Pre-exposure prophylaxis for prevention of HIV infection

Opening Vignette

Ryan, a 27-year-old cisgender man who has sex with men (MSM), heard about human immunodeficiency syndrome (HIV) pre-exposure prophylaxis (PrEP) from his friend. He is not in a long-term relationship and usually meets casual partners online and at social venues, with inconsistent condom use during intercourse. He visits your clinic to find out if he would benefit from HIV PrEP.

WHAT IS HIV PRE-EXPOSURE PROPHYLAXIS?

Human immunodeficiency syndrome pre-exposure prophylaxis (HIV PrEP) is the use of oral antiretroviral medications among high-risk individuals to reduce the risk of contracting HIV. Currently, HIV PrEP in Singapore includes the prescription of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) (coformulated as a single tablet, Truvada®), or tenofovir alafenamide (TAF) and FTC (coformulated as a single pill, Descovy®, or bioequivalent generics). When taken as prescribed, PrEP is effective in reducing the risk of HIV transmission by 99% via sexual activity and 74% among injection drug users.[1]

HOW RELEVANT IS THIS TO MY PRACTICE?

The Joint United Nations Programme on HIV/acquired immunodeficiency syndrome (AIDS), or UNAIDS, has a ‘90–90–90: Treatment for all’ vision to end the AIDS epidemic. UNAIDS targets to have 30 million people on treatment by 2020, 90% of people living with HIV being aware of their status, 90% of people who are aware of their HIV-positive status to be on antiretroviral therapy and 90% of people on antiretroviral therapy to be virally suppressed.[2] This is in line with the target set at the United Nations General Assembly in 2015 and the goal for HIV of the World Health Organization Global Health Sector strategy — to end the AIDS epidemic as a public health threat by 2030.[3] One of the strategies includes normalising and scaling up the use of PrEP in the hope of reducing HIV transmission rates. This involves expanding access to PrEP by training more healthcare professionals and building the capacity, including primary care and community groups, to provide HIV services (including PrEP) to affected populations.[4-6]

HOW COMMON IS THIS IN MY PRACTICE?

In 2020, there were 261 newly reported HIV infections in Singapore. Of the 8,879 cases of HIV infections at the end of 2020, close to a quarter of these individuals (n=2,146, 24.16%) had passed away by then. HIV PrEP functions as an effective supplementary prevention for HIV infection, with an ongoing emphasis on safe sexual practices. Of the 261 reported cases in 2020, sexual intercourse accounted for 95% of the mode of transmission.[7]

WHAT CAN I DO IN MY PRACTICE?

Patient evaluation

A detailed history is necessary to assess the patient’s risk of acquiring HIV or other sexually transmitted infections (STIs). Sexual history should be objectively taken as part of standard medical history. When the doctor approaches the topic with practiced routine and sex being a normal part of healthy adult life, it places the patient at ease. It is good to pre-empt the patient with the question, “I may need to ask some sensitive questions to determine your risk of acquiring sexually transmitted infections.”

First, determine the number of lifetime sexual partners, sex and gender of sexual partners, type of intercourse that the patient practises (vaginal, oral or anal intercourse), and whether there is a correct and consistent use of barrier protection, such as condoms, during intercourse. Next, ask the patient about behaviour associated with a higher risk of STI, such as whether the patient and his/her partner has a past diagnosis of STI, whether the patient has intercourse with partners who have sex in exchange for money, and whether there is use of alcohol and/or drugs during intercourse. It is also advisable to check when the patient had his/her last STI screening. Lastly, ask the patient whether he/she has a past diagnosis of chronic kidney disease (CKD) or osteoporosis and assess if the patient is at risk of developing either of these conditions. It is important to ascertain the patient’s risk, as prolonged use of TDF is associated with possible renal toxicity and osteoporosis.[8-10] A meta-analysis showed a modest increase in the risk of moderate–severe creatinine elevation (defined as >1.3 the upper limit of normal) among patients who received TDF/FTC as PrEP compared to those who received a placebo.[8] In cases where there was substantive decline (i.e., more than 25% of baseline) in the estimated glomerular filtration rate (eGFR), cessation of PrEP resulted in normalisation of eGFR in almost all patients.[9] It has also been shown that participants on TDF/FTC as PrEP may develop a lower bone mineral density, but there was no increased risk of developing a fracture compared to those who received a placebo.[10]

In patients with mild–moderate renal impairment (eGFR above 30 mL/min) or osteoporosis, TAF/FTC can be considered, as it has a lower risk of renal toxicity and decline in bone mineral density compared to TDF/FTC.[11] However, TAF/FTC is currently approved only in cisgender MSM and transgender women who have sex with men as daily PrEP regimen. It should not be used as on-demand PrEP. In general, the decision for PrEP should be individualised after balancing the risk of renal disease or osteoporosis against the risk of acquiring HIV infection. Box 1 shows the candidates who may be suitable for PrEP based on the Guidance for the Prescription of HIV PrEP in Singapore.[12] If an eligible patient has been counselled for PrEP and is committed to regular medication adherence and close follow-up, it is recommended to perform baseline laboratory tests to assess for potential risks of treatment with PrEP [Table 1].

Box 1.

Candidates suitable for PrEP.

• Sexual partner of someone with HIV who is not on suppressive antiretroviral therapy

– HIV viral suppression is defined as plasma viral load <200 copies/mL for >6 months

• Someone who engages in vaginal or anal intercourse without consistent use of condoms with more than one partner in the last six months

– Exclude possible acute HIV seroconversion prior to commencing PrEP

– If high-risk exposure was beyond 72 hours but within 28 days of window period, HIV testing should be repeated after 4 weeks prior to starting PrEP

– Alternatively, HIV RNA viral load can be done if the patient is keen to start PrEP immediately

• Someone with sexually transmitted infection (in particular, syphilis) in the last six months (laboratory confirmed, self-reported or received treatment)

• Someone who received HIV post-exposure prophylaxis in the last six months

• Someone who reported concerns about consistent use of condoms in the future (e.g., difficulties using condoms)

• Someone who engages or indicates that he/she engages in sexual activities under the influence of alcohol or other drugs

• Someone who requests for PrEP on a case-by-case basis (e.g., left a monogamous partnership and will likely be having condomless sex in future)

HIV: human immunodeficiency virus, PrEP: pre-exposure prophylaxis

Table 1.

Laboratory tests before initiation of PrEP.

Test	Clinical rationale
Baseline
Fourth-generation HIV test within the past 4 weeks or rapid POCT finger-prick blood test on the day of consultation if no concern of recent exposure	If there is recent highrisk exposure, consider post-exposure prophylaxis if it is within 72 h. Advise the patient to repeat HIV testing after 4 weeks. PrEP is contraindicated in patients with HIV infection.
Serum creatinine	PrEP is contraindicated if eGFR is less than 60 mL/min for TDF/FTC or less than 30 mL/min for TAF/FTC.
Urinalysis for proteinuria	Only for patients with preexisting risk for renal impairment, e.g., diabetes mellitus, hypertension.
HBsAg and anti-HBs	Vaccination against hepatitis B should be offered to nonimmune individuals. If a patient tests positive for hepatitis B, he/she should be considered for hepatitis B treatment and not be offered on-demand PrEP.
Screening for other conditions
Anti-HCV	Refer patients to hepatitis C treatment if positive.
STIs including syphilis, gonorrhoea and chlamydia	At relevant and appropriate sites based on sexual history when screening for gonorrhoea and chlamydia.
Urinary beta-HCG (for women)	Contraception should be discussed and provided for women who are on PrEP and do not wish to become pregnant.

anti-HBs: hepatitis B surface antibody, anti-HCV: hepatitis C antibody, eGFR: estimated glomerular filtration rate, FTC: emtricitabine, HBsAg: hepatitis B surface antigen, HCG: human chorionic gonadotropin, HIV: human immunodeficiency virus, POCT: point-of-care testing, PrEP: pre-exposure prophylaxis, STI: sexually transmitted infection, TAF: tenofovir alafenamide, TDF: tenofovir disoproxil fumarate

Patients with underlying chronic hepatitis B virus (HBV) infection who are taking PrEP should be monitored for reactivation of HBV or development of TDF- or TAF-resistant HBV infection. This is because TDF, TAF and FTC are each active against HIV and HBV infections. Such patients should be managed by clinicians who are experienced in the treatment of HBV infections or comanaged with an infectious diseases specialist or hepatologist.[13]

Prescription of PrEP

There are two methods to take PrEP — daily or on-demand. Daily PrEP usually consists of daily dosing of coformulated TDF/FTC or TAF/FTC. This regimen is suitable for all individuals who have indications for PrEP. PrEP should be taken for at least 7 days before high levels of protection are achieved for both vaginal and rectal exposure to HIV. On-demand PrEP is only suitable for cisgender MSM. A double dose of TDF/FTC should be taken 2–24 h before intercourse, followed by single doses 24 h and 48 h after the initial dose. When potential exposure is sustained for more than a 24-h period, one tablet per day should be taken until 48 h following the last sexual exposure.

Follow-up visit

It is recommended to review the patient 4 weeks after initiation of PrEP, followed by a regular review every 3–6 months. At the four-week review, check whether the patients are taking PrEP as prescribed and whether they had any side effects from the medication. During the visit, consider repeat HIV testing via the use of fourth-generation HIV test. At the routine review every 3–6 months, assess for medication adherence and any side effects, and order the recommended laboratory tests [Table 2] for patients on PrEP.[12]

Table 2.

Laboratory tests before initiation of PrEP.

Test	Frequency
Third/fourthgeneration HIV testa	• Every three months
Urinary beta-HCG (for women)	• Every three months
STI screening and treatment	• Syphilis, gonorrhoea and chlamydia screening every three to six months
	• Frequency of screening depends on patient-reported sexual risk behaviour
Anti-HCV	• Every year
	• Consider doing it every three months for individuals with very high-risk behaviour (MSM and transgender women)
Serum creatinine	• At least once a year if aged >50 years or individuals with kidney-related comorbidities
	• No serum creatinine monitoring required if aged <50 years without any comorbidities

^aEither routine HIV enzyme-linked immunoassay or rapid point-of-care testing fingerprick blood test. Anti-HCV: hepatitis C antibody, HCG: human chorionic gonadotropin, HIV: human immunodeficiency virus, MSM: men who have sex with men, STI: sexually transmitted infection

It is important to note that routine testing of HIV infection is necessary, as TDF/FTC or TAF/FTC alone might increase the risk of drug-resistant HIV should the patient develop HIV infection while taking PrEP. Patients on PrEP should be reviewed regularly, and prescription for PrEP should not exceed 3 months or 90 days. The need for continued PrEP should be determined based on assessment of the patient’s risk of HIV infection on a yearly basis. Patients who wish to discontinue PrEP should continue to take daily PrEP for 28 days after the last high-risk exposure before cessation. Only cisgender MSM can safely stop PrEP after taking a dose 24 h and 48 h after the last at-risk exposure. Test for HIV should be done when PrEP is discontinued.

Other aspects of a holistic approach to sexual health

Safe sex practices and counselling

Patients should always be counselled on safe sexual practices for HIV prevention. A good framework that is routinely used is the ‘ABCD’ framework — Abstain from casual sex, Be faithful to your partner, Consistent and correct use of condoms, and early Detection of HIV infection.[14] As HIV is mainly transmitted via bodily fluids, abstaining from casual sex and being in monogamous relationships reduce the risk of contracting HIV. Patients should also be educated on the correct use of condoms and be advised to use it consistently during sexual intercourse to protect against HIV and other STIs. Patients who engage in high-risk sexual activities should be encouraged to go for regular screening for HIV.

Screening and treatment of STIs

Patients seeking HIV PrEP should also be counselled for STI screening, as PrEP does not protect against other STIs. There has been mixed data on the risk of STI and PrEP use. While studies such as PROUD, iPrEx and TDF2 do not show increased STI transmission risk with PrEP use, there are other studies that have shown contrasting results.[15-18] However, the majority of STIs are treatable, and a potential rise in the incidence of STI does not negate the overall benefits of PrEP in preventing HIV. Hence, frequent monitoring and surveillance for STIs while patients are on PrEP is important. Screening for HIV and STIs should be done every three to six months, with a shorter interval between screening if the individual is at a higher risk. Common STIs to screen for include syphilis, gonorrhoea and chlamydia. Appropriate treatment should be given should any tests return positive.

Contraception advice

Women of childbearing age on PrEP should be offered contraception to prevent pregnancy if they do not wish to get pregnant, as PrEP is not a form of contraception. The most sensible approach would be to encourage barrier contraception (condoms), as it not only prevents other STIs, but can also prevent pregnancy by up to 95%–98% if used consistently and correctly. Other forms of contraception include hormonal methods (oral contraceptive pills, patch, injectable, implantable), intrauterine contraceptive devices (caution in women with multiple sexual partners, recurrent urogenital infections), fertility awareness method and surgical intervention (vasectomy or tubal ligation). However, these forms of contraception do not offer protection against STIs.

Vaccinations and cervical cancer screening

Human papillomavirus (HPV) vaccination can be offered to women aged ≤26 years who are on PrEP to prevent specific types of HPV infection that can lead to cervical cancer, in accordance with Singapore’s National Adult Immunisation Schedule.[19] The United States Advisory Committee on Immunization Practices also included males aged ≤26 years in their recommended routine HPV vaccination. Although not routinely recommended for older adults (aged >26 years), vaccination for this age group can be offered after discussion and shared clinical decision-making with the patients based on their risk of HPV exposure.[20] Patients should be screened for hepatitis A/B and offered vaccinations if they are not immune to these viruses. Sexually active women should be advised to undergo regular screening for cervical cancer — Pap smear three yearly for patients aged between 25 and 29 years, and HPV screening five yearly for those aged above 30 years.

WHEN SHOULD I REFER TO A SPECIALIST?

Patients should be referred to a an infectious diseases specialist if they fulfil the following: (a) HIV-positive; (b) have indeterminate western blot result; and/or (c) have chronic HBV infection and are keen on HIV PrEP.

TAKE HOME MESSAGES

1. HIV PrEP is the use of antiretroviral drugs for the prevention of HIV infection in at-risk individuals.

2. PrEP is highly effective if taken as prescribed as part of an overall HIV prevention strategy.

3. Patient selection for PrEP is important. A formal evaluation including a detailed history is necessary to assess the patient’s risk of acquiring HIV infection, the risk associated with treatment and the patient’s motivation to comply with treatment.

4. PrEP should be used with caution in patients who are at risk of renal disease or osteoporosis.

5. Close follow-up (no longer than three monthly) and regular HIV screening are necessary for patients on PrEP.

6. Other essential components of a holistic approach to sexual health include counselling on safe sex practices (ABCD framework), screening and treatment of STIs, contraception advice and vaccinations.

Closing Vignette

After a detailed evaluation, Ryan is counselled on the benefits and risks of TDF/FTC for HIV PrEP. He is agreeable to start on daily oral therapy of TDF/FTC and continues to be on follow-up with your practice every three months.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

SMC CATEGORY 3B CME PROGRAMME

Online Quiz: https://www.sma.org.sg/cme-programme

Deadline for submission: 6 pm, 10 November 2023

Question	True	False
1. Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) is the use of oral antiretroviral medications among all individuals who are keen to reduce the risk of contracting HIV.
2. The HIV PrEP functions as an effective supplementary prevention for HIV infection, with ongoing emphasis on safe sexual practices.
3. When taken as prescribed, PrEP is effective in reducing the risk of HIV transmission by sexual activity and among injection drug users by 99% and 74%, respectively
4. In 2020, there were 61 newly reported HIV infections in Singapore.
5. Use of alcohol or drugs during intercourse is a risk factor for acquiring HIV infection.
6. The decision for PrEP should be individualised after balancing the risk of renal disease or osteoporosis against the risk of acquiring HIV infection.
7. Tenofovir alafenamide and emtricitabine (TAF/FTC) can be taken as on-demand PrEP.
8. A patient who received HIV post-exposure prophylaxis in the last 6 months is a suitable candidate for PrEP.
9. The baseline laboratory tests before initiation of PrEP include HIV, serum creatinine, urinalysis, and hepatitis B surface antigen and antibody.
10. Tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) can be considered if the patient has an estimated glomerular filtration rate of 45 mL/min.
11. PrEP should be taken for at least 14 days before high levels of protection are achieved for both vaginal and rectal exposure to HIV.
12. For on-demand PrEP, a double dose of TDF/FTC should be taken 2–24 h before intercourse, followed by single doses 24 and 48 h after the initial dose.
13. Serum creatinine should be screened within 1–3 months after PrEP is started.
14. Patients on PrEP should go for third/fourth-generation HIV screening every three months.
15. It is recommended to screen patients on PrEP for syphilis, gonorrhoea and chlamydia every three to six months.
16. Patients on PrEP should be reviewed regularly, and prescription for PrEP should not exceed six months.
17. A good framework for safe sexual practices for HIV prevention is the ‘ABCD’ framework — Abstain from casual sex, Be faithful to your partner, Consistent and correct use of condoms and early Detection of HIV infection
18. Barrier contraception is recommended for females as it not only prevents other sexually transmitted infection, but also can prevent pregnancy by up to 95%–98% if used consistently and correctly.
19. Human papillomavirus vaccination can be offered to women on PrEP aged 36 years and below.
20. An individual with an indeterminate western blot result while taking PrEP should be referred to an infectious disease specialist.