PrEP for Understudied Populations: Exploring Questions About Efficacy and Safety
Multiple studies have shown that oral pre-exposure prophylaxis (PrEP) is a highly effective strategy to prevent HIV transmission in many populations at high risk for HIV. However, there is limited research evidence on PrEP effectiveness and safety for certain populations and in certain situations. While that doesn't mean that PrEP won't work or shouldn't be taken in those circumstances, the lack of knowledge can raise questions or concerns. This article will look at what we know about PrEP use during pregnancy and when chestfeeding (breastfeeding), and its use by trans women, trans men and people who inject drugs.
PrEP Use During Pregnancy and/or Chestfeeding
Canadian and international guidelines recommend PrEP for people who are at high risk for HIV transmission during pregnancy and/or chestfeeding.12 The Canadian guideline on HIV pre-exposure prophylaxis (PrEP) and nonoccupational postexposure prophylaxis (nPEP) states that oral PrEP may be considered for use during pregnancy and chestfeeding after a discussion with the PrEP user about its benefits and risks.1 Similarly, the World Health Organization (WHO) states that PrEP can safely be taken throughout pregnancy and chestfeeding when the person has a substantial risk of getting HIV during this time.2
There are many reasons why PrEP may be a good HIV prevention option during pregnancy and/or chestfeeding. If HIV is acquired during pregnancy or when a person is chestfeeding there is a higher risk of passing HIV to the newborn due to a high initial viral load.2 People who are at high risk for HIV and already taking PrEP may become pregnant if they are not using other contraceptive methods. Additionally, HIV-negative people in serodiscordant relationships (with an HIV-positive partner) may want to take PrEP to prevent HIV transmission while trying to conceive and during pregnancy.
No clinical trials have specifically evaluated the effectiveness or safety of PrEP during pregnancy, and in most PrEP clinical trials PrEP was stopped if pregnancy occurred.4 However, multiple studies in different populations of cisgender women have shown that when oral PrEP is used consistently and correctly it is highly effective at preventing HIV transmission.5 See the section on trans men for the available effectiveness evidence.
There is some evidence showing that tenofovir (TDF) and emtricitabine (FTC), the drugs in PrEP, take longer to reach maximum levels in the vagina compared to the rectum, and that drug levels are lower in the vagina. This suggests that high adherence to daily PrEP dosing may be more important for cisgender women and trans men having vaginal sex so that they maintain sufficiently high drug levels to help prevent HIV infection.
Some people may be concerned about the safety of using PrEP during pregnancy or when chestfeeding. However, thousands of pregnant cisgender women living with HIV have used TDF and FTC as part of their HIV treatment, and there is also research on pregnant cisgender women using TDF for hepatitis B treatment.3,4 Research on these populations has found that TDF and FTC are generally safe and well-tolerated by pregnant cisgender women and their developing fetuses.3,4,6
A systematic review on the safety of TDF during pregnancy and lactation found no increased rates of birth defects or other adverse pregnancy outcomes (such as preterm delivery or low birth weight) in cisgender women taking TDF compared to cisgender women taking other HIV medications or placebo (no drugs).4 However, limited evidence has found that infants born to cisgender women taking TDF may have lower bone density than infants who were not exposed to TDF.4,7
While the available data suggests PrEP is safe to take during pregnancy and when chestfeeding, PrEP guidelines note the importance of ongoing monitoring for people using PrEP and their infants during this time.2
PrEP Use by Trans Women
Canada's PrEP guideline recommends PrEP for trans women who are at high risk of getting HIV through sex.1 Trans women are disproportionately affected by HIV in countries such as Canada and the US where HIV epidemics are concentrated within key populations.8
Canadian and US guideline recommendations for trans women are based on studies conducted mostly in cisgender men who have sex with men (MSM).1,9 PrEP studies that have enrolled MSM often include trans women as well; however, only one study (the iPrEx study) has explicitly reported findings on trans women as a subgroup within the study.10,12 The iPrEx study was a randomized controlled trial (RCT) that compared the use of oral PrEP to placebo among MSM and trans women. After demonstrating high effectiveness, the study continued as an open-label extension where all participants were offered PrEP, knowing that they were taking PrEP and that it is effective.
Among 2,499 participants in the RCT phase, 339 (14%) were classified as trans women because they either identified as women, identified as trans, or reported using feminizing hormones regardless of gender identity.11 Among trans women in the iPrEx RCT, low adherence to PrEP resulted in a lack of effectiveness for this group. Eleven trans women in the PrEP group and 10 in the placebo group acquired HIV; however, none had any PrEP drugs detected in their blood at the time of HIV diagnosis.11
When the study continued as an open-label extension with all participants offered PrEP, 151 trans women participated. Two trans women acquired HIV in the open-label extension -- one had no detectable PrEP in the blood and one had drug concentrations indicating use of less than two pills per week. No HIV infections occurred among trans women who had drug concentrations indicating use of two to three pills per week or more.
Overall, trans women in this study differed from MSM in several important ways. Trans women demonstrated lower adherence and less consistent use of PrEP over time, compared to MSM.11 Trans women in this study were also more likely to report having transactional sex, condomless receptive anal sex, and more than five partners in the past three months, compared to MSM. Trans women with higher risk behaviour (that is, those reporting condomless receptive anal sex) were less likely to use PrEP consistently, whereas MSM with the same higher risk behaviours were more likely to use PrEP.
Evidence from iPrEx suggests that PrEP is effective at preventing HIV in trans women when taken consistently, but that trans women may struggle to maintain adherence to PrEP. The authors suggest that barriers to taking PrEP among trans women may include: lack of access to trans-inclusive and culturally competent services, lack of trust with service providers, and concerns about PrEP interactions with gender-affirming hormones.11
More Research Needed
While PrEP is shown to be effective when taken consistently by trans women, certain issues related to trans women and PrEP remain understudied.
No studies have directly investigated drug interactions in trans women who use PrEP while taking feminizing hormones.11,12 However, no drug interactions are expected based on the available evidence.11,13-16 This is because feminizing hormones are metabolized by the liver, whereas the drugs in PrEP are cleared in the kidneys, which makes interactions between the drugs much less likely.11,13 Additionally, research has shown that PrEP drugs do not interact with hormonal contraceptives taken by women to avoid pregnancy,14-16 although these are different from gender-affirming hormones.11More research is needed to better understand how PrEP drugs might interact with feminizing hormones used by some trans women.11,17 This is an important area of further study, especially given that concerns about drug interactions may impact adherence to PrEP among trans women.11
There have been no studies looking at PrEP drug concentrations in genital tissues of trans women who have had gender-affirming surgeries, such as the surgical construction of a vagina.17 This could be an important area of study since there is some evidence that the drugs in PrEP take more or less time to reach maximum levels in different body tissues.17-20
Studies on the effectiveness of PrEP in trans men are underway but this population has been excluded from studies of PrEP effectiveness to date. Trans men may be at risk for HIV, particularly if they have sex with other men. Trans men who identify as gay men and/or have MSM as sexual partners can have the same risks for HIV as other MSM.21
Although there is no data on the effectiveness of PrEP in trans men specifically, there is no reason to believe that PrEP is not highly effective when taken consistently and correctly by trans men. In theory, guidance about the high adherence needed to reach optimal protection from PrEP for cisgender women should be similar for trans men, depending on the type of sex they are having -- whether anal or vaginal/frontal sex. As mentioned earlier, research has found that the drugs in PrEP take longer to reach maximum levels in vaginal tissues compared to rectal tissues, and that high adherence to daily dosing is needed for high effectiveness in the vagina compared to the rectum.18-20
One study examining trans men's knowledge and attitudes about PrEP found that they have concerns about the safety and efficacy of PrEP for trans men, given the lack of research in this population, including potential interactions with hormonal contraceptives, testosterone and other recreational drugs.21 These concerns are similar to those of trans women. The authors note that while there are no suspected interactions between PrEP drugs and hormones or hormonal contraceptives, there is no data on interactions between PrEP drugs and the hormonal intrauterine device (IUD) or testosterone.21
People Who Inject Drugs
PrEP has not been widely taken up by people who inject drugs, although it is recommended in Canada's PrEP guideline for this population if they share injection drug use equipment or participate in sexual practices that place them at high risk for HIV.1 People who inject drugs can be at risk of getting HIV if they share needles or other equipment used to inject drugs, and through sex. The mechanism of HIV transmission through needle sharing is different than through sex, because HIV has direct access to the blood stream when needle sharing occurs. It is therefore reasonable to question whether PrEP is as effective at preventing HIV transmission through needle sharing.
Experts agree that PrEP does work to prevent HIV for people who inject drugs when adherence is high. Although the vast majority of PrEP studies have looked at its effectiveness in preventing sexual HIV transmission, one major PrEP study was conducted in people who inject drugs. The Bangkok Tenofovir Study evaluated the daily use of TDF alone as daily PrEP among people who inject drugs in Thailand.22 This study found an 84% reduced risk of getting HIV among people who were highly adherent to daily PrEP, compared to those taking a placebo drug.23
This estimated level of protection is not as high as estimates from some other PrEP studies. One possible explanation is that TDF alone is not the standard of care for oral PrEP. The current standard of care for PrEP, used in the majority of PrEP studies, includes TDF and FTC. In addition, since people who inject drugs may be at risk of HIV through both needle sharing and sex, it is difficult to determine whether PrEP is as effective at preventing HIV transmission through needle sharing compared to sexual transmission.1
Advocates and researchers have identified a number of concerns with PrEP for people who inject drugs because they fear it may be prioritized over access to and scale-up of other harm reduction programs and HIV treatment services.24 There is already limited access to proven harm reduction interventions for people who use drugs, such as sterile needle and syringe distribution and supervised injection facilities,24 and people who use drugs also have low access to HIV treatment drugs.25
Recommendations for Service Providers
It is important for service providers to know that most people who are at high risk for HIV can safely take PrEP, and that it will be highly effective at preventing HIV transmission if taken consistently and correctly. When clients from the populations discussed above are interested in taking PrEP, service providers can offer counselling tailored to their specific circumstances.
- Service providers can talk to clients about the available evidence showing PrEP is effective when taken consistently and correctly and that the drugs in PrEP are safe to take during pregnancy and chestfeeding.
- Talk to clients about their HIV risk, as PrEP should only be considered if there is a high risk for HIV throughout pregnancy and/or chestfeeding.
- Advise clients to talk to their doctor about the risks and benefits of taking antiretroviral drugs during pregnancy and to ask about the ongoing monitoring that they and their babies will receive.
- Clients can also be counselled on a variety of other HIV prevention strategies, such as condoms, the use of an undetectable viral load to prevent HIV transmission, and harm reduction strategies.
- Service providers can talk to trans clients about the available evidence that suggests PrEP is effective for trans people when taken consistently and correctly, and that while the safety evidence is limited, experts think the drugs in PrEP will not interact with hormones used by trans people.
- Acknowledge that there is limited evidence on the effectiveness of PrEP in trans people and in particular how PrEP works in bodies that have undergone gender-affirming surgeries.
- When making referrals to PrEP services for trans people, consider that PrEP should be provided in clinics/settings that provide gender-affirming care (for example, where chosen names and pronouns are respected, patients can use the bathroom of their choice, and staff are culturally competent).
- Offer adherence counselling and provide clients with strategies to improve adherence such as setting a reminder alarm, using a dosette to organize pills, or downloading an adherence phone app.
- Advise clients to talk to their doctor about the risks and benefits of taking PrEP and to ask about the ongoing monitoring that they will receive.
- Trans people can also be counselled on a variety of other HIV prevention strategies, such as condoms, the use of an undetectable viral load to prevent HIV transmission, and harm reduction strategies.
People who inject drugs:
- Service providers can talk to people who inject drugs about the available evidence that suggests PrEP is effective for them when taken consistently and correctly.
- Ensure that clients are educated on safer injection practices and are aware of local harm reduction services such as needle/syringe distribution programs and supervised injection services. Also, talk to clients about ways to reduce their sexual HIV risk.
- Offer adherence counselling and provide strategies to improve adherence to PrEP.
- Advise clients to talk to their doctor about the risks and benefits of taking PrEP and to ask about the ongoing monitoring that they will receive.
Note that accessing PrEP can be challenging for many reasons. First, PrEP drugs are expensive and are only covered by some provincial and private health insurance plans in Canada. Service providers can help clients determine whether or not they have access to insurance coverage for PrEP. In addition, finding a doctor to prescribe PrEP and provide the necessary follow-up care can be challenging because many doctors are still unaware of or unwilling to prescribe PrEP. Furthermore, help prepare people for discussions with their doctors, as it can be difficult for some people to talk openly about sex or drug use with their doctor.
The only people who should definitively not take PrEP are people who have HIV. An HIV test is required before starting PrEP, and people who test positive should be referred to HIV treatment and care. It is recommended that people with kidney disease should also not use PrEP,1,2 since PrEP drugs are processed by the kidneys.
Oral pre-exposure prophylaxis (PrEP) -- CATIE fact sheet
- Tan DHS, Hull MW, Yoong D, et al. Canadian guideline on HIV pre-exposure prophylaxis and nonoccupational postexposure prophylaxis. Canadian Medical Association Journal. 2017 November 27;189(47):E1448-E1458. Available from: www.cmaj.ca/content/189/47/E1448
- World Health Organization. WHO Implementation tool for pre-exposure prophylaxis (PrEP) of HIV infection. Module 1: Clinical. Geneva: World Health Organization; 2017 (WHO/HIV/2017.17). Available from: www.who.int/hiv/pub/prep/prep-implementation-tool/en/
- Bailey JL, Molino ST, Vega AD, et al. A review of HIV pre-exposure prophylaxis: The female perspective. Infectious Diseases and Therapy. 2017 Sept;6(3):363-382.
- Mofenson LM, Baggaley RC, Mameletzis I. Tenofovir disoproxil fumarate safety for women and their infants during pregnancy and breastfeeding. AIDS. 2017;31(2):213-232.
- Hanscom B, Janes HE, Guarino PD, et al. Brief report: Preventing HIV-1 infection in women using oral preexposure prophylaxis: A meta-analysis of current evidence. Journal of Acquired Immune Deficiency Syndromes. 2016 Dec 15;73(5):606-608.
- Rough K, Seage GR, Williams PL, et al. Birth outcomes for pregnant women with HIV using tenofovir-emtricitabine. The New England Journal of Medicine. 2018 Apr 26;378:1593-1603.
- Siberry GK, Jacobson DL, Kalkwarf HJ, et al. Pediatric HIV/AIDS Cohort Study. Lower newborn bone mineral content associated with maternal use of tenofovir disoproxil fumarate during pregnancy. Clinical Infectious Diseases. 2015; 61:996-1003.
- Baral SD, Poteat T, Stromdahl S, et al. Worldwide burden of HIV in transgender women: a systematic review and meta-analysis. Lancet Infectious Diseases. 2013 Mar;13:214-222.
- Centers for Disease Control and Prevention. US Public Health Service: Preexposure prophylaxis for the prevention of HIV infection in the United States -- 2017 Update: a clinical practice guideline. Published March 2018. Available from:www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2017.pdf
- Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. _The New England Journal of Me_dicine. 2010 Dec 30;363(27):2587-2599.
- Deutsch MB, Glidden DV, Sevelius J, et al. HIV pre-exposure prophylaxis in transgender women: a subgroup analysis of the iPrEx trial. Lancet HIV. 2015 Dec;2:e512-e519.
- Desai M, Field N, Grant R et al. Recent advances in pre-exposure prophylaxis for HIV. BMJ. 2017 Dec 11;359:j5011.
- Anderson PL, Reirden D, Castillo-Mancilla J. Pharmacologic considerations for preexposure prophylaxis in transgender women. Journal of Acquired Immune Deficiency Syndromes. 2016 Aug 15;72 Suppl 3:S230-S234.
- Kearney BP, Mathias A. Lack of effect of tenofovir disoproxil fumarate on pharmacokinetics of hormonal contraceptives. Pharmacotherapy. 2009;29:924-929.
- Murnane PM, Heffron R, Ronald A, et al. Pre-exposure prophylaxis for HIV-1 prevention does not diminish the pregnancy prevention effectiveness of hormonal contraception. AIDS. 2014;28:1825-1830.
- Heffron R, Mugo N, Were E, et al. Preexposure prophylaxis is efficacious for HIV-1 prevention among women using depot medroxyprogesterone acetate for contraception. AIDS. 2014;28:2771-2776.
- Grant RM, Sevelius JM, Guanira JV, et al. Transgender women in clinical trials of pre-exposure prophylaxis. Journal of Acquired Immune Deficiency Syndromes. 2016 Aug 15;72(S3):S226-S229.
- 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, Yang KH, Prince H, et al. Predicting effective Truvada PrEP dosing strategies with a novel PK-PD model incorporating tissue active metabolites and endogenous nucleotides. Presented at: HIV research for prevention (R4P); Cape Town, South Africa, 2014.
- Cottrell ML, Yang KH, Prince H, et al. A translational pharmacology approach to predicting HIV pre-exposure prophylaxis outcomes in men and women using tenofovir disproxil fumarate + emtricitabine. Journal of Infectious Diseases. 2016 Jul 1;214(1):55-64.
- Rowniak S, Ong-Flaherty C, Selix N, et al. Attitudes, beliefs, and barriers to PrEP among trans men. AIDS Education and Prevention. 2017 Aug;29(4):302-314.
- 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 Jun;381(9883):2083-2090.
- Martin M, Vanichseni S, Suntharasamai P, et al. The impact of adherence to preexposure prophylaxis on the risk of HIV infection among people who inject drugs. AIDS. 2015 Apr 24;29(7):819-824.
- Guise A, Albers ER, Strathdee SA. 'PrEP is not ready for our community, and our community is not ready for PrEP': pre-exposure prophylaxis for HIV for people who inject drugs and limits to the HIV prevention response. Addiction. 2017 Apr;112(4):572-578.
- Krusi A, Wood E, Montaner J, Kerr T. Social and structural determinants of HAART access and adherence among injection drug users. International Journal of Drug Policy. 2010;21:4-9.
Camille Arkell is CATIE's Knowledge Specialist, Biomedical Science of Prevention. She has a Master of Public Health degree in Health Promotion from the University of Toronto, and has been working in HIV education and research since 2010.
[Note from TheBodyPRO: This article was originally published by CATIE on in July 2018. We have cross-posted it with their permission.]