics for Truvada has cautions about renal safety and monitoring, and states that it is not recommended for PrEP in people with creatinine clearance <60 ml/min. Cases of elevated creatinine levels were seen with Truvada in the 4 trials reviewed in this evidence summary.

  • The summary of product characteristics for Truvada has cautions about bone safety. Small decreases in bone mineral density were seen with Truvada in a sub-study of iPrEx.

  • Emtricitabine and tenofovir have shown activity against hepatitis B virus and stopping Truvada in people infected with hepatitis B virus may be associated with severe acute exacerbations.

  • A potential disadvantage of PrEP is the development and transmission of drug-resistant viruses. The risk of drug resistance seems low overall, and occurs mainly in people infected with HIV when PrEP is started, but monitoring at a population level is important. Truvada for PrEP is contraindicated in people with unknown or positive HIV-1 status, and the summary of product characteristics recommends reconfirming HIV-negative status at frequent intervals during use.

Patient factors

  • The summary of product characteristics for Truvada states that people should be counselled to strictly adhere to the recommended dosing schedule. The effectiveness of Truvada for PrEP is strongly correlated with adherence as demonstrated by measurable drug levels in blood. Drug level monitoring in studies suggested varying levels of adherence.

  • The licence extension for Truvada for PrEP is for a dose of 1 tablet taken once daily. 'On demand' use of Truvada is not licensed for PrEP.

  • The summary of product characteristics lists the most frequently reported adverse reaction to Truvada for PrEP as headache (1%).

  • There have been concerns that sexual behaviour could become more high-risk if people are taking PrEP. However, providing PrEP may increase access to other health services such as HIV testing, sexually transmitted infection and hepatitis B screening, and support for high-risk sexual behaviour and recreational drug and alcohol use. Monitoring such data at a population level is important to assess the ongoing impact of PrEP.

Resource implications

  • The NHS list price of Truvada is £355.73 for 30 tablets (MIMS, August 2016). However, it is currently purchased at a discounted net price for treating HIV.

Introduction and current guidance

The number of people living with HIV in the UK continues to increase and the number living with undiagnosed HIV remains high (Public Health England, situation report 2015). The HIV epidemic remains largely concentrated among gay, bisexual and other men who have sex with men and among men and women of black African ethnicity. Despite a decline in undiagnosed HIV infections among men who have sex with men there is evidence that rates of ongoing HIV transmission remain high and the Public Health England report emphasises the need for high impact, appropriately tailored combination prevention strategies and programmes in this population. This includes early diagnosis of HIV infection through HIV testing, antiretroviral therapy for those diagnosed positive to reduce the risk of onward transmission, correct and consistent condom use, and addressing the wider determinants of poor sexual health in this population.

In June 2015, the use of antiretroviral therapy by people who are HIV positive to both prevent as well as treat HIV infection (treatment as prevention or TasP) was approved by NHS England (NHS England, Treatment as Prevention in HIV infected adults, 2015). At present there is no publicly funded pre-exposure prophylaxis (PrEP) programme in the UK. See the NHS England website for current information around the commissioning of PrEP.

This evidence summary considers the best available evidence for the efficacy and safety of Truvada (emtricitabine/tenofovir disoproxil 200 mg/245 mg) for the licence extension for PrEP in the UK setting.

Full text of introduction and current guidance.

Product overview

Truvada is an antiretroviral drug licensed for combination therapy for treating HIV-1 infected adults aged 18 years and over. Each tablet contains 200 mg of emtricitabine and 245 mg of tenofovir disoproxil (equivalent to 300 mg of tenofovir disoproxil fumarate or 136 mg of tenofovir). In August 2016, the European Medicines Agency (EMA) approved a licence extension for the use of Truvada for PrEP. The new indication is for the use of once-daily Truvada in combination with safer sex practices for pre-exposure prophylaxis to reduce the risk of sexually acquired HIV-1 infection in adults at high risk (Truvada summary of product characteristics).

Full text of product overview.

Evidence review

The EMA submission for the licence extension for the use of Truvada (emtricitabine/tenofovir disoproxil 200 mg/245 mg) for PrEP was based on that submitted to the US Food and Drug Administration (FDA) for the US licence (personal communication, Gilead, June 2016). The key clinical studies therefore supporting the European application are the iPrEX study (Grant et al. 2010) and the Partners PrEP study (Baeten et al. 2012 and Baeten et al. 2014). The application also mentions the PROUD study (McCormack et al. 2016) and the IPERGAY study (Molina et al. 2015). See the European Public Assessment Report (EPAR) for more information.

This evidence summary focuses on these 4 randomised trials as they provide the best available evidence for the use of Truvada for PrEP in a UK setting. It also considers a World Health Organisation (WHO) systematic review and meta-analysis of oral PrEP for all populations (Fonner et al. 2015), which includes 9 other studies of Truvada for PrEP and 4 studies of tenofovir disoproxil alone for PrEP.

  • The iPrEx study (Grant et al. 2010) was a double-blind RCT evaluating once-daily Truvada or placebo in 2499 HIV-negative men or transgender women who have sex with men with evidence of high-risk behaviour for HIV infection. In was conducted in Peru, Ecuador, Brazil, the US, Thailand and South Africa.

  • The Partners PrEP study (Baeten et al. 2012 and Baeten et al. 2014) was a double-blind RCT evaluating once-daily single agent tenofovir disoproxil or Truvada or placebo in 4747 HIV-negative individuals in a heterosexual partnership with a person already infected with HIV (a serodiscordant heterosexual couple) in Kenya and Uganda.

  • The PROUD study (McCormack et al. 2016) was an open-label trial of once-daily Truvada in 544 HIV-negative men or transgender women who have sex with men in England. Participants were randomised to start PrEP with Truvada immediately on study entry or after a deferral period.

  • The IPERGAY study (Molina et al. 2015) was a double-blind RCT evaluating Truvada or placebo taken 'on demand' before and after sexual activity in 414 high-risk men who have sex with men in France and Canada.

Effect of emtricitabine and tenofovir disoproxil (Truvada) on HIV acquisition

In 3 of the 4 randomised trials reviewed in this evidence summary, Truvada (emtricitabine/tenofovir disoproxil 200 mg/245 mg) was evaluated for PrEP in HIV-negative men or transgender women who have sex with men (iPrEx, PROUD and IPERGAY). Men with high-risk sexual behaviour for HIV infection were recruited, and Truvada was given in addition to a comprehensive package of prevention services including HIV testing, risk-reduction counselling, condoms, and sexually transmitted infection management.

  • In iPrEx (Grant et al. 2010, which had a median follow-up of 1.2 years), once-daily Truvada reduced the relative risk of acquiring HIV infection by 44% compared with placebo. In the Truvada group 36/1224 had emergent HIV infection and in the placebo group this was 64/1217 (hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.37 to 0.85, p=0.005). However, efficacy was strongly correlated with adherence (see below). In a secondary analysis of this study (Buchbinder et al. 2014), the HIV incidence in the placebo group was calculated at 3.9 cases per 100 person-years, and the overall NNT was 62 per year (95% CI 44 to 147).

  • In PROUD (McCormack et al. 2016, which had 243-person years of follow-up in the immediate PrEP group and 222-person years of follow-up in the deferred PrEP group) once-daily Truvada reduced the relative risk of acquiring HIV infection by 86% compared with no prophylaxis. There were 3/268 people with emergent HIV infection in the group randomised to Truvada immediately on study entry compared with 20/255 in the group where Truvada was deferred and people received no prophylaxis. This equated to a rate difference of 7.8 cases per 100 person-years (90% CI 4.3 to 11.3; 1.2 cases per 100 person-years in the immediate group compared with 9.0 cases per 100 person-years in the deferred group; relative risk reduction [RRR] 86%, 90% CI 64% to 96%; NNT 13 per year, 90% CI 9 to 23).

  • In IPERGAY (Molina et al. 2015, which had a median follow-up of 9.3 months), Truvada was given 'on demand' before and after sexual activity rather than regularly once daily. Participants took a median of 15 tablets per month (interquartile range 11 to 21 in the Truvada group). 'On-demand' Truvada reduced the relative risk of acquiring HIV infection by 86% compared with placebo. In the Truvada group 2/199 had emergent HIV infection, a rate of 0.9 cases per 100 person-years, and in the placebo group this was 14/201, a rate of 6.6 cases per 100 person-years (RRR 86%; 95% CI 40% to 98%, p=0.002). This equates to a rate difference of 5.7 cases per 100 person-years or an NNT of 18 per year (95% CI 15 to 38).

The fourth randomised trial reviewed in this evidence summary (Partners PrEP; Baeten et al. 2012 and Baeten et al. 2014, which had an initial median follow-up of 23 months) evaluated Truvada for PrEP in HIV-negative individuals from serodiscordant heterosexual couples in Kenya and Uganda. It found once-daily Truvada reduced the relative risk of acquiring HIV infection by 75% compared with placebo. There were 13/1568 people with emergent HIV infection in the Truvada group, a rate of 0.50 cases per 100 person-years, compared with 52/1568 in the placebo group, a rate of 1.99 cases per 100 person-years (HR 0.25; 95% CI 0.13 to 0.45, p<0.001). This equates to a rate difference of 1.49 cases per 100 person-years or an NNT of 68 per year (95% CI 58 to 92).

Uptake and adherence

  • In the iPrEx study, the 44% reduction in the relative risk of acquiring HIV infection was not as high as had been hypothesised and was less than that seen in other studies. Although the reported use of Truvada was high in this study (pill count suggested a median range of 89% to 95% use), drug level monitoring in a pre-specified subgroup found that exposure was substantially lower than this (emtricitabine or tenofovir was detected in only 9% of people with HIV infection and 51% of people who were HIV-negative).

  • In the immediate Truvada group in the PROUD study, sufficient study drug was prescribed for 88% of the total follow up time, and tenofovir was detected in all 52 sampled participants who reported they were taking PrEP.

  • In the IPERGAY study, participants took a median of 15 tablets per month in both the Truvada and placebo groups (interquartile range 11 to 21 in the Truvada group). However, individual patterns of tablet use showed large interpatient and intrapatient variability over time. The rates of detection for tenofovir diphosphate and emtricitabine were 86% and 82% respectively in participants in the active treatment group who had drug levels measured. However, based on computer-assisted structured interviews, although 43% of people took the assigned drug correctly during the most recent sexual intercourse, 29% took a suboptimal dose and 28% did not take the assigned drug at all.

Sexual practices

  • In the iPrEx study, self-reported sexual practices were similar in the Truvada and placebo groups at all time points. However, one purpose of using placebo was to avoid confounding bias due to risk compensation (participants knew they might be taking an inactive treatment), and in both groups a comprehensive package of prevention services was given. The self-reported total number of sexual partners decreased and the percentage who used a condom increased in both groups after enrolment in the study. In the open-label follow-up of this study and others (Grant et al. 2014), the self-reported total number of sexual partners and non-condom anal intercourse decreased during follow-up in the group receiving PrEP and in the group not receiving PrEP. Syphilis incidence was also similar in both groups.

  • In the PROUD study, where no placebo was given and people knew whether they were taking PrEP or not, questionnaires about sexual behaviour in the previous 90 days found that there was no difference between groups in the total number of sexual partners (p=0.57) at 1 year. However, more people in the immediate Truvada group reported receptive anal sex with 10 or more partners without a condom compared with the deferred group (21% compared with 12%, p=0.03). The frequency of bacterial sexually transmitted infections was not statistically significantly different between groups when adjusted for the number of screens for infections (p=0.74). Antiretroviral post-exposure prophylaxis was prescribed to 12 people (14 courses) in the immediate Truvada group and 85 people (174 courses) in the deferred group.

  • In the IPERGAY study, sexual practices did not change overall during the study period compared with baseline in either the active or placebo group.

HIV-drug-resistance

  • In the iPrEx study, among 10 people who had HIV infection at enrolment, 3 people had an emtricitabine-resistant infection and none had a tenofovir-resistant infection. Among 100 people who became infected with HIV during the study (36 of whom were randomised to active treatment), no emtricitabine or tenofovir resistance was detected.

  • In the Partners PrEP study, among 8 people in the tenofovir disoproxil alone or Truvada groups who were infected with HIV at baseline, 1 person had an emtricitabine-resistant infection and 1 person had a tenofovir-resistant infection. No participants who acquired HIV after randomisation were infected with a resistant HIV strain.

  • In the PROUD study, 2 people in the immediate Truvada group who had HIV infection at baseline or at the 4-week visit developed an emtricitabine-resistant mutation. No resistance was detected in people who developed HIV at later time points and no participants developed a tenofovir-resistant mutation.

  • In the IPERGAY study, none of the 16 people who developed HIV infection after enrolment had resistant mutations to tenofovir or emtricitabine.

Safety issues

  • The safety data such as that contained in the summary of product characteristics (SPC) for Truvada (emtricitabine/tenofovir disoproxil 200 mg/245 mg) are largely derived from its use as treatment in people who are HIV positive. The risk of adverse effects when Truvada is used for PrEP is less well described, although some information is available in the SPC.

  • The SPC for Truvada states that emtricitabine and tenofovir are primarily excreted by the kidneys, and renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy have been reported with the use of tenofovir disoproxil for treating HIV infection. The SPC recommends that creatinine clearance is calculated in all people before starting Truvada for either treatment or prevention and renal function should also be monitored during use. There are cautions around use in people with impaired renal function, and concurrent or recent use of a nephrotoxic medicine (including NSAIDs; see the SPC for details). The SPC states that Truvada for PrEP has not been studied in people with creatinine clearance <60 ml/min and is therefore not recommended for use in this population.

  • Elevated creatinine levels were seen in 2% of the Truvada group and 1% of the placebo group (p=0.08) in the iPrEx study, but all resolved after the study drug was stopped. Elevated creatinine levels were also seen in 18% of the Truvada group and 10% of the placebo group (p=0.03) in the IPERGAY study, but none led to discontinuation of the study drug. In PROUD, 3/275 people in the immediate Truvada group interrupted treatment because of high creatinine levels, but the study drug was restarted in all these people.

  • The SPC states that small decreases in bone mineral density of the hip and spine were seen in a study of treatment with tenofovir disoproxil in people who were antiretroviral-naive, but there was no increased risk of fractures or evidence for clinically relevant bone abnormalities.

  • In a sub-study of iPrEx (Mulligan et al. 2015), a statistically significant decrease in bone mineral density of −0.91% in the spine (p=0.001) and −0.61% in the hip (p=0.001) was seen with Truvada compared with placebo by 24 weeks. Among all people in the main iPrEx study there were fractures in 1.7% of the Truvada group and 1.4% of the placebo group (p=0.62).

  • The SPC states that people with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. The safety and efficacy of Truvada for PrEP in people with hepatitis B or C has not been established. Emtricitabine and tenofovir individually and in combination have shown activity against hepatitis B virus in pharmacodynamic studies, and discontinuation of Truvada in people infected with hepatitis B virus may be associated with severe acute exacerbations of hepatitis.

  • The SPC states that the most frequently reported adverse reactions considered possibly or probably related to treatment with emtricitabine or tenofovir disoproxil fumarate are nausea (12%) and diarrhoea (7%). It also states that no new adverse reactions were identified from the iPrEx and Partners PrEP studies, and the most frequent adverse reaction reported in the Truvada group in the iPrEx study was headache (1%). In iPrEx and IPERGAY there were increased rates of gastrointestinal events with Truvada compared with placebo. In the Partners PrEP study, there were increased reports of gastrointestinal side effects and fatigue in the Truvada group, mainly during the first month. In PROUD, 21/275 (8%) people in the immediate Truvada group interrupted or missed doses because of adverse events (most commonly nausea, headache and arthralgia), but study drug was restarted in 20 of these people.

Evidence strengths and limitations

  • Of the 4 randomised trials reviewed in this evidence summary, 3 evaluated Truvada (emtricitabine/tenofovir disoproxil 200 mg/245 mg) for PrEP in HIV-negative men or transgender women who have sex with men. These were the iPrEx study conducted in Peru, Ecuador, Brazil, US, Thailand and South Africa; the PROUD study conducted in England; and the IPERGAY study conducted in France and Canada.

  • The PROUD study is directly relevant to the use of Truvada for PrEP in the UK but its design has strengths and limitations. Its open-label, real-world design represents how PrEP would be used in routine clinical practice, but it increases the risk of bias because both participants and clinicians knew the allocation of study treatment. The incidence of HIV infection was high in the control group in this study, and this was the main determinant of the NNT of 13, which was lower than in other studies.

  • The IPERGAY study assessed 'on demand' use of Truvada before and after sexual activity rather than regular once-daily use as in the UK licence extension for PrEP. Participants in IPERGAY took a median of 15 tablets per month, but individual patterns of tablet use showed large interpatient and intrapatient variability over time.

  • The fourth randomised trial (Partners PrEP) evaluated Truvada for PrEP in HIV-negative heterosexual men and women. This RCT was conducted in Africa and the findings may be less relevant to a UK population.

  • Other trials of Truvada in heterosexual men and women have been published, but these were largely conducted in Africa (for example VOICE, TDF2 and FEM-PrEP).

  • The WHO systematic review included 1 study of PrEP in people who inject drugs (the Bangkok tenofovir study). However, this was with tenofovir disoproxil only and was conducted in drug-treatment clinics in Thailand, which are not representative of the population of people who inject drugs in the UK.

Full text of evidence review.

Context

Prevention strategies for HIV include early diagnosis of HIV infection through HIV testing, antiretroviral therapy for those diagnosed positive to reduce onward transmission (treatment as prevention [TasP]), correct and consistent condom use, and addressing the wider determinants of high-risk sexual behaviour. Using antiretroviral agents to prevent HIV acquisition in those who are HIV negative (PrEP) is also an option (Public Health England, situation report 2015).

In the European AIDS Clinical Society (EACS) guidelines from 2015 the recommended PrEP regimen is 1 tablet of emtricitabine/tenofovir disoproxil 200 mg/245 mg once daily. For men who have sex with men with high-risk sexual behaviour, these guidelines recommend that 'on demand' emtricitabine/tenofovir disoproxil 200 mg/245 mg may be given. WHO guidelines from 2016 recommend oral PrEP containing tenofovir disoproxil (no particular regimen is recommended).

The cost of Truvada is £355.73 for 30 tablets (MIMS, August 2016). However, it is currently purchased for treating HIV at discounted net price through the Commercial Medicines Unit (CMU) regional framework (personal communication, Gilead, June 2016). Costs of Truvada given 'on demand' (based on an average use of 15 tablets per month) or as separate tenofovir disoproxil 245 mg (Viread) and emtricitabine 200 mg (Emtriva) tablets are given in the full evidence summary. However, Truvada is the only antiretroviral product licensed for use as PrEP in the UK. The licence extension is for once-daily use: 'on demand' use of Truvada, tenofovir disoproxil (Viread) alone, or with emtricitabine (Emtriva) as separate tablets, is not licensed for PrEP.

Full text of context.

Estimated impact for the NHS

Likely place in therapy

At present there is no publicly funded PrEP programme in the UK. See the NHS England website for current information around the commissioning of PrEP.

European AIDS Clinical Society (EACS) guidelines from 2015 and WHO guidelines from 2016 both recommend PrEP for people at high-risk of acquiring HIV infection. The European guidelines recommend PrEP for HIV-negative men who have sex with men and transgender individuals who are inconsistent in their use of condoms with casual partners or with HIV-positive partners who are not on treatment. These guidelines also state that PrEP may be considered in HIV-negative heterosexual women and men who are inconsistent in their use of condoms and are likely to have HIV-positive partners who are not on treatment. The WHO guidelines recommend PrEP as an additional prevention choice for people at 'substantial risk' of HIV infection (populations with a HIV incidence of around 3 cases per 100 person-years or higher), such as men who have sex with men, transgender women, and heterosexual men and women who have sexual partners with undiagnosed or untreated HIV infection.

In May 2016, BHIVA and BASHH published a position statement on PrEP in the UK, which recommends that PrEP be made available within a comprehensive HIV prevention package to:

  • men who have sex with men, trans men and trans women who are engaging in condomless anal sex

  • HIV-negative partners who are in serodiscordant heterosexual and same-sex relationships with a HIV-positive partner whose viral replication is not supressed

  • other heterosexuals considered to be at high risk.

Evidence for the use of Truvada for PrEP that is most relevant to the UK population relates to its use by men who have sex with men. This group in particular has ongoing high rates of HIV transmission and acquisition, and the Public Health England situation report on HIV emphasises the need for high impact, appropriately tailored combination prevention strategies and programmes for this group. Both the Public Health England report and the BHIVA-BASHH position statement stress that PrEP is only one of several prevention tools for HIV, and early diagnosis through testing, antiretroviral therapy for people who are HIV-positive to reduce the risk of onward transmission, correct and consistent condom use, and addressing the wider determinants of poor sexual health among this population are also important.

There is little doubt that Truvada is effective in reducing HIV acquisition in high-risk people who are HIV-negative. However, issues relating to uptake, adherence, sexual behaviour, drug resistance, safety, prioritisation for prophylaxis and cost-effectiveness are also important to consider, especially at a population level.

Full text of estimated impact for the NHS.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.