B08 Pre- and post-exposure prophylaxis
Antiretroviral therapy plays a key role in the clinical management of people living with HIV/AIDS (PLWHA).[Chapter C10] Application of antiretroviral therapy, as evidenced in studies demonstrating impacts on virus transmission, is complementing behavioural intervention as a new approach to HIV prevention referred as biomedical HIV prevention. In practice, antiretrovirals (ARV) are an integral part of two main forms of HIV biomedical prevention – post-exposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP). This chapter provides an overview of rationale and development of both PEP and PrEP, followed by discussions on their implementations with a local perspective, i.e. with specific relevance to Hong Kong.
PEP – historical and recent development
The use of ARV for PEP following exposure to HIV could be traced back to the 1980s when proof-of-concept studies with SIV or HIV-2 in nonhuman primates showed moderate degree of success if treatment was started early. It was in the early 1990s that ARVs were prescribed for PEP following occupational exposure to HIV for healthcare workers. Human data were mainly derived from one case-controlled study in healthcare workers, in which zidovudine (ZDV) use was associated with an 81% reduction in transmission risk. During the past two decades, the efficacy of ARVs in preventing HIV infection following exposure has been further supported by the demonstration of its effectiveness in preventing mother-to-child transmission (MTCT), [Chapter F33] and more recently, as inferred from pre-exposure prophylaxis (PrEP).
Traditionally, separate PEP guidelines have been developed according to exposure type. However, systematic reviews of the effectiveness of PEP suggested that the use of ARV following both occupational and non-occupational exposure reduces the risk of acquiring HV infection and is likely to be cost-effective in high-risk communities. PEP was increasingly offered outside occupational setting, which includes exposure following unprotected sexual exposure, injection drug use, trauma and sexual assault. With supporting evidence, WHO updated its guidelines on PEP in 2014, providing recommendations across both occupational and non-occupational exposures with an aim to improve uptake and completion rates for PEP via simplifying prescribing approaches.[Further reading A] In the UK and USA, updates of guidelines on non-occupational post-exposure prophylaxis were made in 2015 and 2016 respectively, with similar drug recommendations made between occupational (oPEP) and non-occupational PEP (nPEP).[Further reading B][Further reading C]
Approach to occupational exposure
Occupational exposures are usually categorised into: i) percutaneous exposure (from needles, instruments, bone fragments etc.); ii) exposure via mucous membranes; iii) exposure via non-intact skin; and iv) human bite with breach of skin. The average risks of HIV transmission after percutaneous and mucocutaneous exposure to HIV-infected blood were estimated to be 0.3% and 0.09% respectively, while that via non-intact skin was <0.1%. In Hong Kong, the prevalence of HIV in the adult population is <0.1%. It is generally believed that the prevalence of blood borne virus infection is higher in hospitalised patients than general population and that it varies with patient risk factors (injecting drug use, multiple sex partners etc.).
Locally, PEP following occupational exposure to HIV for healthcare workers has been in place since 1995. An integrated approach taking into consideration concurrent risk of acquiring two other important blood borne infections, i.e. hepatitis B virus (HBV) and hepatitis C virus (HCV) during occupational exposure is adopted. While the management of occupational exposure to HBV and HCV falls outside the scope of this chapter, its details can be referred to in the guidelines updated by the Scientific Committee on AIDS and STI (SCAS) in 2014.[HK Guidelines 36A] Under occupational setting, management after exposure to blood borne virus involves provision of first aid, reporting, risk assessment, counselling and additional procedures specific to individual pathogens implicated. [Algorithm 8A]
Following an exposure with potential risk of HIV infection, the initial assessment should include details of the nature of exposure, HIV serostatus of the source; and when the serostatus cannot be ascertained, the HIV prevalence of the community group to which the source belongs should be considered during risk stratification. Regarding nature of exposure, deep injury, visible blood on device, procedure involving needle placed in artery or vein and terminal illness in HIV-infected source patient not on treatment are factors associated with higher risk of HIV transmission. Factors that have been proven to have led to reduced PEP effectiveness include large dose of inocula, delay in time to PEP, shortened duration of PEP and suboptimal dosing of PEP. Animal studies suggested that ARV would not be effective if begun more than 72 hours after exposure. After careful and individualised assessment, those who are eligible for PEP should be put on a 3-drug regimen as soon as possible, referred to clinics with expertise in antiretroviral therapy and counselling, and with course of PEP continued for 4 weeks. Delayed initiation after 72 hours may be considered only on an exceptional basis if the likelihood of benefit clearly outweighs the risks. Counselling and support would be offered to enhance adherence and follow-up testing would be performed at 3 to 6 months.
Non-occupational PEP (nPEP)
Non-occupational exposure to HIV refers to an isolated exposure to blood, genital secretions, or other potentially infectious body fluids outside of healthcare settings. Back in the 1980s and 90s, the use of nPEP had been controversial due to paucity of scientific evidence of its efficacy and case heterogeneity. A position statement issued by the Scientific Committee on AIDS and STI (SCAS) in 2006 cautioned that nPEP should only be considered in the event of high-risk exposure to a source known to be HIV positive within 72 hours of exposure and should not be recommended for routine use. However, with accumulating evidence from the use of ARV in preventing MTCT and for PrEP, a worldwide trend of implementing PEP outside of occupational setting has established itself in the past decade.
Over the years, demand for nPEP in Hong Kong has been steadily rising, especially from those sexually exposed. There was an increase in the number of nPEP prescriptions by both Department of Health and Hospital Authority in the past few years. Based on figures from Therapeutic Prevention Clinic (TPC), Special Preventive Programme, Department of Health (DH), clients put on nPEP against HIV have outnumbered those on oPEP following occupational exposure since 2007, contributing 57% to 100% of all cases on HIV PEP annually in the past 10 years. In 2018, SCAS reviewed the local practice and updated the recommendations to provide a standardised approach to the use of nPEP, with an aim to minimise and overcome the barriers for those exposed to substantial HIV risk in non-occupational setting. [HK Guidelines 8B]
In accordance with SCAS’s recommendations, the importance of enhancing access to care and streamlining the care pathway for people seeking nPEP was highlighted. [Algorithm 8B] nPEP shared much similarities with that of oPEP but emphasis is needed to advise regular testing in case of ongoing risk exposure and counselling on a bundle of other prevention strategies to reduce future risk exposure.
With regard to treatment eligibility, in contrast to oPEP for which the source is mostly traceable, the estimation of risk is mainly based on the likelihood of the source being HIV infected multiplied by the per-act risk of acquiring HIV from an infected source. Thus, an understanding of the local epidemiology and the per-act risk for acquiring HIV from an infected source is essential. [Box 8.1] [Box 8.2] Referencing the UK BASHH guideline, [Further reading B] nPEP is recommended when the transmission risk is >0.1%; considered when the risk is between 0.01% to 0.1%; and not recommended when the transmission risk is <0.01%. It should be noted that aggravating factors, e.g. high plasma HIV viral load in the source, presence of concurrent sexually transmitted infections (STI), breaches of mucosal barrier, repetitive exposures in the context of chemsex etc., should be examined during individual risk assessment. Moreover, with emerging evidence supporting the notion of U=U (i.e. Undetectable equals untransmittable), the guideline also aligns with international recommendations and no longer recommends nPEP for sexual exposure if the source is on antiretroviral treatment with sustained (≥6 months) undetectable plasma HIV viral load of <200 copies/mL.
The choice of ARV for both occupational and non-occupational PEP is the same in principle and a three-drug regimen for 28 days should be employed except for specific scenario when the source is HIV infected with known resistance profile. In general, two ARVs of the nucleoside reverse transcriptase inhibitor (NRTI) class (the backbone) in combination with a third compound of either the protease inhibitor (PI) class or integrase inhibitor (INSTI) class is recommended. Their selection should be based on availability, toxicity and individual patient profile including potential drug-drug interactions.
In contrast to occupational exposure, there is a subpopulation of people seeking nPEP who might have ongoing exposure to HIV due to their behavioral risk. In such circumstance, assessment for nPEP itself provides an opportunity for the delivery of a combined package of prevention approaches tailored for the individuals. Counselling on safer sex practices and harm reduction strategies should be redoubled for clients presenting for nPEP, whether or not nPEP is eventually indicated. It should also be emphasised that PEP should not be considered or encouraged as a sole method of HIV prevention. Where indicated, individuals should also be referred to appropriate facilities for hepatitis A and B vaccination, screening and treatment of other STI and for emergency contraception.
Box 8.1. Estimated HIV prevalence in different population groups in Hong Kong according to local surveys and programmes
|Population group||Survey/Programmes||Prevalence (95% CI for Prevalence (%))|
|Men who have sex with men (MSM)||HARiS 2014||5.85% (4.2-8.1)|
|PRiSM 2017||6.54% (5.66-7.42)|
|Female Sex Workers||HARiS 2013||0% (0.0-0.6)|
|Drug users attending methadone clinic||Universal testing programme in Methadone Clinics 2016||1.13 (0.852-1.458)|
|Drug users attending drug treatment centres/institutions||Unlinked anonymous screening 2016||0.623 (0.075-2.251)|
|Data from Special Preventive Programme, Centre for Health Protection, Department of Health, Hong Kong SAR. HIV Surveillance Report – 2016 Update https://www.aids.gov.hk/english/surveillance/sur_report/hiv16.pdf.|
Box 8.2. Risk of HIV transmission per exposure from a known HIV-positive individual not on antiretroviral therapy (ART) (adapted from UK BASHH Guideline [Further reading B] and CDC Guideline [Further reading C])
|Type of exposure||Estimated risk of HIV transmission per exposure from a known HIV-positive individual not on ARTs|
|Receptive anal intercourse||1 in 90|
|Receptive anal intercourse, with ejaculation||1 in 65|
|Receptive anal intercourse, no ejaculation||1 in 170|
|Insertive anal intercourse||1 in 666|
|Insertive anal intercourse not circumcised||1 in 161|
|Insertive anal intercourse and circumcised||1 in 909|
|Receptive vaginal intercourse||1 in 1000|
|Insertive vaginal intercourse||1 in 1,219|
|Semen splash to eye||<1 in 10,000|
|Receptive oral sex (giving fellatio)||<1 in 10,000|
|Insertive oral sex (receiving fellatio)||<1 in 10,000|
|Blood transfusion (one unit)||1 in 1|
|Needlestick injury||1 in 333|
|Sharing injecting equipment (includes chemsex by injection)||1 in 149|
|Human bite||<1 in 10,000|
PrEP – science and controversies
The concept of using ARV for PrEP dates back to the 1990s. In ACTG 076, ZDV was shown to reduce MTCT of HIV in a regimen which extended from antepartum to intrapartum and postpartum periods. It was then hypothesised that it worked by means of pre-exposure as well as post-exposure prophylaxis. This concept was subsequently supported by animal studies, in which daily tenofovir (TDF) and emtricitabine (FTC) were shown to protect macaques against rectal challenge of simian/human immunodeficiency virus (SHIV). Furthermore, these studies suggested that two drugs work better than one, and intermittent, on demand, use of antiretrovirals could also be efficacious.
In 2010, results of the iPrEX study were published. In 2499 men who have sex with men (MSM) and transgender women, use of daily Truvada (fixed dose combination of TDF and FTC) was associated with a 44% reduction of HIV infection (95% CI 15-63; p=0.005). Importantly, in those with blood samples showing detectable tenofovir, effectiveness reached 92%. The drug was well tolerated with only mild toxicity. This and similar studies thus established the effectiveness of PrEP, not only for MSM but also for heterosexual transmission and people who inject drugs (PWID). They also highlighted adherence as the major determinant of effectiveness. Furthermore, women may especially require a higher level of adherence than men for equivalent protection because of a lower drug level in the female genital tract than in the rectum. In 2015, WHO made the recommendation that PrEP should be offered as an additional choice of HIV prevention to those populations with an annual HIV incidence exceeding 3%.[Further reading D]
Despite strong science and recommendations by health authorities, global uptake of PrEP has been relatively slow. The high cost of Truvada is one reason. Paradoxically, this could disproportionately affect resource-replete settings where Truvada® is only available as the brand name product. There is also concern that users of PrEP may exhibit risk compensation, engaging in condomless sex. This would make them susceptible to other STI, hepatitis C included, and resistant HIV strains not preventable by Truvada. Nevertheless, PrEP has been gaining acceptance. Recent declines in new HIV infections in the US and Australia have been attributed to PrEP. In contrast, Hong Kong continues to face a high level of infections with approximately 700 reported cases per year, mostly among MSM.
Approach to PrEP in Hong Kong
As of today (2019), PrEP is available in Hong Kong only in the private sector or through clinical trials. Anecdotal reports also had it that a sizeable number of gay men self-medicated with drugs purchased overseas or on-line. If true, this raised the spectre of drug toxicity and development of HIV drug resistance. In view of this, SCAS has issued an interim statement on PrEP. Besides affirming the effectiveness of PrEP, the statement outlined the parameters for the safe and effective use of this important tool of prevention.[HK Guidelines 8C]
Truvada is a prescription drug. It follows that it should be prescribed only in a medically supervised setting. It is now approved for use as PrEP as well as for treatment of established adult HIV infection. Any adverse effect of PrEP should be reported to the Department of Health (www.drugoffice.gov.hk). The following are the main approaches to PrEP implementation, with special reference to the setting in Hong Kong.
Target only those at high risk – The UK PROUD study of PrEP was able to show a remarkably high effectiveness of 86%. This was partly attributed to a high background HIV incidence of 9% in the comparator arm. The HIV epidemic in Hong Kong is similarly concentrated in the MSM population in whom there is a prevalence of 6.5%, and an estimated incidence of 1.1%. In comparison, the HIV prevalence of the second most affected population, PWID, is 1%. This suggests that PrEP should be prioritised for MSM at high risk in Hong Kong.
In particular, MSM who in the previous six months have had unprotected receptive anal sex, recreational drug use with sex (so called chemsex or chemfun) [Chapter F37] or newly acquired syphilis have further elevated risk. These individuals are therefore appropriate candidates for consideration of PrEP. In addition, partners of those with untreated HIV infection are at elevated risk and could benefit. However, if these HIV-infected partners are on effective HIV treatment with an undetectable viral load, transmission risks are minimal and PrEP would not be necessary. It is important to realise that PrEP is ultimately indicated by risk activities. Those who have ceased risk behaviour should also cease PrEP.
Rule out contraindications – An obvious contraindication to using Truvada for PrEP is pre-existing or acute HIV infection. All patients considered for PrEP should therefore be tested for HIV with a sensitive assay, preferably within 1 week before initiating PrEP and regularly thereafter. Failing to do so will risk development of drug resistance as Truvada alone is inadequate treatment of established HIV infection. In fact, most PrEP ‘failures’ reported in literature were due to failure to rule out HIV infection before PrEP initiation. HBV infection should also be tested for. Both TDF and FTC are effective agents against HBV; its cessation may be followed by serious hepatitis flare. Therefore, if indicated, PrEP should only be given in consultation with experts in hepatitis B treatment, and those who discontinue Truvada should be carefully followed for reactivation of hepatitis. On the other hand, those clients who are found to be susceptible to hepatitis B should be vaccinated since HBV and HIV share similar transmission routes.
Tenofovir is associated with renal and bone toxicity. It should not be used in those with an estimated creatinine clearance less than 60 mL/min. Neither should it be used by those with osteoporosis or a history of fragility fractures. Creatinine clearance should be monitored in the course of treatment. In those at high risk of osteoporosis, dual energy x-ray absorptiometry scan should be considered for follow up, especially with prolonged PrEP use.
Daily rather than on-demand PrEP is preferred – Although an on-demand regimen has been shown to be effective, it is complex. The regimen requires an individual to take two Truvada tablets at least two hours but no more than 24 hours before sexual activity. Thereafter, one additional tablet at 24 and at 48 hours is still required. This regimen may not be ideal in the real world where sexual activity is often unplanned. It may also be less effective for women, and risky for those with HBV infection.
A daily rather than intermittent regimen should be more conducive to adherence which is crucial for success. In this vein, it is emphasised that adherence should be carefully monitored by pill count or at least patient report. Any obstacle to adherence should be evaluated and the client given advice to overcome it. When it becomes obvious that the client cannot adhere to treatment, it should be discontinued. Truvada not appropriately taken is ineffective; as such it should be discontinued. In this case, further emphasis on other prevention tools should be given.
PrEP is used in the context of combination HIV prevention – As recommended by WHO, PrEP is a choice of protection in addition to a package of prevention tools tailored to the patient profile. PrEP alone can fail. Other than HIV infections that pre-existed before PrEP, most failures result from non-adherence or by acquisition of resistant virus. In one report, a homosexual man acquired drug-sensitive HIV despite being fully adherent to PrEP. Of note, he exhibited a high level of risk compensation during treatment, engaging in frequent condomless sex with multiple partners, as well as heavy use of various recreational drugs. These factors likely contributed to the PrEP failure. Overseas experience has shown that risk compensation does frequently occur. In a meta-analysis of 18 cohort studies, occurrence of gonorrhoea, Chlamydia trachomatis infection and syphilis was found to be substantially increased up to 45 times for MSM on PrEP. Untreated STI increases susceptibility to HIV acquisition and therefore has to be regularly screened for and expeditiously treated. Recently, there have also been signs of sexually transmitted HCV infection emerging among users of PrEP. Clients should be educated on the signs and symptoms of HIV seroconversion so that breakthrough infections can be quickly diagnosed and effective treatment started. Risk compensation and the fact that PrEP is not foolproof highlight the importance of employing a full gamut of HIV prevention tools together with PrEP. In most instances, it means that condom use should continue to be advised and chemsex avoided.
Regular medical followup – Taking the above into considerations, a fairly straightforward PrEP protocol can be devised. [Algorithm 8C] In brief, upon determination of a high risk of HIV infection and the acceptance of a candidate to use PrEP, a standard battery of tests should be performed: an HIV test with a rapid turnaround of no more than 1 week, creatinine (for estimation of creatinine clearance), HBV serology, and screening tests for gonorrhoea, Chlamydia trachomatis, and syphilis. If susceptible to HBV, vaccination should be advised or given. HCV serology should also be considered.
Following PrEP initiation, the first re-visit should be within 1 month, and thereafter the client should return at least 3-monthly. In each visit, review should be made of continuing risk, adherence, adverse effects, intercurrent STI, and creatinine with or without full renal function tests. Combination prevention should continue to be emphasised, while PrEP should be discontinued if a user has acquired HIV adherence is poor, or evaluation shows that risk of HIV infection has become non-substantial.
Positioning PEP and PrEP in Hong Kong’s prevention programme
The indication of nPEP was extrapolated from minimal clinical data derived from oPEP rather than well-designed clinical trials. Despite its inclusion in international and national guidelines, there’s little scientific evidence for PEP to be an effective strategy for achieving HIV prevention on a population level. Making PEP available in isolation is unlikely to be impactful in preventing HIV transmission in the community. For individuals at high risk of HIV exposure especially through sex, PrEP is a preferred strategy to PEP. That PrEP offers an additional, effective tool of prevention exists is welcome news. However, the impact of PrEP in bending the current trajectory of our HIV epidemic will likely depend on how and to what extent it is delivered. In Hong Kong, implementation studies are currently in progress, which also provide access to those in need (www.nonewhiv.hk). Regardless, it is appropriate in the clinical setting to prescribe PrEP for HIV negative MSM at high risk of HIV infection, as indicated by such factors as recent unprotected anal sex, acquisition of syphilis, or use of chemsex. PrEP properly prescribed in tandem with a combination prevention approach, and monitored for adherence, toxicity and breakthrough infections is highly effective in preventing HIV infection.
Algorithm 8A. Management of occupational exposure to HBV, HCV and HIV
Algorithm 8B. Care pathway for people seeking post-exposure prophylaxis after non-occupational exposure to HIV
Algorithm 8C. Clinical approach to using PrEP
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Hong Kong Guidelines
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- Scientific Committee on AIDS and STI (SCAS). Recommendations on the use of non-occupational post-exposure prophylaxis against HIV. Hong Kong: Department of Health, 2018. Available from APPENDIX II X2 and link
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- Scientific Committee on AIDS and STI, Centre for Health Protection, Hong Kong. Recommendations on the management of HIV and tuberculosis co-infection. Hong Kong: Department of Health, 2015. Available from APPENDIX II X6 and link