Tenofovir with emtricitabine for HIV pre-exposure prophylaxis (PrEP) 

• Tenofovir disoproxil with emtricitabine is effective in reducing the incidence of human immunodeficiency virus (HIV) when taken as pre-exposure prophylaxis (PrEP)
  When compared with placebo, PrEP significantly reduced rates of HIV transmission among adults at medium to high risk of infection. In all study trials, participants also received standard prevention practices such as risk-reduction counselling, condom use and sexually transmitted infection (STI) screening.
• PrEP effectiveness is highly dependent on adherence
  In clinical trials, full treatment adherence with PrEP reduced the risk of HIV infection by up to 99%.
• PrEP should only be used for HIV-negative patients
  A patient must be HIV-negative at treatment initiation, and return negative HIV tests at 3-monthly intervals to continue prophylaxis treatment.
• Patients taking PrEP should be reviewed every 3 months
  This review includes a treatment adherence assessment and tests for HIV and other STIs. 

Authority required (streamlined)

Tenofovir disoproxil with emtricitabine is PBS-listed as Authority required (streamlined) for HIV PrEP among eligible adults (> 18 years of age) who are at medium to high risk of HIV infection as defined by the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) PrEP guidelines, and have a negative HIV test result prior to starting treatment.^1,2

Three products containing tenofovir disoproxil with emtricitabine have been PBS-listed for use as PrEP:

• tenofovir disoproxil fumarate 300 mg + emtricitabine 200 mg (Truvada)
  
• tenofovir disoproxil maleate 300 mg + emtricitabine 200 mg (Tenofovir Disoproxil Emtricitabine Mylan 300/200)
  
• tenofovir disoproxil phosphate 291 mg + emtricitabine 200 mg (Tenofovir EMT GH).
  

Irrespective of the salt form, each tablet contains the equivalent of 245 mg of tenofovir disoproxil.² These forms are bioequivalent for the purposes of substitution.

May be prescribed by nurse practitioners

Authorised nurse practitioners may prescribe this medicine on the PBS. See the PBS website for more information on nurse practitioner PBS prescribing.

Tenofovir disoproxil (a nucleotide reverse transcriptase inhibitor) and emtricitabine (a nucleoside reverse transcriptase inhibitor) are antiretroviral medicines. They are taken in combination with other antiretroviral agents for the treatment people with HIV infection.^3-6

Active metabolites of tenofovir disoproxil and emtricitabine exert their antiviral effects by inhibiting the activity of the enzyme HIV-1 reverse transcriptase, which stops viral DNA synthesis. This action halts or slows down the production of new virus in HIV-infected cells.^3-6

Current evidence suggests that protective levels of tenofovir disoproxil for pre-exposure prophylaxis are attained after seven days of daily dosing, and that high adherence is required to maintain adequate levels.^7,8 In addition, protective levels of PrEP are thought to persist only for up to seven days after stopping PrEP.⁸ ASHM guidelines currently advise clinicians to recommend that people continue to take daily PrEP for 28 days after the last sexual exposure that put them at high risk of HIV infection.⁸ 

Tenofovir disoproxil with emtricitabine is indicated for use as pharmacological pre-exposure prophylaxis in combination with other safer sex practices for HIV-negative adults (aged 18 years and above) at high risk of sexually acquired HIV-1 infection.^4-6

Prior to PBS listing, access to PrEP in Australia was through clinical trials, personal importation or private script.

The Pharmaceutical Benefits Advisory Committee (PBAC) emphasises that daily use of tenofovir disoproxil with emtricitabine as PrEP should form part of a comprehensive approach to sexual health and complement other safe sex practices, including condom use.¹

Determining patient risk of contracting HIV

The ASHM PrEP guidelines were designed to assess medium- to high-risk HIV acquisition in men who have sex with men (MSM), people who inject drugs (PWID), heterosexual people, and transgender and gender-diverse people.⁸

The risk criteria are based on behaviour, assessing sexual and/or drug injecting activity over the last 3 months and likely activity in the next 3 months (indicating sustained risk).^8,9 In addition, the guidelines suggest that clinicians should use their discretion to prescribe PrEP for those patients who do not technically meet the guidelines’ behavioural eligibility criteria.

More details on behaviours that may indicate medium or high risk in each of these populations can be found in the ASHM PrEP guidelines.

If PrEP treatment is initiated, individual risk level should be re-evaluated every 3 months. A change in risk (eg, a patient separating from an HIV-positive partner who has a detectable viral load) can mean a person is no longer eligible for PrEP.⁸

The PrEP prescribing pathway

ASHM has prepared a PrEP tool to support primary care providers wishing to prescribe PrEP. In addition to behavioural eligibility and confirmation of HIV status, a medical history (including renal function) is recommended. HIV, renal function and STI tests, as well as some vaccinations (if necessary), can be carried out on the same day that the person is provided with a script for PrEP. Most patients should be able to commence PrEP on the day that they have their initial evaluation because HIV and renal function test results are typically available within 24 hours, so if an unexpected result is found (eg, the patient is HIV-positive or has impaired renal function), little harm will result from them having taken one to two doses of PrEP. The patient should return every 3 months for monitoring and repeat prescriptions for PrEP.⁸

In some instances, individuals will be advised not to commence PrEP until their HIV, hepatitis B or renal function tests results are available.

Further information on PrEP in clinical practice is available on the NPS MedicineWise website.

Established primary HIV-prevention strategies in Australia focus on the use of safer sex practices, including condoms, clean needles and biomedical strategies.⁸ Other harm-reduction strategies include HIV testing, immediate HIV treatment to reduce HIV viral load, and HIV post-exposure prophylaxis. In recent years, the use of oral antiretroviral medicines for PrEP has become an additional prevention choice.

Several trials have investigated the effectiveness of tenofovir disoproxil with emtricitabine as PrEP in reducing HIV transmission in at-risk populations. These include the large multinational Preexposure Prophylaxis Initiative (iPrEx)¹⁰ and the Pre-exposure Option for Reducing HIV in the UK: Immediate or Deferred (UK PROUD) studies.¹¹

The iPrEx study was a randomised, placebo-controlled study of HIV-seronegative men and transgender women who have sex with men (n = 2499). Participants received either tenofovir disoproxil fumarate with emtricitabine (TDF-FTC) or a placebo, once daily, against a background of standard care (ie, HIV testing, risk-reduction counselling, condom use and management of STIs).

At follow-up (median 1.2 years) emergent HIV infection in the modified intention-to-treat population was significantly lower among participants from the TDF-FTC group (n = 36) compared with the placebo arm (n = 64, RRR 44%, 95% CI 15–63, p = 0.005).

In the TDF-FTC arm, participants with a detectable study-medicine level had a 92% relative reduction in risk of HIV infection (95% CI 40–99, p < 0.001) compared with those without a detectable study-medicine level.¹⁰

The UK PROUD study was an open-label randomised trial (n = 544) conducted in 13 sexual health clinics in England.¹¹ Being open-label it may give a better indication of the effect of PrEP in a real-world setting. Participants were randomly assigned to receive daily TDF-FTC immediately or after a deferral period of 1 year. Three cases of HIV infection occurred in the group receiving PrEP compared with 20 cases in the deferred group (RRR 86%, 90% CI 64–96, p = 0.0001). The study authors concluded that these findings demonstrate that the effectiveness of PrEP is not compromised in a real-world setting.¹¹ 

Among at-risk heterosexual populations, the efficacy of oral daily tenofovir disoproxil with emtricitabine ranged from RRR 62% (95% CI 22–83, p = 0.03) to RRR 75% (95% CI 55–87, p < 0.0001).^12,13

Adherence is important

It has been noted in clinical trials and guidelines and at governmental level that adherence to tenofovir disoproxil with emtricitabine as PrEP is a major factor in achieving maximum benefit.^{8,9,11,12,14,15} In iPrEx, for example, greater reductions in HIV-1 risk were observed among participants with higher reported adherence and detectable study-medicine levels.¹⁰

In Australia, tenofovir disoproxil with emtricitabine is indicated for use as a daily medicine, and this regimen is recommended by the ASHM PrEP guidelines for all eligible individuals.⁸

Optimal medicine adherence may also reduce the potential risk of drug-resistance if subsequent HIV infection occurs.^8,16

Non-daily doses studied but not yet recommended

Results from the IPERGAY study and the follow-up, open-label study, IPERGAY-OLE, reported that an alternative dosage regimen (pre- and post-sex use only) of tenofovir disoproxil with emtricitabine can also lower HIV infection risk compared with placebo.¹⁷ IPERGAY, a randomised, placebo-controlled trial enrolling MSM, was designed to evaluate the efficacy of an on-demand PrEP regimen. The dosing regimen comprised taking two pills of TDF-FTC, versus placebo, 2–24 hours before potential sexual exposure to HIV with additional single doses taken at both 24 and 48 hours following the initial dose. The incidence of HIV was high in the placebo group but a risk reduction of 86% was reported in the TDF-FTC group. This risk reduction rose to 97% in IPERGAY OLE.¹⁸ As in iPrEx, adherence to the medicines (as measured using blood plasma samples) was found to be important in reducing HIV infection.

However, until additional evidence on the efficacy of alternative dosing regimens becomes available, the Australian guidelines – along with many international guidelines – do not recommend non-daily tenofovir disoproxil with emtricitabine.

In clinical trials, tenofovir disoproxil with emtricitabine as PrEP has been associated with gastrointestinal side effects, including nausea and vomiting, but most occur in the first month and resolve with continued exposure.⁹ Other adverse events reported are headache,^10,11,19 arthralgia¹¹ and unintentional weight loss.¹⁰

In the IPERGAY study,¹⁷ gastrointestinal adverse events occurred in 14% of participants in the TDF-FTC group compared with 5% in the placebo group (p = 0.002), with increases also reported in the PROUD and iPrEx trials.^10,11 

Clinicians should discuss the use of over-the-counter medicines for headache, nausea and flatulence should they occur.⁸

For information about reporting adverse reactions to the TGA, or to report suspected adverse reactions online, see the TGA website.

Renal effects

Elevations in creatinine concentrations and declines in creatinine clearance have been reported in several studies using tenofovir disoproxil with emtricitabine as PrEP.

In an open-label extension of the iPrEx study (iPrEx-OLE), over 72 weeks the average decline in creatinine clearance was –2.9%.²⁰

In the IPERGAY study, elevated serum creatinine levels were seen in 18% of participants in the TDF-FTC group and 10% in the placebo group. Only 1 participant’s creatinine level was seen above 1.5 times the normal range, and this was in the placebo group.^17,21

In the PROUD trial, high creatinine concentrations were reported among 3 participants from the immediate TDF-FTC group (n = 275). In each case the study-medicine was interrupted temporarily. According to the participants clinicians, one of these test results was identified as probably being related to the study medicine, one as possibly related and one as unlikely to be related.¹¹

In the US Safety Study, 13 of 557 individuals (2.3%) experienced elevated creatinine levels; however, only 3 elevations among 3 participants were confirmed on repeated testing results and all resolved within 2–20 weeks without stopping PrEP.²²

Factors that have been associated with a greater likelihood of a decline in creatinine clearance are age less than 25 years and over 40 years, a baseline creatinine clearance less than 90 mL/min and high PrEP adherence.^8,20,22

Upon cessation of PrEP in the Partners PrEP study, changes in estimated glomerular filtration rate returned to normal in the majority of study participants.²³

Guidelines recommend avoiding administration of tenofovir disoproxil with emtricitabine alongside medicines that can cause renal toxicity, such as NSAIDs.^8,24 The Liverpool HIV drug interaction checker can be used for more information on medicine interactions with HIV medicines.

Bone effects

The use of tenofovir disoproxil as PrEP, as a single agent and in combination with emtricitabine, has been associated with loss of bone mineral density (BMD). In a RCT of TDF (300 mg daily immediately or deferred, vs daily placebo immediately or deferred), a small but statistically significant net decrease in BMD from baseline was associated with the use of TDF, in the intention-to-treat analysis.²⁵ This decline was measured at two anatomical sites, the femoral hip and the total hip. The study also reported that approximately 10% of participants were found to have low BMD at baseline. Factors associated with low baseline BMD were amphetamine and inhalant use, while participants taking vitamin D, calcium or a multivitamin were less likely to have low BMD.²⁵ 

During a follow-up of the iPrEx study, participants in the active study arm had a small but statistically significant decline in BMD at week 24 of the study. BMD was observed to reverse upon PrEP cessation.²⁶

Pregnancy and breastfeeding

PrEP can be used in pregnancy for women at substantial risk of HIV infection.⁸ Among HIV-negative women, pregnancy is a period of elevated risk of HIV infection. Infection acquired during pregnancy may be more likely to be transmitted to the infant than a pre-existing infection,⁸ meaning that HIV protection is particularly important for both mother and child. In the Partners PrEP study, 30 women became pregnant on PrEP and elected to remain on PrEP throughout their pregnancies. The study found that there was no increase in adverse pregnancy outcomes or restricted growth of infants in the PrEP-exposed mothers compared with the unexposed.²⁷

Tenofovir disoproxil and emtricitabine are secreted in breast milk at very low concentrations (0.3% and 2%, respectively, of the doses recommended for treatment of HIV infection in infants).²⁸ Experience with these medicines during breastfeeding is limited to short-term studies and case studies. A 2014 study evaluating tenofovir use in pregnancy – to prevent vertical transmission of hepatitis B – reported no adverse events among 36 infants who were breastfed while their mothers took TDF for 12 weeks postpartum.²⁹ In another short-term study of 50 HIV-negative breastfeeding women taking TDF-FTC daily as PrEP, infant plasma concentrations of tenofovir and emtricitabine were 0.01% and 0.5% of the proposed infant therapeutic doses, respectively.³⁰ 

In a 2017 meta-analysis of 33 articles on the use of tenofovir-containing regimens by HIV-positive and HIV-negative women, the authors concluded that there were no safety-related concerns that should preclude women from using PrEP during pregnancy and/or breastfeeding.³¹

ASHM guidelines recommend that PrEP may be continued during breastfeeding for women at substantial risk of HIV infection.^8,31

PrEP, sexual behaviour and STIs

With the availability of PrEP as a prevention tool for HIV infection, concerns have been raised regarding the potential for patients to deprioritise other risk-mitigating sexual practices such as condom use.³²

When data from RCTs and observational studies were considered by PBAC, there was some evidence of changes in risk behaviour (less condom use) and an increased incidence of STIs.^9,33,34

As a result, to continue their PrEP treatment, patients on PrEP are required to visit their clinician for HIV, STI and pregnancy testing every 3 months, with kidney function testing after 1 month and six-monthly thereafter.⁸ This requirement provides clinicians with a regular opportunity to discuss adherence to PrEP and support the optimisation of sexual health among high-risk populations.⁹ 

The Authority required (streamlined) PBS listing follows a positive recommendation from the PBAC in December 2017. The PBAC was satisfied that tenofovir disoproxil with emtricitabine provides, for some patients, a significant reduction in the risk of sexually-acquired HIV, in combination with other safe sex practices, compared with safe sex practices alone.¹

Tenofovir with emtricitabine as PrEP was initially considered by the PBAC in July 2016. At that time, the PBAC rejected the application and considered that it might be more appropriate to broaden the eligible population rather than restrict it solely to individuals at very high risk of HIV infection. PBAC suggested that it would be more appropriate if the clinician and the patient judged the benefits against the risks. The PBAC also noted that to provide the treatment to this larger at-risk population, a substantial reduction in price would be needed to achieve cost-effectiveness. Given that the efficacy of tenofovir with emtricitabine as PrEP is highly dependent on adherence, there were also concerns that adherence levels in the relevant populations might be too low.³⁵

A subsequent application was assessed in July 2017 and the decision was deferred to the December 2017 meeting, pending preparation of additional economic analyses and use scenarios by the Kirby Institute.³⁶ 

Treatment continuation should be reassessed every 3 months, and discontinued if the patient no longer meets the ASHM risk criteria for PrEP eligibility.

One tablet, taken orally, once daily (with or without food)

Tenofovir disoproxil with emtricitabine is a fixed-dose combination product available as a single tablet. Dosage is one tablet daily, and adherence is critical for HIV protection to be effective.

When initiating PrEP, the clinician should educate the patient about the active ingredients and the regimen, including what constitutes a missed dose and what to do if this occurs.⁸ The patient should be told to take a single missed dose as soon as they remember it, unless it is almost time for the next dose. In this case, the patient should skip the missed dose and continue with the regular dosing schedule.

The importance of adherence

Adherence to PrEP dosing regimens is crucial to optimise treatment benefits and reduce the risk of developing treatment-resistant HIV.^8,37

When counselling patients about medication adherence, consider the following strategies:.⁸

• Provide simple explanations about the medicine dosage and schedule, how to manage common side effects, and the relationship between adherence and effectiveness of PrEP.
  
• Explain the signs and symptoms of acute HIV infection and recommended actions to take if these occur.
  
• Work with the patient to establish a dosing routine that fits in with their daily routine and schedule (eg, with tooth brushing, before bed).
  
• Identify reminders and devices to minimise forgotten doses.
  
• Identify any barriers to adherence and work with the patient to address these.
  

Medicine adherence should be assessed at each follow-up visit, with support offered where appropriate. If the patient repeatedly reports adherence that is sufficiently suboptimal to compromise both PrEP’s efficacy (fewer than 4 tablets per week) and the patient’s safety, PrEP should be discontinued.⁸

Discuss the Truvada, Tenofovir Disoproxil Emtricitabine Mylan or Tenofovir EMT Consumer Medicine Information (CMI) leaflet with the patient.