Biomedical prevention of HIV

Anna Pierce : Infectious Diseases Unit, The Alfred Hospital, Melbourne VI
Iryna Zablotska : The Kirby Institute, UNSW Australia NSW

This chapter covers two human immunodeficiency virus (HIV) prevention approaches based on the prophylactic use of antiretroviral drugs following recent (post-exposure prophylaxis [PEP]) in both occupational and non-occupational settings) or ongoing (pre-exposure prophylaxis [PrEP]) high-risk exposure to HIV. It provides an understanding of the risks of HIV transmission in both occupational and non-occupational settings and the rationale for both prevention strategies, as well as recommendations for management including consideration and initiation. It is not a replacement or substitute for detailed guidelines which should be referred to for more specific advice. Readers are referred to the most recent literature reviews and sources of detailed information about both prevention approaches, as well as to the guidance for their use.

Introduction

The most effective way of preventing HIV infection is preventing exposure to HIV. However, the use of antiretroviral drugs as prophylaxis for HIV infection might be beneficial in two specific sets of circumstances: following unanticipated, known or suspected, exposure to HIV and as a shield against infection during a period of ongoing high risk sexual or injecting drug use (IDU) behaviour.

The history of antiretroviral prophylaxis of HIV goes back to the early days of antiretroviral therapy, when the practice of giving healthcare workers zidovudine (AZT) to prevent HIV seroconversion after an occupational exposure decreased the incidence of HIV acquisition in occupational settings.1 Now, a 28-day course of antiretroviral drugs as PEP is a preventive strategy that aims to avert HIV acquisition in people exposed to HIV for any reason. The settings where exposure to HIV may happen – non-occupational (including exposures through unprotected anal or vaginal sex, needle-stick injuries or sharing needles) and occupational – gave rise to a more specific terminology differentiating non-occupational (NPEP) and occupational PEP (OPEP).The successful application of PEP led to research into PrEP of HIV – an approach of taking daily antiretroviral medication in anticipation of a situation where an exposure to HIV is highly likely. Recent evidence supports the effectiveness of this preventive approach under certain conditions.2,3 

Rationale

The rationale for both PEP and PrEP was established in the mid-1990s. Studies in the pathogenesis of HIV infection revealed a window of opportunity (up to 72 hours) after exposure to HIV and before the systemic spread of the virus during which HIV infection could be prevented.4 In animal studies, antiretroviral prophylaxis during this period significantly reduced the risk of simian immunodeficiency virus (SIV) infection in macaques.5-7 All of the evidence for human efficacy of antiretroviral prophylaxis has been gathered from a case-control study of occupational HIV exposure, studies of the highly successful prevention of mother-to-child HIV transmission and PrEP. The World Health Organization (WHO) has issued guidance on HIV prevention using each of these strategies: PEP,8 prevention of mother-to-child HIV transmission9 and PrEP.10 See the ASHM website for Australian guidelines on the use of these strategies.11

PEP or PrEP?

PEP and PrEP are often confused. PEP has been in use since 1996 and consists of a 28-day course of two or three antiretroviral drugs that must be administered within the first 72 hours after exposure to HIV. Its efficacy depends on how soon after the exposure treatment is commenced but it is close to 100%.5,4 PEP is intended for infrequent, one-time exposure - not for regular use. For people who are potentially exposed to HIV on a regular basis, PrEP taken consistently every day alongside other prevention measures such as condoms, is a more suitable option. It may also be considered as one of the options to prevent HIV transmission in serodiscordant couples trying to conceive.

PEP

HIV PEP is the prescription of one or more antiretroviral drugs to reduce the risk of transmission of HIV following a known or possible exposure to HIV. This exposure may be in an occupational setting percutaneously, via mucous membranes or non-intact skin, or a non-occupational setting where the most common exposures are via sexual contact, IDU or accidental needle-stick injury. While PEP plays a role in the management of exposure to HIV, the most important management strategy remains prevention of exposure. The availability of PEP does not replace the need for the universal application of standard precautions for the prevention of HIV in the healthcare setting and adherence to safer sexual and injection practices in the non-occupational setting.

Most of the evidence to support the efficacy of HIV PEP comes from animal studies performed in non-human primates. These studies have shown that PEP is most effective when given early (within 24 hours of exposure) and efficacy is reduced if administration is delayed (especially beyond 72 hours). Efficacy is also reduced with a large viral inoculum, and if the dose of PEP is reduced or the duration of prophylaxis too short. These results have led to the recommendation that PEP be commenced as soon as possible after the exposure, within 72 hours, and that PEP should not be offered more than 72 hours after the exposure. The standard duration of treatment has been accepted as 28 days.5

Only one randomised, placebo-controlled study in humans has ever been set up to determine the efficacy of PEP in the healthcare setting but this study failed to fully recruit and was never completed.6 A multicentre, case-control study of 712 healthcare workers exposed to HIV demonstrated that the use of zidovudine prophylaxis reduced the odds of HIV infection by 81%.1 This study led to the implementation of PEP as part of standard management for occupational exposure to HIV. Although the US Centers for Disease Control and Prevention (CDC) published guidelines for occupational exposure and PEP in 1998, they declined to make recommendations for NPEP until 2005 due to lack of evidence.7,8 Australian national guidelines recommending NPEP were first published in 2001.9

There is no direct clinical trial evidence to support the use of PEP in the non-occupational setting. In addition to evidence from animal models, the data from the above case control study as well as results of post-natal, antiretroviral prophylaxis studies have been extrapolated to the non-occupational setting.

Risk

Occupational exposure

In the occupational setting, the source is usually able to be identified and tested for HIV, and PEP is prescribed only for those who have definitely been exposed to HIV. The risks carried by exposures that occur in the occupational setting are outlined below.

Percutaneous needle-stick injuries

Prospective studies in healthcare workers have estimated the risk of HIV transmission after percutaneous exposure to HIV-infected blood to be approximately 0.3% (95% confidence interval [CI]; 0.2%-0.5%).10 Although the average risk is estimated to be 0.3%, the case-control study in healthcare workers by Cardo and colleagues identified potential risk factors associated with increased transmission,1 including: visible blood on the device; needle used in artery or vein; deep injuries; and large bore hollow needle. These potential risk factors are presumed to be surrogate markers of a greater volume of blood from the source patient. Terminal illness in the source patients was also associated with increased risk of transmission. It is presumed that the raised risk was due to higher plasma HIV RNA levels.

Percutaneous needle-stick injuries occurring in the community most commonly result from needles discarded in public places (in rubbish, parks and on beaches). These injuries frequently result in significant anxiety and media attention; however the actual risk of HIV transmission from such an injury is very low. Laboratory studies have demonstrated viability of virus survival in needle syringes stored at room temperature for up to 30 days, although this depends on a number of factors including: viral titre, volume of blood in syringe, temperature and humidity.11,12 However, there have been no published reports of HIV transmission from community needle-stick exposures; NPEP for HIV is generally not indicated for community needle-stick exposures (unless the source is known to be HIV positive).

The use of needle and syringe programs in Australia has been successful in keeping the seroprevalence of HIV in people who inject drugs (PWID) low. In this population, seroprevalence has increased from 1.1% in 2004 to 2.1% in 2013.13 Therefore, the risk estimate for needle-stick injury from an unknown source is calculated at 1/300 (risk of transmission from known HIV-positive source) x 0.02 (2% HIV seroprevalence in PWID population) = 1/15,000. PEP is not recommended. However, in the subgroup of PWID who identify as men who have sex with men, the prevalence of HIV is higher and in 2012 was reported as 21.4%.19

Mucous membrane and non-intact skin exposures

HIV transmission is also known to occur following mucocutaneous exposure, and US National Surveillance data have documented eight cases of HIV seroconversion in healthcare workers following exposure via this route.20 However, the actual risk per exposure is less well defined. There has only been one case of documented seroconversion following mucocutaneous exposure in six prospective studies of 1107 healthcare workers and the risk is estimated at 0.09% (95% CI; 0.006-0.50).14 The risk from non-intact skin exposure is thought to be even less, and there have been no documented seroconversions after isolated skin exposure in prospective studies.

Non-occupational exposure

There are now a number of prospective studies that estimate per contact probability of HIV transmission, however they are predominantly in heterosexuals.15 Data are limited about the per contact probability of HIV transmission in men who have sex with men; there are only two prospective cohorts that address HIV transmission via anal intercourse in men who have sex with men.16,17 A meta-analysis by Baggaley et al that included only one of these prospective studies estimated the per contact probability of HIV transmission by receptive anal intercourse (RAI) as 1.4% (1/71).26 This is exactly the same as that estimated by the Sydney Health in Men (HIM) cohort (and not included in the meta-analysis) at 1.43%.25 This study also reported a reduction in risk when withdrawal occurred prior to ejaculation. Data from these studies have been used to create the risk estimates in Table 1, however it is important to recognise that these data come from studies with different study designs, from different countries and different at-risk populations.

While these risk estimates are important at a population health level, they do not adequately estimate an individual’s risk after a single exposure. HIV transmission may be increased by numerous factors including viral load of the source, sexually transmitted infections (STI), breaches in mucosal barriers and circumcision status (see co-factors related to HIV transmission below). In addition, there is considerable genetic heterogeneity between individuals which affects HIV infectiousness and susceptibility.

Co-factors related to transmission

Source viral load

There is now strong evidence that indicates significant reduction in risk of HIV transmission in heterosexuals when the source viral load is undetectable1 All viral load tests have a cut-off point below which HIV cannot be reliably detected and below which viral load is considered to be undetectable. In most commonly used tests, a viral load below 50 copies/mL is considered undetectable, although some very sensitive tests can measure below 20 copies/mL. The HIV Prevention Trials Network conducted a multicontinent, randomised, controlled trial called HPTN 052; the study reported a 96% reduction in sexual transmission with early initiation of antiretroviral therapy.27 Therefore the transmission risk for vaginal intercourse with an HIV-positive partner with an undetectable viral load may be estimated to be decreased by a factor of 20. Of note, this decreased transmission risk occurred in a clinical research study where the study’s HIV serodiscordant couples were routinely encouraged to practise safer sex and have regular STI testing at study visits.

There are limited data on the effect of viral load on transmission via anal sex; only 2% of participants (37 couples) in HPTN 052 were men who have sex with men. Two prospective observational studies are underway internationally to address this issue: the PARTNER study in Europe (recruiting both heterosexuals and men who have sex with men) and Opposites Attract (recruiting only men who have sex with men) in Australia. Results of a planned interim analysis from the PARTNER study were presented at the Conference on Retroviruses and Opportunistic Infections (CROI) 2014.18 To be eligible, couples had to report having had condom-less sex, the negative partner could not be on PEP or PrEP and the viral load of the positive partner had to be < 200 copies/mL. By November 2013, 1110 couples were recruited, of which 767 couples contributed 894 eligible couple years of follow-up (308 in male couples). Despite a significant number of condom-less sexual acts, there was no HIV transmission recorded. There is however some uncertainty over the upper limit of risk, particularly with anal sex. The upper limit of the 95% confidence interval was 0.96, which equates to an approximate 10% risk over 10 years. As more couples are followed over longer periods of time, the uncertainty over these upper limits of transmission risk will reduce. Both studies are still recruiting.

Circumcision status

The Health in Men (HIM) cohort study is the first prospective study to estimate the per-contact transmission risk of insertive anal intercourse (IAI) in men who have sex with men. In that study, in a small subset of men who practised almost exclusive IAI, the per-contact probability of IAI was 0.11% if the insertive partner was circumcised, and 0.62% when not circumcised.29 A Cochrane review reported a 73% (95% CI of RRR 56-83%) relative risk reduction of circumcision in men who mainly report the insertive role in anal intercourse.30 This rate was calculated from observational studies only as there have been no randomised controlled trials (RCTs) in men who have sex with men. In heterosexual men the relative risk reduction of circumcision has been calculated at 50% in a systematic review of randomised trials.31

Other factors

Other factors that may increase the risk of HIV transmission include:

  • Sexually transmissible infection in the source or exposed individual, especially when genital ulcer disease and/or inflammation is present
  • A breach in genital mucosal integrity (e.g. trauma, genital piercing or genital tract infection)
  • A breach in oral mucosal integrity when performing oral sex.
HIV transmission risk

Risk of HIV transmission = Risk per exposure x Risk of source being HIV positive

Ideally, active attempts should be made to contact the source and ask him or her to have an urgent HIV test, however the often anonymous nature of exposures makes this impractical.

If the source discloses he or she is HIV positive, consent should be gained to seek treatment details from his or her doctor. At the very least it is useful to know if they are on treatment or not and if their viral load is undetectable.

If the source cannot be contacted, seroprevalence data (see Table 1) will assist in determining the risk of HIV transmission and the need for PEP.

Table 1 HIV seroprevalence in Australian populations
Community group HIV seroprevalence (%)
Men who have sex with men21 8-12

People who inject drugs19

  • Homosexual
  • Others
  • 21.4
  • 2.1

Heterosexuals in Australia19

  • Blood donors (% donations)
  • STI clinic attendees
    • Men
    • women 
  • 0.0004
  • 0.7
  • 0.05 
Commercial sex workers (Australia)21 < 0.1
HIV seroprevalence in overseas populations

The seroprevalence overseas varies widely, not only between countries but also in different risk groups. Highest seroprevalence is in Southern Africa (up to 25%) and in IDU in South East Asia (up to 40% in Thailand). For seroprevalence for individual countries, go to http://www.unaids.org/en/dataanalysis/datatools/aidsinfo/

Considerations for non-occupational post exposure prophylaxis including number and choice of antiretroviral drugs

Two versus three drug regimens and choice of antiretroviral drugs The recommendation for the number of drugs is based on the estimated risk of exposure. In the treatment of HIV, triple combination therapy provides superior viral suppression to dual combination therapy and has been the basis for the recommendation of three-drug NPEP for higher risk exposures.15 Many guidelines now recommend that where PEP is indicated three drugs always be used as there may be difficulty in determining the risk of HIV transmission for individual exposures.19,20 However, there is no evidence to support greater efficacy of three drugs over two in the setting of post-exposure prophylaxis. In the prevention of mother-to-child transmission, the US National Institute of Child Health and Human Development [NICHD] and HIV Prevention Trials Network (HPTN) study, NICHD-HPTN 040/PACTG 1043, demonstrated superior efficacy of two or three drugs over zidovudine monotherapy, however no difference was seen between two and three drugs. This finding is the basis for the recommendation of two drugs (rather than three) for post-exposure prophylaxis for newborns in this setting.21 In addition, both toxicity and discontinuation rates are higher for three-drug versus two-drug PEP regimens, and modelling studies have shown that under many conditions the benefits of completing a better-tolerated, two-drug PEP regimen may exceed the benefits of a three-drug PEP regimen.22

Previous Australian guidelines recommended that three-drug PEP be given to all those whose source was known to be HIV positive. However, in the setting of budgetary constraints, lack of evidence for superiority of three-drug vs two-drug PEP, absence of seroconversions in patients receiving two-drug PEP from the Victorian NPEP Service23 and the increasing evidence for the efficacy of Truvada® (a fixed dose combination of tenofovir and emtricitabine) for pre-exposure prophylaxis, this recommendation may be revised.

Table 2  Exposure Estimated risk of transmission per exposure Recommendation Source
Exposure Estimated risk of transmission per exposure Recommendation 
    Source viral load undetectable   Source not on treatment or on treatment with detectable viral load 
Receptive anal intercourse
- ejaculation
- withdrawal

1/70

1/155

2 drugs 3 drugs
Contaminated injecting equipment 1/125 2 drugs 3 drugs
Insertive anal intercourse (uncircumcised) 1/160 2 drugs 3 drugs
Insertive anal intercourse (circumcised) 1/900 Consider 2 drugs if STI, trauma or blood 3 drugs
Receptive vaginal intercourse 1/1250 Not recommended* 3 drugs
Insertive vaginal intercourse 1/1250 Not recommended* 3 drugs
Receptive or insertive oral intercourse Not measurable Not recommended Not recommended†
Mucous membrane and non-intact skin exposure ≤1/1000 Not recommended 3 drugs

*Provided source is adherent to medication, attends regular follow-up and has no intercurrent STI
†PEP (2 drugs) may be recommended for receptive oral intercourse with ejaculation if the exposed person has a breach in his or her oral mucous membrane

 

Table 3  Post-exposure prophylaxis recommendations for exposure to a source of unknown HIV status
Exposure Estimated risk of transmission per exposure Recommendation 
Receptive anal intercourse
- ejaculation
- withdrawal

1/700*
1/1550*

2** drugs if source MSM or from high prevalence country
Contaminated injecting equipment 1/12,500†
(1/1250 – 1/415‡ if source MSM)
2 drugs if source MSM or from high prevalence country
Insertive anal intercourse (uncircumcised) 1/1600* 2 drugs
Insertive anal intercourse (circumcised) 1/9000* Consider 2 drugs if STI, trauma or blood
Receptive vaginal intercourse 1/1,250,000^ Not recommended (Consider 2 drugs if source MSM or from high prevalence country)
Insertive vaginal intercourse 1/1,250,000^ Not recommended (Consider 2 drugs if source from high prevalence country)
Receptive or insertive oral intercourse Not measurable Not recommended
Mucous membrane and non-intact skin exposure ≤ 1/10,000* (MSM exposure) Not recommended
Needlestick injury from a discarded needle in community Not measurable Not recommended

MSM: men who have sex with men; RAI: receptive anal intercourse
* based on estimated seroprevalence of 10% (9.6%) in MSM
† based on estimated seroprevalence of 1.0%
‡ based on estimated seroprevalence of 29%
^ based on estimated seroprevalence of 0.1%
**2 drugs continue to be recommended despite a new risk estimate for RAI that is higher than the risk estimates for some exposures where 3 drugs are recommended. Risk estimate figures may not always correlate directly with number of drugs recommended

While these risk estimates are important at a population health level, they do not adequately estimate an individual’s risk after a single exposure. In particular, when HIV prevalence data is used to calculate a risk estimate for an unknown source, the figures in Tables 2 and 3 cannot be used to adequately assess an individual’s risk. For such an exposure, the risk is either that the source is positive, or that the source does not have HIV infection.

Recommended PEP regimens

The most commonly prescribed two-drug PEP regimen is the combination of tenofovir and emtricitabine, co-formulated as Truvada, however the use of generic drugs may be used to reduce cost. When a third drug is added, a protease inhibitor such as Kaletra® (Iopinavir and ritonavir) has been commonly used. It has been argued that protease inhibitors are inappropriate for use as PEP due to their mode and site of action; drugs that act before integration of HIV into target cells are more appropriate for use as PEP.24 The integrase inhibitor, raltegravir, may be a logical choice for a third drug in a PEP regimen and is now recommended in some occupational guidelines, as well as the Victorian NPEP Service guidelines,25 however caution should be taken as there has been a case of rhabdomyolysis reported with its use as PEP.26 Dolutegravir, a new once daily integrase inhibitor, may be an even better choice for a third drug and is currently being studied in a clinical trial in Sydney and Melbourne.

Drugs not to use for PEP:

  • Nevirapine, a non-nucleoside reverse transcriptase inhibitor (NNRTI): due to severe adverse events including liver failure requiring liver transplant in healthcare workers taking PEP regimens containing nevirapine15,17,19
  • Co-administration of stavudine and didanosine is not recommended, and is contraindicated in pregnancy27,28
  • Abacavir, a nucleoside reverse transcriptase inhibitor (NRTI), is associated with hypersensitivity reactions which make it unsuitable to use as PEP
  • Efavirenz, a NNRTI, is contraindicated in pregnancy and neurological side-effects may make it less suitable for PEP.30

When the source is known to have HIV infection, it is important to try and determine the antiretroviral medication history of the source so an appropriate PEP regimen can be constructed.

Toxicity and adherence

NPEP has been reported to cause side-effects in 45-75% of patients in Australia, the USA and Europe.31-32 In an analysis of 648 patients who received NPEP in Australia between 1998 and 2002, the prescription of two or three antiretroviral drugs was associated with side-effects in 72% of those receiving two drugs compared with 76% receiving three drugs. Fifty-six per cent of patients taking a three-drug regimen had full adherence compared to 62% of patients taking a two-drug regimen.43 The US National NPEP Registry reported that 22% of prescribed regimens were modified because of side-effects.33 However, many of these regimens contained zidovudine which is less well tolerated than tenofovir-based regimens which are now commonly used.

Cost

The cost-effectiveness of NPEP has been assessed in the USA and Canada. It has been shown to be cost effective when a two-drug regimen was used for unprotected, receptive anal intercourse with a person known to have HIV infection or to be at high risk of having HIV infection.34-35 A retrospective cost analysis in Australia concluded that NPEP may be cost-effective for high-risk exposures such as receptive anal intercourse and injecting drug use with a known HIV-positive source; the overall cost per seroconversion avoided was $1,740,134.32.00 (AUD).36 These cost-effectiveness analyses are sensitive to the figure used for HIV transmission risk. Given the risk for HIV transmission is significantly reduced if the source has undetectable viral load, these cost effective estimates may no longer be valid.

Management algorithm

The initial management of PEP is the same regardless of whether the exposure occurs in an occupational setting or in the community:

  • Wash wounds and skin sites that have been in contact with blood or body fluids with soap and water
  • After oral exposure to blood or body fluids, spit out fluids and rinse with water
  • Irrigate mucous membranes and eyes (remove contact lenses) with water or saline
  • Vaginal or rectal douching is not recommended following sexual exposure
  • Do not inject antiseptics or disinfectants into wounds.

Clinical assessment and follow-up are similar for both occupational and non-occupational exposures (Table 4).32 The main difference lies in the assessment of the exposed person: additional sexual history including other recent exposures, history of NPEP and evaluation for STI should be obtained in the setting of non-occupational exposure. Based on the clinical assessment and an estimate of the risk of HIV transmission, a decision regarding the need for PEP should be made.

Table 4 Clinical assessment and follow-up for non-occupational post-exposure prophylaxis

These details should be documented in the patient’s history:
1. The time of the assessment and first dose, if prescribed
2. Of the exposure (when, what, where and with whom?)

a) Time of exposure
b) Place of exposure
c) Exact mode and details of exposure (including contributory factors)
d) Amount of blood or body fluid involved, including trauma
e) First aid measures applied

3. Of the exposed person

a) Most recent HIV test and result
b) Potential exposures within the last 3 months (and earlier as indicated)
c) Previous post-exposure prophylaxis and history of this treatment
d) Evaluation of current sexually transmitted infections (STI), hepatitis B virus (HBV) and hepatitis C virus (HCV) infection
e) Pregnancy risk, contraception and lactation (consider emergency contraception)
f) Medical history, including illnesses, medications and drug allergies
g) Psychiatric history
h) Drug and alcohol history
i) Patient’s knowledge of the source (if unavailable for interview)

4. Of the source

a) HIV status and other relevant demographic features
b) If HIV positive:

(i) plasma viral load and CD4 cell count
(ii) antiretroviral treatment history (has resistance been an issue, if so with which drugs?)
(iii) recent HIV resistance genotyping

c) Current or past STI, HBV and HCV status

5. Pre-test and pre-NPEP discussion
An explanation of NPEP and its indications and effectiveness, risks and benefits are provided to all potential candidates. A thorough pre-test discussion for HIV, including risk assessment, is a fundamental part of the clinical assessment. Refer to the National HIV Testing Policy 2011 available at: http://testingportal.ashm.org.au/hiv

6. Follow-up
A person found to have HIV infection on baseline testing or during follow-up requires information, support, counselling, clinical assessment and referral. NPEP should be ceased in these cases. There is a theoretical risk of resistance to antiretroviral therapy developing if NPEP is continued, potentially limiting therapeutic options. Ongoing management must also be provided for those at risk of other infections or pregnancy resulting from the exposure.

NPEP: non-occupational post-exposure prophylaxis.

Source: Adapted from: National Guidelines for post-exposure prophylaxis after non-occupational and occupational exposure to HIV. ASHM: 2013.

Laboratory evaluations and follow-up

Table 5 outlines the recommended laboratory evaluations for a person who receives PEP and is adapted from the US Department of Health and Human Services (DHHS) guidelines.15

Baseline investigation of full blood count, electrolytes and liver function tests are generally not necessary as PEP is predominantly sought by healthy younger adults. Investigations may be performed at the clinician’s discretion but should be considered if there is any evidence of co-existing medical conditions, in particular renal impairment.

Table 5 Recommended laboratory evaluations for people exposed to HIV
Test Baseline Week 1 after exposure Week 4-6 after exposure Week 12 after exposure

HIV antibody 

 √    √  √

Hepatitis A serology1

 √      

Hepatitis B serology2

 √      

 Hepatitis C serology3

 √      √3

STI screen

4 5  

FBE6, U&E6, LFT6, CK7

6      

Pregnancy test8

8      

Adapted from the 2005 DHHS guidelines.15

FBE: full blood examination; U&E: urea, electrolytes; LFT: liver function test; CK: creatine kinase

  1. Men who have sex with men who have negative hepatitis A serology should be immunised.
  2. Individuals screened for hepatitis B may be a) immune and require no further follow-up b) non-immune and require immunisation and follow-up or c) have chronic infection and require appropriate management.
  3. Test for hepatitis C up to 6 months where the exposure was high risk for hepatitis C (e.g. involved injecting drug use or sexual exposure which may have involved mucosal trauma including fisting).
  4. Perform STI screen at baseline if exposed individual has symptoms of an STI.
  5. Repeat syphilis serology after sexual exposure.
  6. Baseline where clinically indicated.
  7. If raltegravir prescribed, repeat renal function tests and CK at least once in the PEP course. Caution patient about rhabdomyolysis and clinically monitor for myalgia.
  8. Perform at baseline in women of reproductive age and whenever clinically indicated during the follow-up period.

Other PEP issues

Repeat PEP presenters

Among most men who have sex with men presenting for and receiving PEP, high HIV-risk sexual behaviour is not a chronic pattern but rather, appears to occur periodically or as a one-off experience in response to co-occurring personal, social or environmental factors at that particular time. However, a small minority of men who have sex with men receiving PEP present with repeat high HIV-risk sexual behaviour.

  • When a patient has multiple presentations for PEP within a 12-month period, discuss the repeated presentations with the patient and offer referral to clinical psychology if appropriate.
  • Where there have been multiple presentations, PEP should not be withheld if risk assessment indicates high-risk exposure to HIV. Each case is assessed on its merits.
  • Pre-exposure prophylaxis (PrEP) is now available in Australia through demonstration projects in Victoria, New South Wales and Queensland.
Patients who have further exposures while on PEP

The fixed-dose combination of tenofovir and emtricitabine (Truvada) has been shown to reduce the risk of HIV acquisition in men who have sex with men when taken as PrEP.2 Furthermore, pharmacokinetic analysis of intracellular drug concentrations in the iPrEX (Pre-Exposure Prophylaxis Initiative) study has been correlated with levels of adherence and drug levels in a separate study (the STRAND study) to estimate PrEP efficacy with different dosing intervals.37 Risk reduction estimates were 76% for two doses of PrEP per week, 96% for four doses per week, and 99% for daily dosing. It is therefore extrapolated that currently being on PEP reduces the risk of HIV acquisition from other exposures that occur while taking PEP.

PrEP

The effectiveness of antiretroviral medications as PrEP has now been established by four clinical trials conducted in homosexual men (iPrEx), heterosexual men and women (Partners PrEP and TDF2), and injecting drug users (Bangkok Tenofovir Study).2,54-38 The daily oral pill containing tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is considered safe and effective to reduce the risk of HIV infection in high-risk adults who are able to take the medication correctly and consistently.38,40 None of the clinical trials has reported any significant increase in behavioural disinhibition, while all trials promoted condom use and safer sex practices. Based on this evidence, the TDF/FTC pill (marketed as Truvada by Gilead Sciences Inc.)41 has been approved by the US Food and Drug Administration as PrEP. Clinical guidance for PrEP prescribers has been issued by the US CDC for all three population groups: homosexual men, high-risk heterosexual men and women, and injecting drug users.59 The 2014 US PrEP guidelines for clinicians are available on the CDC website at: http://www.cdc.gov/hiv/pdf/PrEPguidelines2014.pdf Australian national guidelines will be available in 2015.

Considerations for pre-exposure prophylaxis of HIV

Clinical trials revealed a wide gap between the average risk reduction provided by antiretroviral drugs and the adherence-adjusted efficacy.3 On average, Truvada efficacy levels were moderate and ranged from 44% among homosexual men to 75% among heterosexuals. However, when measured in the same studies among individuals with detectable TDF in blood, Truvada efficacy levels rose significantly to 92% in homosexual men and 84% in heterosexuals. On the other hand, the FEM-PrEP60 and VOICE61 trials, where participating women were not able to adhere to the same medication, were stopped for futility. The observed gap between average and adherence-adjusted levels of protection appears to vary not only across studies, but also across countries and research sites. This is best illustrated by the iPrEx study, which found better adherence to PrEP among homosexual men in the US as opposed to the study sites in other countries.2 The iPrEx study and its open-label extension demonstrated that higher levels of adherence can be expected among self-selected, motivated PrEP users and among those who are better informed about PrEP and HIV prevention.62 The levels of adherence also vary depending on the adherence measures used.63 For example, in the iPrEx study daily Truvada use was self-reported by 95% of participants; however pill counts adjusted adherence down to 86%, while TDF was detected in only 51% of blood samples from HIV-negative participants and 9% of seroconverters.2

Medication adherence is critical not only in achieving the maximum prevention benefit, but also for reducing the risk of selecting for a drug-resistant virus if non-adherence leads to HIV acquisition.64,42

The lead time from initiating daily PrEP to achieving steady drug levels in blood, rectal and vaginal tissues remains unknown, as there has only been limited evidence from pharmacokinetic studies.63 Levels of medication adherence associated with satisfactory levels of protection among HIV-negative antiretroviral users are also not clear. However, the study of pharmacokinetics of directly observed TDF dosing combined with detection-efficacy modelling on iPrEx data reported that HIV risk reduction efficacy of 99% corresponded to 7 doses per week, 96% to 4 doses per week, and 76% to 2 doses per week.53 In at least one study (a US study among young men who have sex with men) adherence levels declined with the duration of daily TDF/FTC use.66 Furthermore, high levels of adherence may be more difficult to achieve with fixed-interval or post-coital dosing regimens as compared to daily dosing.67 Currently, two clinical trials (IPERGAY and HPTN 067) are investigating adherence to and the efficacy of non-daily PrEP and will report their results in 2015-2016 (for more details, visit: www.ipergaymtl.com/en/about-us.html and www.hptn.org).

The safety profile of daily TDF/FTC use for HIV-negative people is known from clinical trials with follow up of participants from 1 to 4 years. Adverse reactions that were reported by more than 2% of Truvada subjects and that were more frequent in treatment than placebo groups were headache, abdominal pain and weight loss. Appendix 2 (Contact and referral information) lists side-effects associated with the use of emtricitabine and tenofovir among HIV-negative people. Truvada prescribing information suggests that serious side-effects experienced by users of antiretroviral nucleoside analogues can include lactic acidosis and severe hepatomegaly with steatosis that may result in liver failure, other complications or death (observed more often in women) and worsening of HBV infection if Truvada is stopped.59 Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported among people with HIV infection with the use of TDF; thus, the warning in the Prescribing Information may relate to longer periods of use. In previous studies, 3-4% decreases in bone mineral density (BMD) have been observed in people being treated for HIV with combination antiretroviral therapy including tenofovir.3,68 Data published from PrEP studies that assessed bone mineral density (BMD) to date (iPrEx; CDC PrEP safety trial in men who have sex with men) found a 1% decline in BMD, but no increase in fragility (atraumatic) fractures over the 1 to 2 years of observation compared to placebo, although the studies were too small and too short to detect any impact of tenofovir on fracture incidence. In these studies, the decline in BMD was observed during the first few months on PrEP, and it either stabilised or returned to normal thereafter.69

One important question is who can most benefit from PrEP. Previous modelling analyses made it clear that daily oral PrEP could not be a prevention strategy for all, and it would only be cost-effective if specifically targeted to the highest risk groups.70 Some approaches to identifying eligible individuals based on high-risk behaviour scoring scales have been suggested for men who have sex with men and transgender women and heterosexuals in the US.71-73 In Australia, the eligibility criteria for PrEP are defined in the national PrEP guidelines (to be released in 2015).

In the context of a relationship where the partners’ HIV status is discordant and an HIV-positive partner is not on treatment or has detectable HIV viral load, administration of PrEP for a partner without HIV infection may reduce the risk of sexually acquired HIV. Additionally, PrEP can be considered as one of several options to protect the partner without HIV infection during conception.3 Although undetectable viral load in HIV-positive partners is associated with 96% risk reduction of HIV transmission to their partners, PrEP can be recommended to women without HIV infection who plan to conceive, regardless of the viral load of their partners with HIV infection.27

The risk of HIV acquisition increases during pregnancy, as does the risk of HIV transmission to a child from a mother who acquires infection during pregnancy or breastfeeding.74 Therefore, an HIV-negative woman at high risk of HIV infection may benefit from continuing PrEP use throughout her pregnancy and breastfeeding to protect herself and her infant. Discussion of PrEP with women without HIV infection at high risk of HIV infection who are pregnant or breastfeeding is recommended, so that a timely informed decision can be made in awareness of what is known and unknown about benefits and risks of continuing PrEP.3

At the time of the publication of this monograph, research is being undertaken on new antiretroviral options, schedules of use and delivery mechanisms aiming to resolve or bypass the critical issue of adherence to the daily oral PrEP schedule,75 and making PrEP easier to use and acceptable to a variety of user groups. In the next few years, publication of efficacy levels is expected for long-acting injectable antiretroviral drugs, medicated vaginal rings and rectal microbicides.76

PrEP in Australia

At the time of publication of this monograph, no antiretroviral drugs have been licensed by the Australian Therapeutic Goods Administration for preventive use. However, Australia maintains a high commitment to reducing rates of HIV infection and recognises that new technological developments should be considered for HIV prevention.77 During 2014-16, PrEP implementation models will be developed and tested in at least three demonstration projects in New South Wales, Victoria and Queensland. All three projects are funded by state Departments of Health committed to incorporate PrEP into a comprehensive package of HIV prevention interventions in keeping with the WHO recommendation to undertake implementation research. Their purpose is not only to give access to PrEP to homosexual men and heterosexual men and women who can benefit from its use, but also to better understand the role of PrEP in response to the local HIV epidemic, to assess local barriers and facilitators to PrEP adherence among the users, and to exert the maximum effect from PrEP in local HIV prevention.

Preliminary work has been undertaken in Australia to understand the needs of high-risk population groups for more effective HIV prevention strategies, awareness about and willingness to use daily PrEP among homosexual men43 and heterosexual men and women in serodiscordant relationships, as well as current levels of informal use, the patterns of use and associated factors.78-81 Similar to reports from other countries (e.g. the US),62 PrEP use in Australia remains low (about 2.5% of gay men in community samples) and is reported by gay men with the highest risk practices for HIV, but interest in this prevention strategy is rapidly growing.82 At the time of this publication, there has been no evidence about the use of PrEP by heterosexual men or women in Australia yet.

Eligibility and risk assessment for PrEP

PrEP is a relatively new HIV prevention approach. It may represent a much-needed additional prevention method for some people at high risk for HIV infection. It is important to remember however that, to reduce the risk of acquiring HIV, this method is not intended to be used alone or to replace other prevention methods, but should be rather used in combination with other methods, particularly condoms and safer sex practices. PrEP cannot replace behavioural approaches aimed at reducing the risk of contracting HIV and avoiding HIV exposure.

Those people eligible for PrEP should be adults who are able to make an informed choice to use PrEP, who are confirmed to be HIV negative, and are at substantial and sustained risk for HIV infection. HIV-negative status should be confirmed no more than 7 days before initiation of PrEP, by using standard-of-care testing procedures. Because the risk of HIV infection cannot be fully eliminated by PrEP, regular HIV testing is essential. At any time, PrEP should be discontinued immediately if a person has symptoms of seroconversion illness or is highly likely to seroconvert (e.g. a known exposure to HIV happened during the time when daily PrEP was not taken). Truvada alone does not constitute a complete treatment regimen for HIV infection.

PrEP is meant to be used by people who are at high and ongoing risk of acquiring HIV. Table 5 summarises different practices and conditions which are known to be associated with increased HIV incidence among men who have sex with men in Australia (data from the Health in Men (HIM) study conducted in 2001-2007).25 Recommendations on how to determine behavioural eligibility for PrEP are provided by the clinical guidance for PrEP prescribers in Australia.

Table 6. Different practices and conditions associated with high HIV incidence among men who have sex with men*
Risk factor Associated HIV incidence
All patients regardless of practices 0.78 per 100 PY
95% CI (0.59-1.02)
Regular sexual partner of a man with HIV infection with whom condoms were not consistently used in the last 3 months (HIV-positive partner is not on treatment and/or has detectable viral load)   5.36 per 100 PY
95% CI (2.78-10.25)
At least one episode of UAI with any casual male partner with HIV infection or a male partner of unknown HIV status during the last 3 months  2.31 per 100 PY
95% CI (1.48-3.63) 
More than one episode of anal intercourse during the last 3 months when proper condom use was not achieved (e.g. condoms slipped off or broke)  1.30 per 100 PY
95% CI (0.95-1.77)
More than one episode of insertive UAI where the serostatus of partner was not known or was HIV positive and not on treatment in the last 3 months  0.94 per 100 PY
95% CI (0.35-2.52)
 - In circumcised men 0.65 per 100 PY
95% CI (0.16-2.61)
 - In uncircumcised men  1.73 per 100 PY
95% CI (0.43-6.90)
Rectal gonorrhoea diagnosis  7.01 per 100 PY
95% CI(2.26-21.74)
Rectal chlamydia diagnosis  3.57 per 100 PY
95% CI (1.34-9.52)
Methamphetamine use  1.89 per 100 PY
95% CI (1.25-2.84)

PY: person years; UAI: receptive unprotected anal intercourse
*Data from the Health in Men (HIM) study conducted in 2001-2007 (REF 25?)

Clinicians should obtain a thorough sexual and drug use history to determine PrEP eligibility and regularly discuss high HIV risk practices with their patients to assess continuing candidacy for PrEP. Patients should be followed regularly not only for HIV infection, but also for other STI according to the STI testing guidelines,83 and renal and liver function due to the known side-effects of Truvada (see Prescribing Information ).59 Women taking PrEP should be regularly assessed for pregnancy. Clinicians should also offer extensive HIV risk-reduction counselling and encourage patients to continue using condom and other risk reduction approaches for safer sex. Referral to drug and alcohol counselling and mental health services may be indicated and should be considered.

Implementation of PrEP

At the time of publication of this monograph, access to PrEP in Australia is not available and PrEP is only offered through demonstration projects in New South Wales, Victoria and Queensland.

References

[1] Cardo DM, Culver DH, Ciesielski CA, et al. A case-control study of HIV seroconversion in health care workers after percutaneous exposure. Centers for Disease Control and Prevention Needlestick Surveillance Group. N Engl J Med 1997;337:1485-90.

[2] Grant RM, Lama JR, Anderson PL, et al; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010;363:2587-99.

[3] Centers for Disease Control and Prevention. US Public Health Service. Preexposure prophylaxis for the prevention of HIV infection in the United States 2014. Clinical practice guideline. Available at: http://www.cdc.gov/hiv/pdf/PrEPguidelines2014.pdf (last accessed 28 January 2015).

[4] Spira AI, Marx PA, Patterson BK, et al. Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques. J Exp Med 1996;183:215-25.

[5] Tsai CC, Emau P, Follis KE, et al. Effectiveness of postinoculation (R)-9-(2-phosphonylmethoxypropyl) adenine treatment for prevention of persistent simian immunodeficiency virus SIVmne infection depends critically on timing of initiation and duration of treatment. J Virol 1998;72:4265-73.

[6] Tsai CC, Emau P, Sun JC, et al. Post-exposure chemoprophylaxis (PECP) against SIV infection of macaques as a model for protection from HIV infection. J Med Primatol 2000;29:248-58.

[7] Otten RA, Smith DK, Adams DR, et al. Efficacy of postexposure prophylaxis after intravaginal exposure of pig-tailed macaques to a human-derived retrovirus (human immunodeficiency virus type 2). J Virol 2000;74:9771-5.

[8] World Health Organization and International Labour Organization. Post-exposure prophylaxis to prevent HIV infection. Joint WHO/ILO guidelines on post-exposure prophylaxis (PEP) to prevent HIV infection. Issued January 2007. Available at: http://www.ilo.org/aids/Publications/WCMS_116563/lang--en/index.htm (last accessed 9 May 2014).

[9] World Health Organization. New guidance on prevention of mother-to-child transmission of HIV and infant feeding in the context of HIV. Geneva: World Health Organization; 2010. Available at: http://www.who.int/hiv/pub/mtct/PMTCTfactsheet.pdf (last accessed 9 May 2014).

[10] World Health Organization. Guidance on pre-exposure oral prophylaxis (PrEP) for serodiscordant couples, men and transgender women who have sex with men at high risk of HIV: recommendations for use in the context of demonstration projects. Geneva: World Health Organization; 2012. Available at: http://www.who.int/hiv/pub/guidelines/en/ (last accessed 9 May 2014).

[11] Australasian Society for HIV Medicine (ASHM) [Internet]. HIV guidelines, policy and strategy. Available at: http://www.ashm.org.au/default2.asp?active_page_id=168 (last accessed 28 January 2015).

[12] Roland ME, Neilands TB, Krone MR, et al. Seroconversion following nonoccupational postexposure prophylaxis against HIV. Clin Infect Dis 2005;41:1507-13.

[13] Savage J and the National PEP Guidelines Reference Group. Literature review for the national guidelines for post-exposure prophylaxis after non-occupational and occupational exposure to HIV. Sydney: Australasian Society for HIV Medicine; 2011. Available at: www.ashm.org. au/pep-guidelines last accessed 28 January 2015).

[14] LaFon SW, Mooney BD, McMullen JP, et al. A double-blind, placebo-controlled study of the safety and efficacy of Retrovir (zidovudine, ZDV) as a chemoprophylactic agent in health care workers exposed to HIV [Abstract 489]. In: Program and abstracts of the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy. Atlanta, GA: American Society for Microbiology, 1990:167.

[15] Centers for Disease Control and Prevention. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States: recommendations from the US Department of Health and Human Services. MMWR 2005;54(No. RR-2):1-19.

[16] Centers for Disease Control and Prevention. US Public Health Service guidelines for the management of health-care worker exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep 1998;47(RR-7):1-33.

[17] Australian National Council on AIDS, Hepatitis C and Related Diseases (ANCAHRD). Guidelines for the management and post exposure prophylaxis of individuals who sustain nonoccupational exposure to HIV. Bulletin No. 28. July 2001.

[18] Bell DM. Occupational risk of human immunodeficiency virus infection in healthcare workers: an overview. Am J Med 1997;102: 9-15.

[19] The Kirby Institute. HIV, viral hepatitis and sexually transmissible infections in Australia. Annual Surveillance Report 2012. Sydney: The Kirby Institute UNSW Australia; 2012.

[20] Do AN, Ciesielski CA, Metler RP, Hammett TA, Li J, Fleming PL. Occupationally acquired human immunodeficiency virus (HIV) infection: national case surveillance data during 20 years of the HIV epidemic in the United States. Infect Control Hosp Epidemiol 2003;24:86-96.

[21] The Kirby Institute. HIV, viral hepatitis and sexually transmissible infections in Australia. Annual Surveillance Report 2014. Sydney: The Kirby Institute UNSW Australia; 2014.

[22] Ippolito G, Puro V, De Carli G. The risk of occupational human immunodeficiency virus infection in health care workers. Italian Multicenter Study. The Italian Study Group on Occupational Risk of HIV infection. Arch Intern Med 1993;153:1451-8.

[23] Boily MC, Baggaley RF, Wang L, et al. Heterosexual risk of HIV-1 infection per sexual act: systematic review and meta-analysis of observational studies. Lancet Infect Dis 2009;9:118-29.

[24] Vittinghoff E, Douglas J, Judson F, McKirnan D, MacQueen K, Buchbinder SP. Per-contact risk of human immunodeficiency virus transmission between male sexual partners. Am J Epidemiol 1999;150:306-11.

[25] Jin F, Jansson J, Law M, et al. Per-contact probability of HIV transmission in homosexual men in Sydney in the era of HAART. AIDS 2010;24:907-13.

[26] Baggaley RF, White RG, Boily MC. HIV transmission risk through anal intercourse: systematic review, meta-analysis and implications for HIV prevention. Int J Epidemiol 2010;39:1048-63.

[27] Cohen MS1, Chen YQ, McCauley M, et al; HPTN 052 Study Team. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011;365:493-505.

[28] Rodger A, Bruun T, Cambiano V, et al; for the PARTNER Study Group. HIV transmission risk through condomless sex if HIV+ partner on suppressive ART: PARTNER study. Abstract 153LB, 2014. In: 21st Conference on Retroviruses and Opportunistic Infections (CROI). 3-6 March 2014. Boston MA.

[29] Templeton D, Jin F, Mao L, et al. Circumcision and risk of HIV infection in Australian homosexual men. AIDS 2009;23:2347-51.

[30] Wiysonge CS, Kongnyuy EJ, Shey M, et al. Male circumcision for prevention of homosexual acquisition of HIV in men. Cochrane Database Syst Rev 2011 Jun 15; (6): CD007496.

[31] Siegfried N, Muller M, Deeks JJ, Volmink J. Male circumcision for prevention of heterosexual acquisition of HIV in men. Cochrane Database Syst Rev 2009 Apr 15;(2):CD003362.

[32] Kuhar DT, Henderson DK, Struble KA, et al. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol 2013;34:875-92.

[33] Benn P, Fisher M, R. Kulasegaram R. UK guideline for the use of post-exposure prophylaxis for HIV following sexual exposure. 2011. Int J STD AIDS 2011;22:695-708.

[34] Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. Available at: http://aidsinfo.nih.gov/guidelines (last accessed 29 January 2015).

[34] Nielsen-Saines K, Watts DH, Veloso VG, et al. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. N Engl J Med. 2012;366:2368-79. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22716975

[35] Bassett IV, Freedberg KA, Walensky RP. Two drugs or three? Balancing efficacy, toxicity, and resistance in postexposure prophylaxis for occupational exposure to HIV. Clin Infect Dis 2004;39:395-401.

[36] Pierce AB, El-Hayek C, Watson K, et al. Two drugs or three? Rates of HIV seroconversion in patients who have previously used NPEP using monitoring and surveillance data to add to the evidence base. Abstract TUPE157. 20th International AIDS Conference. 20-25 July 2014. Melbourne Australia.

[37] McAllister J. Carr A. Should a protease inhibitor be standard of care for HIV postexposure prophylaxis? AIDS 2011;25:721-2.

[38] New York State Department of Health AIDS Institute website. HIV prophylaxis following occupational exposure. Updated October 2014. Available at: http://www.hivguidelines.org/clinical-guidelines/post-exposure-prophylaxis/hiv-prophylaxis-following-occupational-exposure/ (last accessed 29 January 2015).

[39] J McAllister, P Read, A McNulty, WWY Tong, A Ingersoll, A Carr HIV Medicine. Raltegravir-emtricitabine-tenofovir as HIV nonoccupational post-exposure prophylaxis in men who have sex with men: safety, tolerability and adherence. 2014; 15(1):13-22.

[40] Sarner L, Fakoya A. Acute onset lactic acidosis and pancreatitis in the third trimester of pregnancy in HIV-1 positive women taking antiretroviral medication. Sex Transm Infect 2002;78:58-9.

[41] Mandelbrot L, Kermarrec N, Marcollet A, et al. Case report: nucleoside analogue-induced lactic acidosis in the third trimester of pregnancy. AIDS 2003;17:272-3.

[42] Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002;359:727-32.

[43] Mofenson LM. Efavirenz reclassified as FDA pregnancy category D. AIDS Clin Care 2005;17:17.

[44] Zheng W, Smith D, Kippax S, Grulich A. Epidemiologically targeted non-occupational post exposure prophylaxis (NPEP) in Australia, 1998-2002 [Abstract]. Australasian Society for HIV Medicine (ASHM) 14th Annual Conference. 23-26 October 2002. Sydney. Presentation available at: www. ashm.org.au/uploads/148c.ppt (last accessed 29 January 2015).

[45] Simon BG, Almeda J, Casabona J, et al. Characteristics for demand and prescription of non occupational post exposure prophylaxis (NONOPEP) for HIV in Europe (Oral presentation Abstract: MoOrD1108]. In: XIV International Conference on AIDS. 27-12 July 2002. Barcelona Spain.

[46] Kahn JO, Martin JN, Roland ME, et al. Feasibility of postexposure prophylaxis (PEP) against human immunodeficiency virus infection after sexual or injection drug use exposure: the San Francisco PEP Study. J Infect Dis 2001;183:707-14.

[47] Grohskopf LA, Smith DK, Kunches LK, et al. Surveillance of post-exposure prophylaxis for non-occupational HIV exposures through the U.S. national registry [Abstract MoOrD1107]. In: XIV International Conference on AIDS27-12 July 2002. Barcelona Spain.

[48] Pinkerton SD, Holtgrave DR, Bloom FR. Cost-effectiveness of post-exposure prophylaxis following sexual exposure to HIV. AIDS 1998;12:1067-78.

[49] Pinkerton SD, Holtgrave DR, Bloom FR. Postexposure treatment of HIV. N Engl J Med 1997;337:500-1.

[50] Pinkerton SD, Holtgrave DR. Prophylaxis after sexual exposure to HIV. Ann Intern Med 1998;129:671. Author reply: 672.

[51] Lurie P, Miller S, Hecht F, Chesney M, Lo B. Postexposure prophylaxis after nonoccupational HIV exposure: clinical, ethical, and policy considerations. JAMA 1998;280:1769-73.

[52] Guinot D, Ho MT, Poynten IM, et al. Cost-effectiveness of HIV nonoccupational post-exposure prophylaxis in Australia. HIV Med 2009;10:99-208.

[53] Anderson PL, Glidden DV, Liu A, et al; iPrEx Study Team. Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Sci Transl Med 2012;4:151ra125.

[54] Baeten JM, Donnell D, Ndase P, et al; Partners PrEP Study Team. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012;367:399-410.

[55] Thigpen MC, Kebaabetswe PM, Paxton LA, et al; TDF2 Study Group.. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med 2012;367:423-34.

[56] 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. Lancet 2013;381:2083-90.

[57] US Food and Drug Administration (FDA) website. FDA approves first drug for reducing the risk of sexually acquired HIV infection. Press release. 16 July 2012. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312210.htm (last accessed 29 January 2015).

[58] Veronese F, Anton P, Fletcher CV, et al ; Workshop Organizing Committee. Implications of HIV PrEP trials results. AIDS Res Hum Retroviruses 2011;27:81-90.

[59] Gilead Sciences, Inc. Truvada® (emtricitabine/tenofovir disoproxil fumarate). Product Information. Revised October 2013. Available at: www.gilead.com/~/media/Files/pdfs/medicines/hiv/truvada/truvada_pi.pdf (last accessed 29 January 2015).

[60] Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med 2012;367:411-22.

[61] Marrazzo J, Ramjee G, Nair G, et al. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE study (MTN 003) [Abstract 26LB]. 20th Conference on Retroviruses and Opportunistic Infections (CROI). 3-6 March 2013. Atlanta GA.

[62] Campbell JD, Herbst JH, Koppenhaver RT, Smith DK. Antiretroviral prophylaxis for sexual and injection drug use acquisition of HIV. Am J Prev Med 2013; 44(1 Suppl 2):S63-9.

[63] Anderson PL, Kiser JJ, Gardner EM, Rower JE, Meditz A, Grant RM. Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection. J Antimicrob Chemother 2011;66:240-50.

[64] Abbas UL, Glaubius R, Mubayi A, Hood G, Mellors JW. Antiretroviral therapy and pre-exposure prophylaxis: combined impact on HIV transmission and drug resistance in South Africa. J Infect Dis 2013;208:224-34.

[65] Celum C, Hallett TB, Baeten JM. HIV-1 prevention with ART and PrEP: mathematical modeling insights into resistance, effectiveness, and public health impact. J Infect Dis 2013;208:189-191.

[66] Grohskopf LA, Gvetadze R, Pathaket S, et al. Preliminary analysis of biomedical data from the phase II clinical safety trial of tenofovir disoproxil fumarate (TDF) for HIV-1 pre-exposure prophylaxis (PrEP) among US men who have sex with men (MSM) [Abstract FRLBC102]. XVIII International AIDS Conference. 18-23 July 2010. Vienna Austria. Available at: http://pag.aids2010.org/Abstracts.aspx?AID=17777 (last accessed 29 January 2015).

[67] Mutua G, Sanders E, Mugo P, et al. Safety and adherence to intermittent pre-exposure prophylaxis (PrEP) for HIV-1 in African men who have sex with men and female sex workers. PloS One 2012;7(4):e33103.

[68] Yin MT, Overton ET. Increasing clarity on bone loss associated with antiretroviral initiation. J Infect Dis 2011;203:1705-7.

[69] Liu AY, Vittinghoff E, Sellmeyer DE, et al. Bone mineral density in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in San Francisco. PLoS One 2011;6(8):e23688.

[70] Schneider K, Gray RT, Wilson DP. A cost-effectiveness analysis of HIV preexposure prophylaxis for men who have sex with men in Australia. Clin Infect Dis 2014;58:1027-34.

[71] Smith DK, Pals SL, Herbst JH, Shinde S, Carey JW. Development of a clinical screening index predictive of incident HIV infection among men who have sex with men in the United States. J Acquir Immune Defic Syndr 2012;60:421-7.

[72] Buchbinder SP, Glidden DV, Liu AY, et al. HIV pre-exposure prophylaxis in men who have sex with men and transgender women: a secondary analysis of a phase 3 randomised controlled efficacy trial. Lancet Infect Dis 2014;14:468-75.

[73] Kahle EM, Hughes JP, Lingappa JR, et al; Partners in Prevention HSVHIV Transmission Study and the Partners PrEP Study Teams. An empiric risk scoring tool for identifying high-risk heterosexual HIV-1-serodiscordant couples for targeted HIV-1 prevention. J Acquir Immune Defic Syndr 2013;62:339-47.

[74] Matthews LT, Smit JA, Cu-Uvin S, Cohan D. Antiretrovirals and safer conception for HIV-serodiscordant couples. Curr Opin HIV AIDS 2012;7:569-78.

[75] Amico, K.R., The key role of adherence for the effectiveness of antiretroviral-based prevention: State of the science and implications for Asia Pacific. Sexual Health, 2014

[76] PrEP Watch website. PrEP Pipeline: ongoing research [Internet]. Available at: http://www.prepwatch.org/prep-research/prep-pipeline-ongoing-research/ (last accessed 30 January 2015).

[77] Australian Government Department of Health and Ageing. Seventh National HIV Strategy 2014-2017 [Internet]. Canberra: Commonwealth of Australia: 2014. Available at: http://www.health.gov.au/internet/main/publishing.nsf/Content/ohp-bbvs-hiv (last accessed 30 January 2015).

[78] Zablotska IB, Prestage G, Holt M, et al. Australian gay men who have taken nonoccupational postexposure prophylaxis for HIV are in need of effective HIV prevention methods. J Acquir Immune Defic Syndr 2011;58:424-8.

[79] Holt M, Murphy DA, Callander D, et al. Willingness to use HIV pre-exposure prophylaxis and the likelihood of decreased condom use are both associated with unprotected anal intercourse and the perceived likelihood of becoming HIV positive among Australian gay and bisexual men. Sex Transm Infect 2012;88:258-63.

[80] Zablotska IB, Prestage G, de Wit J, Grulich AE, Mao L, Holt M. The informal use of antiretrovirals for preexposure prophylaxis of HIV infection among gay men in Australia. J Acquir Immune Defic Syndr 2013;62:334-8.

[81] Zablotska IGA, Prestage G. Current awareness about PrEP and willingness to use it among Australian gay men (Paper 217). Oral presentation. Australasian HIV/AIDS Conference 21-23 October 2013. Darwin Australia. Available at: https://www.eiseverywhere.com/file_uploads/1f37e2e30f7733ef7941fee261615650_CA13-CA13S2013_JOINT__ABSTRACTS_V2.pdf

[82] Zablotska I. The emerging use of antiretroviral medications for pre-exposure prophylaxis of HIV (PrEP) among Australian gay men. Oral presentation. Australasian HIV/AIDS Conference 21-23 October 2013. Darwin Australia.

[83] Sexually Transmissible Infections in Gay Men Action Group (STIGMA). STI testing guidelines for MSM. Issued October 2010. Available at: http://stipu.nsw.gov.au/stigma/sti-testing-guidelines-for-msm/ (last accessed 28 January 2015).