Wednesday 29 June, 2016 13.00 EDT
Moving PrEP into practice: an update on research and implementation
For more current information, please see CATIE statement on the use of pre-exposure prophylaxis (PrEP) to prevent the sexual transmission of HIV.
The use of daily Truvada pills as pre-exposure prophylaxis (PrEP) is a new HIV prevention strategy recently found to be effective in clinical trials. While generating a significant amount of excitement and hope, current use of PrEP in Canada is low and there are several unanswered questions about how this strategy can be safely and effectively implemented.
This article reviews the research on PrEP, what has happened to move this tool into practice, and the role front-line service providers can play in its safe and effective implementation in Canada.
PrEP refers to the ongoing use of anti-HIV drugs by an HIV-negative person in an effort to reduce their risk of becoming infected with HIV. It is a potential HIV prevention option during periods where a person is at “high risk” of HIV infection.
Many types of PrEP may be possible and are currently being researched, but only one type has been found effective in multiple clinical trials and approved by the Food and Drug Administration (FDA) in the United States. This form of PrEP involves taking a daily oral pill called Truvada (starting before a potential exposure to HIV and continuing afterwards). Truvada is a single pill that contains two anti-HIV drugs (tenofovir and emtricitabine). Tenofovir alone was also found to be effective in two PrEP clinical trials.
Before daily Truvada was found effective as PrEP, it was (and still is) commonly used in combination with other drugs for the treatment of HIV infection. Truvada is also used in combination with other drugs for preventing HIV after a high-risk exposure (post-exposure prophylaxis – PEP).
While this article defines PrEP as the daily use of Truvada, it is important to note that other types of PrEP are being researched. For example, the IPERGAY study – which has sites in Montreal and France – is currently investigating the effectiveness of Truvada when taken on an intermittent basis (instead of daily).
More than taking a pill a day
The use of daily Truvada as PrEP is a tool for HIV-negative people at “high risk” of HIV infection. Therefore its use must be preceded with an HIV test and a risk assessment to determine if a person’s level of risk makes them a good candidate (eligible) for PrEP.
Those who are eligible for PrEP, and decide to use it, also need to commit to regular medical appointments – generally every three months. At each visit the client is monitored for side effects and toxicity, and tested for HIV (if a person tests HIV positive, their PrEP use must be discontinued) and sexually transmitted infections (STIs). PrEP does not protect against other STIs, such as gonorrhea, chlamydia, herpes and syphilis, and their presence may decrease the ability of PrEP to prevent HIV infection.
PrEP also needs to be combined with ongoing adherence support and additional HIV prevention services, such as risk-reduction counselling and access to condoms. Ongoing risk assessments are important to determine if a PrEP user is still at “high risk” and eligible for PrEP.
It works…when taken
Several randomized placebo-controlled trials have investigated the effectiveness of daily Truvada as PrEP. These trials show that PrEP can reduce the risk of HIV infection when used by several different populations, including gay men and other men who have sex with men (MSM), transgender women who have sex with men, people who use injection drugs, and heterosexual men and women.
The overall effectiveness of PrEP in these trials has ranged widely; from 0 to 75%.1,2,3,4,5,6 The general consensus among researchers is that the varying levels of adherence to pill-taking among study participants is responsible for this wide range, as some participants were only taking their pills occasionally and others were not taking their pills at all.7
For example, a study known as iPrEX found PrEP to be 44% effective overall but further investigation found that only half of the study participants had anti-HIV drugs in their blood, suggesting that many were not taking their pills consistently.1 Therefore, this 44% effectiveness is an underestimate of the effectiveness of PrEP when taken consistently. Adherence was so low in two other trials that PrEP was not found to be any more effective than a placebo pill at reducing the risk of HIV infection.3,6,7
It is unclear how much PrEP can reduce the risk of HIV infection when used consistently. In the iPrEX study, participants who were randomized to take PrEP and self-reported greater than 90% adherence to daily pill taking were 73% less likely to become infected with HIV compared to participants who were randomized to take a placebo pill and also reported high adherence.
Some studies have limited their analyses to participants randomized to take PrEP (and ignored participants randomized to take a placebo pill). These studies compared the risk of HIV infection among those with anti-HIV drugs in their blood (which suggests they were using PrEP consistently) to those who did not have these drugs in their blood. Promisingly, these analyses suggest that the consistent use of PrEP may be able to reduce the risk of HIV infection by over 90%.1,2,8
However, since these analyses only looked at those who were assigned to take PrEP and randomization was not used to determine who had drug levels in their blood and who did not, their findings are observational (not protected by randomization). In general, observational evidence is considered to be less strong than randomized evidence because other factors, which are unaccounted for, may partly explain their findings.
Although the research on PrEP effectiveness can be difficult to interpret, the bottom line is that PrEP works and it works better when taken consistently.
[UPDATE: PrEP is currently synonymous with the use of daily Truvada as PrEP. As discussed below, this is the only type of PrEP currently approved by the FDA in the United States and recommended by the World Health Organization and Centers for Disease Control and Prevention. However, a recent study known as IPERGAY found that an intermittent, “on demand” Truvada-based strategy was effective for gay men who have frequent sex. Despite this research, the daily use of Truvada remains the only type of PrEP recommended by health authorities.]
PrEP appears to be safe and well tolerated
The use of Truvada as PrEP seems to be generally safe and well tolerated. In clinical trials, some participants (10% or less) developed mild nausea, diarrhea, headaches, and/or weight loss, but these side effects mostly disappeared after a few weeks of taking PrEP.1,2,3,4,5,6
Little is known about the long-term health effects of taking PrEP, as most clinical trials only lasted a few years. However, reductions in bone-mineral density and kidney health have been observed in some HIV-positive people taking Truvada as part of their long-term treatment for HIV. Similar toxicities were also seen in a very small proportion of PrEP users but the kidney damage resolved after stopping PrEP.
Another concern is the potential for the development of drug resistance. If an HIV-negative person becomes HIV positive while using PrEP, their virus could develop resistance to Truvada. This is because Truvada must be used in combination with other anti-HIV drugs to effectively control HIV replication and treat HIV infection. The use of Truvada alone in an HIV-infected person could allow the virus to mutate and become resistant to Truvada. If drug resistance develops, this could limit future treatment options.
In clinical trials, those who started PrEP when they were already HIV positive (their infection was missed during initial screening for HIV because they were recently infected and in the “window period”) were at very high risk of developing drug resistance. On the other hand, those who started PrEP when they were HIV negative, and became infected while taking it, appeared to have a very low risk of developing drug resistance.
It is unclear whether the risks of side-effects, toxicity, and drug resistance observed in clinical trials will be the same when PrEP is used in the “real-world”. It is possible that clinical trials underestimated these risks, as a large proportion of study participants were not taking PrEP consistently.
Moving PrEP into practice – where are we with implementation?
Now that the research is in, and we know the use of daily Truvada as PrEP can be safe and effective, what has (or hasn’t) happened to move PrEP into practice in Canada and other parts of the world?
While Truvada is approved for the treatment of people living with HIV in most countries in the world, the United States is the only country to approve Truvada for the prevention of HIV infection.
Health Canada (the regulatory agency in Canada) has not approved Truvada for use as PrEP. This would require the pharmaceutical company that manufactures Truvada to apply to Health Canada for approval. To date this has not been done.
Although the use of Truvada as PrEP has not been approved by Health Canada, some healthcare providers are already prescribing it for this purpose.9 This is possible because Truvada has already been approved for the treatment of HIV. When an approved drug is prescribed for an unapproved use, this is called an “off-label” prescription. These types of prescriptions are legal and – for some types of drugs – common.
In other words, a person in Canada can currently access PrEP if they can find a doctor who is willing to prescribe Truvada “off-label” for prevention. In a recent survey of Canadian healthcare providers relatively knowledgeable about HIV, 13% said they had prescribed PrEP.9 In a separate survey of Canadian AIDS Service Organization (ASO) workers, 11% knew of one or more people using PrEP.10
PrEP is expensive and a month-long course of Truvada costs between $700 and $1000.
Some public and private health insurance plans in Canada may cover the cost of the drug. For example, Quebec’s public health insurance covers most of the cost of PrEP and there are reports of some private insurance plans across Canada doing the same.11,12 If Truvada is ever approved for PrEP by Health Canada, this may pave the way to wider financial coverage for PrEP.
Awareness Campaigns and Educational Resources
In the United States, there have been campaigns to improve awareness and knowledge of PrEP. Also, some organizations have created educational resources to help people decide if PrEP is right for them and to assist healthcare providers and service providers talk to patients about PrEP.
While some Canadian organizations have integrated information on PrEP into their resources, and one province (Quebec) has developed a PrEP position statement (in French only), overall awareness and knowledge remains low. In a recent survey of gay men testing for HIV at an STI clinic in downtown Toronto, only 26% were aware of PrEP.13 Also, in a survey of Canadian ASO workers, 64% felt their organization did not have enough current knowledge about PrEP.10
Guidelines for service providers
PrEP use needs to be preceded and combined with several clinical services (prescription, HIV and STI testing, monitoring of side-effects and toxicity) and non-clinical services (education, risk and eligibility assessments, adherence and risk-reduction counselling) to mitigate potential concerns and ensure it is safe and effective. Consequently, guidelines are needed to support a range of providers (including doctors, nurses and non-clinical community-based workers) in the delivery of these services to clients and patients.
While the United States, South Africa and Quebec have developed PrEP guidelines for healthcare providers, no guidelines exist for other types of service providers or for healthcare providers in other parts of Canada or the world.
Demonstration and pilot projects
Several unanswered questions remain with regards to the delivery and use of PrEP outside of a clinical trial. In response, the World Health Organization (WHO) released guidelines in 2012 recommending that countries undertake demonstration and pilot PrEP projects to answer these questions.
Demonstration/pilot projects involve the provision of PrEP to a small number of HIV-negative people to answer important implementation questions. Several such projects are ongoing or planned, mostly in the United States and Eastern and Southern Africa, and are integrating PrEP into a range of settings, including STI and HIV testing clinics and community health centres.
Some of the questions these projects are attempting to answer include:
- How can PrEP be integrated into a comprehensive set of services for people at “high risk” of HIV infection?
- Is it feasible to integrate PrEP into existing services?
- What is the best setting for PrEP delivery?
- How many people, and who, want to use PrEP?
- How well are people able to take PrEP every day?
- Do people increase their risk behaviour while taking PrEP?
- What are the best ways to support adherence and prevent increases in risk behaviour?
- What impact does using PrEP have on overall health and well-being?
- Are PrEP users stigmatized and, if so, what effect does this have?
[UPDATE: Data from these demonstration and pilot projects is beginning to emerge. To learn more, see:
- Uptake of PrEP in the United States
- Use of daily Truvada as PrEP is highly effective for gay men in PROUD demonstration project
- On-demand” PrEP strategy highly effective for gay men who have frequent sex
- PrEP use in the “real world”: Results from the iPrEX open label extension]
Canadian Pilot Projects
Clinique médicale l’Actuel, a centre of excellence in HIV, STIs and hepatitis for almost 30 years has, since January 2013, provided PrEP to individuals who, as a result of their behaviour, are at recurrent high risk for HIV. A committee clearly established that PrEP would be beneficial for l’Actuel’s clients, who are largely gay men of all ages.
An evaluation protocol was developed by nurses and doctors to best identify the behaviours of potential PrEP users. A medical history, descriptions of sexual behaviours and drug use, an HIV testing history and typical positioning during sex (receptive or insertive partner) are all reviewed. A physical exam and blood tests including STI and HIV screening are also part of the initial examination.
The client’s answers and the results of the blood work – potential users must be HIV negative – determine if a person will be prescribed PrEP for three months. If applicable, an initial follow-up appointment with a nurse and doctor is scheduled at the end of the first month of treatment. The client is asked to talk about how treatment is going, including any side effects they have experienced. Adherence support is the primary focus of the appointment and for those who need it, risk-reduction counselling is also offered. This same process – behavioural questionnaire, blood work, adherence and risk-reduction counselling – happens every three months until PrEP is discontinued.
To date, l’Actuel’s doctors have prescribed PrEP to 24 patients, the vast majority of them gay men. No woman has yet to be prescribed PrEP. The program is currently being evaluated and there is no date set for the end of the pilot project.
Another pilot project is planned at St. Michael’s Hospital in Toronto. This project will enroll 50 gay men and other MSM and is using a similar protocol to the Clinique médicale l’Actuel’s program. Enrollment will begin in 2014.
What is the role of service providers in PrEP implementation?
PrEP is no longer a strategy on the horizon but one that is currently available and being used. While its emergence is exciting and might benefit some of the clients and patients we work with, its use also raises several concerns.
People working in HIV prevention (including front-line service providers) have an important role to play in addressing these concerns and ensuring PrEP is implemented in a safe and effective way.
Improving awareness and knowledge of PrEP and supporting decisions related to PrEP
Awareness and knowledge of PrEP can be improved by engaging those at “high risk” through outreach, educational resources, campaigns and counselling. These efforts need to ensure that clients know what PrEP is and who it is for and that any decisions related to starting or stopping PrEP are well informed. Efforts also need to engage other service providers (including doctors, nurses, pharmacists and front-line workers) and address their lack of PrEP knowledge and awareness.
Service providers may need to be prepared to talk about risk perception with clients. Someone who requests PrEP may actually be at low risk and not need PrEP, while someone else may perceive themselves to be at low risk when in reality their behaviour puts them at high risk for HIV infection.
Although PrEP is not meant to replace other effective HIV prevention strategies (such as condoms and new needles), it may provide an important prevention option during periods where a client is struggling to manage their HIV risk in other ways. Since PrEP carries risks and is expensive, it is not a strategy that a client would necessarily need or want to take for a long period of time.
Facilitating access to PrEP
Front-line service providers need to be aware of – and develop partnerships with – local healthcare providers, clinics, health centres and demo/pilot projects that are willing to prescribe PrEP. This can ensure that clients who may benefit from PrEP, and are interested in using it, are linked to a location where it is available. To further facilitate access, clients may need support in talking to healthcare providers about PrEP.
It is also important to know whether the cost of PrEP is covered by your province or territory’s drug plan. Clients can also check with their private health insurance, if they have one, to see if PrEP is covered by their specific plan.
Supporting adherence to PrEP in combination with other risk-reduction strategies
Adherence to daily pill-taking is important for PrEP to be effective and may be challenging for some clients. Service providers can support PrEP adherence in a number of different ways, such as counselling, support groups, and other innovative strategies (such as cell phone reminders).
Service providers can help a client using PrEP reduce their overall risk of HIV infection by addressing the underlying factors (such as mental health, substance use, housing and poverty) that may be increasing their risk behaviours and by helping them adopt additional prevention strategies (such as using condoms and new needles). If clients are able to significantly decrease their risk of HIV infection in other ways, they may be able to stop using PrEP. On the other hand, if a person using PrEP increases their risk behaviour while using PrEP (such as reducing their use of condoms or increasing their number of sex partners), they may inadvertently increase their overall risk of HIV infection. Therefore, counselling to prevent increases in risk behaviour is important.
Supporting adherence and risk reduction may need to go beyond direct interventions (such as risk-reduction counselling) and involve linking clients to additional services (such as housing and mental health services).
Thanks to Clinique médicale l’Actuel for their help in preparing this article.
Pre-exposure prophylaxis (PrEP) – CATIE fact sheet
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