HIV in Canada: A primer for service providers
Pre-exposure prophylaxis (PrEP)
- The consistent and correct use of oral Truvada as pre-exposure prophylaxis (PrEP) is a highly effective strategy to help prevent the sexual transmission of HIV. When this highly effective strategy is used consistently and correctly it is rare for HIV to be transmitted.
- PrEP involves the use of antiretroviral drugs starting before an HIV exposure and continuing throughout periods of high risk.
- PrEP works after HIV has made its way into the body. If this happens the medications in PrEP may prevent the virus from multiplying and spreading throughout the body.
Oral PrEP involves the use of antiretroviral drugs by an HIV-negative person to reduce their risk of becoming infected with HIV. Oral PrEP refers to the use of a pill called Truvada, starting before someone is exposed to HIV and continuing afterwards. Truvada is also used as a treatment for HIV-positive people and contains two antiretroviral drugs: tenofovir (also called TDF) and emtricitabine (also called FTC).
The daily use of Truvada as oral PrEP has been approved by Health Canada to reduce the risk of the sexual transmission of HIV in combination with safer sex practices in people at high risk for HIV infection. This approval did not include transmission through injection drug use. However, daily oral PrEP is recommended by the Centers for Disease Control and Prevention (CDC) in the United States and by the World Health Organization (WHO) to reduce the risk of HIV transmission in people at high risk through sexual activities and injection drug use.
PrEP interferes with the pathways that HIV uses to cause a permanent infection. For HIV to cause infection the virus must gain entry into the body, infect certain immune cells, make copies of itself (replicate) within these immune cells, then spread throughout the body.
When oral PrEP is taken consistently and correctly, antiretroviral drugs get into the bloodstream and genital and rectal tissues. The drugs work to help prevent HIV from replicating within the body’s immune cells, which helps to prevent a permanent infection.
For PrEP to help stop HIV replication from happening, drug levels in the body must remain high. If pills are not taken consistently as prescribed there may not be enough medication in the body to reduce the risk of HIV infection.
There is evidence from randomized clinical controlled trials (RCTs) that daily oral PrEP is a highly effective strategy to reduce the risk of the sexual transmission of HIV if taken consistently and correctly as part of a comprehensive prevention package in gay men and other men who have sex with men (MSM) and in heterosexual men and women. In addition, limited evidence from one RCT found that daily oral PrEP (with tenofovir alone), when used consistently and correctly, is effective at reducing the risk of HIV transmission among people who inject drugs.
In all the clinical trials, PrEP was provided as part of a comprehensive prevention package that included regular testing and treatment for sexually transmitted infections (STIs), free condoms and ongoing behavioural counselling.
Adherence (taking medications exactly as prescribed) is crucial for oral PrEP to work. The evidence shows that higher adherence is associated with greater protection.
Before taking adherence into account, the overall risk reduction provided by a daily oral PrEP regimen in RCTs ranged from zero to 86%. All of these studies evaluated the sexual transmission risk except for one, which found a 49% overall risk reduction in people who inject drugs. The wide range of protection observed in these trials has been explained by varying levels of adherence to daily pill taking.
To demonstrate the importance of adherence, additional analyses in these trials looked at drug levels in the blood of people who were taking oral PrEP consistently compared to those who were not. These analyses found that daily oral PrEP reduced the risk of HIV transmission by between 85% and 92% among MSM and heterosexual men and women who took the drug consistently compared to those who did not. In people who inject drugs, daily oral PrEP with tenofovir alone reduced the risk of HIV transmission by 84% among people who used the drug consistently compared to those who did not.
The daily use of oral PrEP has also been evaluated in “open-label” studies, predominantly among MSM. In these types of studies, no placebo is used and all participants know they are taking PrEP and that it is effective at preventing HIV transmission. These studies support the finding that oral PrEP is highly effective at reducing HIV transmission when taken consistently and correctly. One open-label study found that the risk for HIV was reduced by 86% overall among MSM who were taking daily oral PrEP compared to those who were not. In open-label studies, adherence to daily pill taking was higher than in RCTs.
There are several well-documented cases of PrEP failure in people who were adherent to PrEP. In two of these cases, men taking PrEP acquired a rare strain of HIV that was resistant to the drugs in Truvada. In a third case of PrEP failure, a gay man acquired a strain of HIV with no drug resistance, and the reason why PrEP failed is unclear. Over an eight-month period of PrEP use, he had many anal sex partners where no condoms were used, experienced episodes of rectal STIs, and used drugs during sex.
This highlights that PrEP does not work 100% of the time, however these are very rare events. In all three cases, the men who became HIV positive were able to diagnose their HIV early and get on treatment immediately because they were on PrEP and having regular medical check-ups.
Evidence suggests that intermittent, or on-demand, PrEP reduces the risk of HIV transmission among MSM. One RCT, known as IPERGAY, evaluated the use of on-demand PrEP among MSM. No studies have been conducted in other populations.
In the IPERGAY trial, MSM were to take two pills two to 24 hours before first sexual activity, followed by one pill taken daily until 48 hours after the last sexual activity. The RCT phase of IPERGAY found an 86% reduced risk of HIV infection among MSM in the on-demand PrEP group compared to those in a placebo group (two participants in the PrEP arm became infected). Men in the RCT phase of this study had sex frequently and – as a result – took their pills on a regular basis (four pills a week on average). IPERGAY continued as an open-label extension with all participants offered on-demand PrEP. Results from the open-label phase showed that one more HIV transmission occurred in 362 participants, over 515 person-years of follow-up (equivalent to following 515 people for one year). None of the three participants who became infected over the entire course of the study had PrEP detected in their blood, which means they were likely not adherent. On-demand PrEP has only been evaluated in MSM and is not recommended for people who have vaginal sex or people who inject drugs.
On-demand oral PrEP is not approved by Health Canada; however, on-demand PrEP can be prescribed ‘off label’ by physicians as an alternative form of PrEP that can be considered for use for MSM only.
Evidence from RCTs suggests that oral PrEP is as effective for women as it is for men when used consistently and correctly, but adherence may be more important for women.
There were initial concerns that PrEP may not work for women because two RCTs did not find a reduced risk of HIV in heterosexual women taking daily oral PrEP. However, adherence was very low in these studies with only a small proportion of women taking PrEP daily.
There is some evidence showing that Truvada takes longer to reach maximum drug levels in vaginal tissues compared to rectal tissues, and that drug levels are lower in vaginal tissues. This suggests that daily dosing of oral PrEP may be more important for women having vaginal sex to maintain sufficient drug levels to help prevent HIV infection.
PrEP should only be used by people who are HIV negative and at high risk for HIV infection. The Truvada product monograph recommends that the following factors may help to identify individuals at high risk:
A sexually active person who:
- has partner(s) known to be living with HIV, or
engages in sexual activity within a high prevalence area or social network and one or more of the following:
- inconsistent or no condom use
- diagnosis of sexually transmitted infections
- exchange of sex for commodities (such as money, food, shelter, or drugs)
- use of illicit drugs or alcohol dependence
- partner(s) of unknown HIV status with any of the factors listed above
Oral PrEP is part of a comprehensive HIV prevention strategy that includes safer sex practices and routine medical appointments.
The first step is to make sure a person is HIV negative before starting PrEP. They will also need to be tested for hepatitis B and other STIs and have their kidney function checked.
A person using oral PrEP needs to take Truvada as prescribed by their healthcare provider. In addition to taking the medication as prescribed, they must also attend regular doctor’s appointments, approximately every three months. These regular visits are necessary in order to be tested for HIV and other STIs, monitored for drug side effects, and receive ongoing adherence and risk-reduction counselling.
A person can develop resistance to the drugs in Truvada if they are HIV positive (and unaware of their positive status) when starting oral PrEP. Drug resistance can limit a person’s future treatment options, so it is important to ensure that they are HIV negative before starting oral PrEP.
A person can also develop drug resistance if they become HIV positive while taking oral PrEP. In clinical trials, the risk of developing drug resistance was low for people who were HIV negative when starting PrEP.
Regular HIV testing is necessary while taking oral PrEP. If a person using PrEP becomes infected with HIV, PrEP use must be discontinued as soon as possible, to reduce the risk of developing drug resistance. If a person’s HIV becomes resistant to the drugs in Truvada, those same drugs may not work to treat HIV.
Truvada may cause side effects, which may negatively affect a person’s quality of life and ability to adhere to their medication schedule.
Although Truvada is generally better tolerated than some of the other drugs used to treat HIV, it is still capable of causing side effects. Some of the possible side effects include nausea, vomiting, diarrhea, headache and dizziness. In clinical trials these side effects were generally mild, temporary, and only affected between 1% and 10% of participants. PrEP may also cause small decreases in kidney, liver and bone health. In oral PrEP trials this did not lead to kidney or liver failure or bone fracture, and the changes were reversible after stopping PrEP.
Although research suggests that the use of Truvada as PrEP is generally safe and well tolerated, the long-term effects of using PrEP are less well known.
Other types of PrEP, including vaginal or rectal gels, intravaginal rings and long-lasting injections are currently in experimental stages. No other forms of PrEP have been approved for use by any regulatory agency in the world, and we do not expect them to be available for use in Canada in the near future.
Oral pre-exposure prophylaxis (PrEP) – CATIE fact sheet
Pre-exposure Prophylaxis (PrEP) – Centers for Disease Control and Prevention (CDC)
Preexposure Prophylaxis for the Prevention of HIV in the United States: A Clinical Practice Guideline – U.S. Public Health Service
Preexposure Prophylaxis for the Prevention of HIV in the United States: Clinical Providers’ Supplement – U.S. Public Health Service
- Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. New England Journal of Medicine. 2010;363(27):2587–2599.
- Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. New England Journal of Medicine. 2012;367(5):399–410.
- Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. New England Journal of Medicine. 2012;367(5):411–422.
- Choopanya K, Martin M, Suntharasamai P, et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. The Lancet. 2013;381(9883):2083–2090.
- Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. New England Journal of Medicine 2012;367(5):423–434.
- Marrazzo J, Ramjee G, Richardson BA et al. Pre-exposure prophylaxis for HIV infection among African women. New England Journal of Medicine 2015; 372: 509-518.
- McCormack S, Dunn DT, Desai M, et al. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. The Lancet. 2016; 387 (10013): 53–60.
- Van der Straten A, Van Damme L, Haberer JE, Bangsberg DR. Unraveling the divergent results of pre-exposure prophylaxis trials for HIV prevention. AIDS. 2012;26(7):F13–19.
- Spinner C, Boesecke C, Zink A, et al. HIV pre-exposure prophylaxis (PrEP): a review of current knowledge or oral systemic HIV PrEP in humans. Infection. 2015 Oct 15:1–8.
- Anderson PL, Glidden DV, Liu A, et al. Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Science Translational Medicine. 2012;4(151):151ra125.
- Grant RM, Anderson PL, McMahan V, et al. Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study. Lancet Infectious Diseases. 2014; 14(9):820–829.
- Patterson KB, Prince HA, Kraft E, et al. Penetration of tenofovir and emtricitabine in mucosal tissues: implications for prevention of HIV-1 transmission. Science Translational Medicine. 2011;3(112):112re114.
- Anderson PL, Kiser JJ, Gardner EM, et al. Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection. Journal of Antimicrobial Chemotherapy. 2011;66(2):240-250.
- Anderson PL. Pharmacology considerations for HIV prevention. 13th International Workshop on Clinical Pharmacology of HIV, 2012.
- Cottrell ML, Srinivas N, Kashuba AD. Pharmacokinetics of antiretrovirals in mucosal tissue. Expert Opinion on Drug Metabolism and Toxicology. 2015; 11: 893–905.
- Cottrell MI YK, Prince Ha, Sykes C, et al. Predicting effective Truvada PrEP dosing strategies with a novel PK-PD model incorporating tissue active metabolites and endogenous nucleotides. HIV Research for Prevention (R4P), 2014.
- Landovitz RJ. PrEP for HIV Prevention: what we know and what we still need to know for implementation. Conference on Retroviruses and Opportunistic Infections (CROI), 2015.
- Knox DC, Tan DH, Harrigan PR, et al. HIV infection with multi-class resistance despite pre-exposure prophylaxis (PrEP). Conference on Retroviruses and Opportunistic Infections (CROI), 22-25 February, 2016. Abstract 169aLB.
- Molina J-M, Capitant C, Spire B, et al. On demand Preexposure Prophylaxis in Men at High risk for HIV-1 Infection. New England Journal of Medicine. 2015; 373(23):2237-2246.
- Molina JM, Charreau I, Spire B, et al. Efficacy of on demand PrEP with TDF-FTC in the ANRS IPERGAY open-label extension study. 21st International AIDS Conference (AIDS 2016). Durban, 2016. Oral Abstract WEAC0102.