Biomedical HIV prevention

John McAllister: St. Vincent's Hospital, Sydney

Introduction

The most effective way to prevent the sexual transmission of human immunodeficiency virus (HIV) is to prevent HIV exposure. The consistent use of condoms is the mainstay of any personal, or population level, sexual risk reduction strategy. However, in an analysis of two large studies of condom use and HIV incidence in men who have sex with men, the overall effectiveness of condoms in preventing HV infection during anal sex was estimated at 70%.[1]  Ineffectiveness was related to condom failure e.g. breakage, slippage, leakage, and delayed and intermittent application during sex.[2]  Men who have sex with men represent the Australian population at most risk of HIV infection and while condom use should continue to be promoted, alone it is unlikely to reduce HIV incidence.

Antiretroviral drugs can be used to treat and prevent HIV infection. The final two decades of the 20th century saw not only the evolution of antiretroviral therapy (ART) used to effectively treat HIV infection but also the increased use of ART to prevent HIV acquisition in occupational, non-occupational, antenatal and postnatal settings. The first 15 years of the 21st century have advanced the use of ART as prevention in HIV-positive and -negative populations most notably in serodiscordant relationships and other groups of men and women at risk of HIV infection. Table 11 describes the various uses of ART as prevention. This section will focus primarily on HIV post-exposure prophylaxis (PEP) and HIV pre-exposure prophylaxis (PrEP) and describe the ways that a nurse might contribute to the assessment and care of HIV-negative men and women using ART.

Table 11: Antiretroviral therapy as prevention

Antiretroviral therapy as prevention

Acronym

Description

Efficacy

Postexposure prophylaxis

PEP

 

OPEP:

occupational PEP

 

NPEP:

non-occupational PEP

28 days of antiretroviral drugs taken as soon after, and within 72 hours of, an occupational or non-occupational (sexual or injecting drug use) actual or potential HIV exposure event

OPEP: 81% risk reduction[3]

NPEP: no empirical data, strongly supported by non-human primate and the prevention of mother-to-child HIV transmission studies[4] [5] 

Prevention of mother-to-child HIV transmission

PMTCT

Universal antenatal HIV screening,

maternal ART, caesarean section,# short-course postnatal ART for the newborn and  avoidance of breast feeding

< 1% risk of vertical transmission (from a 13-40% risk without intervention)[6]

Treatment as prevention

 

TasP

ART to men or women with HIV infection in serodiscordant relationships

≥ 96%[7]

*Pre-exposure prophylaxis

PrEP

Daily ART (usually coformulated tenofovir disoproxil fumarate and emtricitabine - Truvada) in HIV negative men and women

Men who have sex with men: 44 - 92%[8]

Heterosexual men and women: 75 - 90%[9]

 

IDU: 49 - 74%[10]

 ART: antiretroviral therapy; HIV: human immunodeficiency virus; IDU: injection drug user

# Additional benefit of caesarean section in women on antiretroviral therapy with an undetectable viral load is unknown
*Maximum efficiency is dependent on high levels of adherence and detectable drug in plasma. The range represents the overall efficacy and, in those participants with detectable drug, best efficacy. The study in injection drug users used tenofovir disoproxil fumarate alone.

Non-occupational postexposure prophylaxis (NPEP)

NPEP has been in wide-spread use in Australia since 1999 and is recommended by the Australian Government’s Department of Health and Ageing.[11] The Australian National NPEP guidelines recommend 28 days of ART (at prescriber’s discretion) with two or three drugs for an HIV transmission risk event of ≥ 1: 15,000. 214  Australian men who have sex with men and, to a lesser extent, people who inject drugs, are the principal target groups.  Nurses have diverse roles in the assessment and provision of PEP (see Table 12).  Any nurse working in HIV and sexual health, family planning, an emergency department or in a general practice requires a minimum of PEP literacy (see Table 13).

Table 12: Nursing roles in non-occupational postexposure prophylaxis (NPEP)

  • Management of statewide services
  • NPEP assessment, initiation and care in emergency departments and sexual health and HIV care settings
  • NPEP hotlines
  • NPEP research
  • Participating in development of state and national guidelines
  • Providing education and support.


Table 13: Minimum post-exposure prophylaxis (PEP) literacy

  • What constitutes a risk event – how to assess risk
  • How to access help (state PEP hotlines, emergency departments, sexual health clinics, HIV care providers, overseas)
  • The importance of timing – NPEP should be started as soon as possible after a risk event
  • The duration of therapy
  • Adherence education and support
  • The need for a high level of adherence to the regimen
  • Choosing the optimum dosing time based on the patient’s routine work and leisure patterns including discussion about the dosing window – a rigid, fixed time to dose sets patients up to miss a dose and fail
  • Strategies to assist adherence – teaching cueing (the act of associating pill taking with a habitual behaviour), visual and electronic reminders, pill boxes, preparing for the unexpected: for example, keeping a supply at work, in the car, in a bag, at a friend’s house.
  • What to do if a dose is missed
  • Likely regimen related side-effects
  • What to do and how to access help if side-effects occur
  • The nurse can provide the first port of call and access to help by encouraging re-presentation and providing telephone access and support

Most potential exposure to HIV occurs outside business hours or over a weekend.  In 2015, 51% of HIV risk events prompting assessment for NPEP at St Vincent’s Hospital, Sydney occurred on a Saturday or Sunday. Of the 170 (49%) that occurred during a week day, 10% were between the hours of 08:30 and 17:00; the usual operating hours of clinics that provide NPEP. Thus, emergency departments assess the majority of presentation for NPEP and nurses who work in emergency departments are a particular group who need to be PEP literate.

In addition to a minimum PEP skill set, nurses provided with adequate training, support and resources are also capable of independently assessing and managing patients requiring ART as PEP.

The National NPEP Guidelines provide comprehensive information about risk assessment, in brief:

  • an HIV risk event needs to have occurred
  • the person with whom the event occurred needs to be HIV positive or from a population likely to have HIV
  • the patient needs to present for assessment within 72 hours of the event

Table 14 presents a simple flow-chart which can be used as a NPEP risk assessment tool.

Table 14: Non-occupational post-exposure prophylaxis (NPEP) risk assessment#

 Consider NPEP if conditions 1, 2 and 3 are met

 

 1 

High-risk exposure

  • Condomless receptive intercourse (anal or vaginal)i
  • Condomless insertive intercourse (anal or vaginal) i
  • Use of contaminated injecting equipment

Condomless means no condom used or condom slippage or breakage

Notes: Condomless receptive oral intercourse with ejaculation MAY BE CONSIDERED as a high-risk exposure providing the source is known to be HIV positive with a detectable HIV viral load and there is oral mucosal disease or an open lesion in the mouth or throat.

Significant exposure of non-intact skin with blood, sperm or vaginal fluids MAY ALSO BE CONSIDERED as a high-risk exposure providing the source is known to be HIV positive with a detectable HIV viral load.

 

 2 

 

Source is known to have HIV infectionii

                                                                        OR

Source is likely to be at increased risk of HIV

      • Men who have sex with men
      • Heterosexual person who injects drugs
      • A person from a high HIV prevalence country (HIV prevalence > 1.0%)iii
      • A sex worker OUTSIDE of Australia

ii NPEP is NOT RECOMMENDED following insertive or receptive anal, vaginal or oral sex, sharing of needles or other injecting equipment, and mucous membrane and non-intact skin exposure when the source’s viral load is KNOWN to be undetectable – this is provided the source is known to be compliant with medication, attends regular follow-up and has no intercurrent sexually transmissible infection (STI).

iiiData available at: http://aidsinfo.unaids.org/

 

 3 

 

The client presents within 72 hours of exposure

1  +  2  +  3  =  NPEP


For a comprehensive guide to risk assessment see the Australian National NPEP guidelines available at: http://www.ashm.org.au/pep-guidelines/

NPEP does not always prevent HIV acquisition. The time to first NPEP dose, incomplete NPEP adherence, continued HIV risk behaviour and primary ART resistance have each been linked to NPEP failure.[12] [13]

Time to first dose

NPEP appears to be most effective when administered as soon as possible after exposure. In macaque monkeys, tenofovir initiated within 24 hours of a simian immunodeficiency virus (SIV) challenge provided 100% protection from infection vs 50% and 25% when initiated at 48 and 72 hours, respectively.[14]  In seven human cases of seroconversion following NPEP, the median time from exposure to first dose of NPEP medication was 45.5 hours (range 14 – 72.4 hours) and three of the seroconversions to HIV in this series initiated NPEP after 48 hours post exposure although this difference was not statistically significant.215 Nurses should be aware of the critical nature of time with regard to PEP, educate accordingly, facilitate rapid referral if required and, in emergency departments, allocate a high triage priority to patients who present for PEP.

Incomplete adherence

Intolerable side-effects result in many clients failing to complete the prescribed course of NPEP. In a meta-analysis of PEP adherence, completion rates were 57% overall and 67% in MSM.[15] Toxicity driven discontinuation was commoner with three-drug regimens than with two-drug regimens (2% vs 9% respectively).[16] The World Health Organization (WHO) recommends that three antiretroviral drugs be universally used.219  Given that between one half and one third of clients do not complete the prescribed course principally because of side-effects, the choice of safe, tolerable drugs for use in NPEP is paramount and nurses have an important role in supporting clients on PEP who experience side-effects (see Table 12). In Australia, Truvada (emtricitabine and tenofovir disoproxil fumarate) with the integrase inhibitor raltegravir is widely used as three-drug NPEP. In men who have sex with men, it has been shown to be well tolerated with high rates of on-drug adherence, treatment completion and, were a protease inhibitor the third drug, a low risk of potentially dangerous drug reactions.[17] More recently, Truvada with the non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine and Truvada with the integrase inhibitor dolutegravir have both been evaluated as three-drug HIV postexposure prophylaxis in men who have sex with men; both have also demonstrated low toxicity, high adherence, high completion rates and the added convenience of once-daily dosing.[18] [19]

Continued risk

NPEP use is a good indicator of future HIV risk and acquisition. Australian men who have sex with men who have ever used NPEP are around three times more likely to eventually acquire HIV infection when compared to men who had never used NPEP.[20] This heightened risk is less about drug failure and more about inability to modify risk or indeed a negative past experience while on NPEP.  The importance of carefully evaluating and choosing the best agents to use as NPEP has been discussed. By employing a variety of behavioural interventions, sexual risk (as measured by condomless anal sex) in men who have sex with men can be reduced, at least in the short term, by about third.[21]  So referral to appropriate services of men who have sex with men interested in addressing risk behaviour remains important in the new era of ART as prevention. NPEP initiation after a risk event is usually a stressful time and clients often reflect on their risk behaviours thus presenting an opportunity for brief intervention and referral. While behavioural interventions in men who have sex with men interested in change are effective, referral of men who have sex with men uninterested or ambivalent about change is not. Lecturing and scare tactics are equally unproductive. In 2014, 294 clients had 375 episodes of NPEP through the Sydney St Vincent’s NPEP clinic. Thirteen percent (39) had NPEP twice, 2% three times and 3% more than three times in that year. Re-presentation for NPEP is a new opportunity to keep an HIV-negative person HIV negative and to explore and address the context of the risk. Nurses have an important role in providing a positive, non-judgmental and enabling environment. ‘I’m really glad you’ve presented for assessment’, ‘I’m really pleased you’ve started (re-started) PEP’ are positive and affirming ways to start a client PEP encounter. An HIV-negative man who has sex with men who has difficulty consistently using condoms who is deterred from using NPEP because of health-care provider attitude or censure may become an HIV-positive man who has sex with men who has difficulty consistently using condoms.

NPEP has been the predominant use of ART as prevention in HIV-negative Australian men who have sex with men and others at high risk of HIV infection, however pre-exposure prophylaxis (PrEP) (see below) has the potential to change this situation. NPEP will still, however, have a place as:

  • a gateway to PrEP
  • an adjunct to PrEP in the context of poor adherence and a high-risk HIV event
  • an option for men who have sex with men who are not at high or imminent risk of HIV acquisition (should use PrEP) but who still have intermittent risk events
  • a risk reduction strategy for men who have sex with men who choose not to use PrEP.

HIV pre-exposure prophylaxis (PrEP)

Up to 1:8 Australian men who have sex with men has HIV infection.[22] . Daily Truvada taken as PrEP has been shown to be highly effective at preventing HIV infection in populations at high risk of HIV acquisition (Table 11). PrEP has the potential to radically reduce HIV incidence in high-risk groups. San Francisco’s HIV epidemic in men who have sex with men is very similar to our Australian experience.  In 2015, the number of new HIV infections diagnosed in San Francisco hit an all-time low with a total of 255. The number of people diagnosed in 2015 decreased by 17% from the number of people diagnosed in 2014 (308 infections). This was also a 34% decrease from 2013 and a 44% decrease from 2012.[23] In 2015, 79% of all new HIV infections in men were among men who have sex with men226 . A recent informal survey of large PrEP providers in San Francisco put the cumulative number of users at more than 6000.[24]  This decline in HIV incidence in men who have sex with men is linked to increased PrEP use in at risk groups but is unlikely to be the only factor. Similar to the NSW HIV strategy, a strategy in San Francisco also promotes frequent HIV testing, rapid linkage to care for the newly diagnosed, early treatment and maintaining engagement in care.

PrEP using daily Truvada is approved by the Australian Therapeutic Goods Administration (TGA) but is not yet available through the Pharmaceutical Benefits Scheme (PBS). National PrEP Guidelines have been published.[25]  In addition to large PrEP implementation projects (principally along the Eastern seaboard of Australia and enrolling in excess of 7000 Australians at risk), generic Truvada can be legally imported for personal use in Australia at a fraction of the cost of a non-PBS prescription. A fact sheet produced by the AIDS Council of New South Wales outlines the process and is available at:  http://www.acon.org.au/access-to-prep-what-you-need-to-know/

Potential risks of PrEP

Daily Truvada used as part of an HIV risk-reduction strategy is not without risk, mainly to the kidneys and bones. Decreases in renal function have been documented, and occasional cases of acute renal failure, including Fanconi syndrome, have occurred among people with HIV infection using tenofovir (TDF) containing regimens.[26]  An estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73m2 precludes daily use of Truvada as PrEP and 3-monthly check of renal function is recommended. People on daily Truvada should be advised against concurrent use nephrotoxic drugs for example, regular use of non-steroidal anti-inflammatory drugs.

Decreases in bone mineral density (BMD) in the region of 3-4% have been observed in people with HIV infection treated with ART including tenofovir disoproxil fumarate-containing regimens.[27] Serial dual-emission X-ray absorptiometry (DEXA) scans on a subset of men who have sex with men in a randomised, placebo controlled trial of Truvada PrEP trials determined that when comparing those persons randomised to receive PrEP medication and those randomised to receive placebo a small but statistically significant (approximately 1%) decline in BMD can occur during the first few months of PrEP which either stabilises or returns to normal.[28] There was no increase in fragility (atraumatic) fractures over the 1-2 years of observation in these studies. In contrast, in a small study of 34 men who have sex with men on daily Truvada as PrEP, about 50% had more than a 5% loss in BMD at one or more bone sites through 12 months of follow-up.[29] A lack of a control or placebo group and no data on other causes for low BMD mean that these data should be interpreted with caution but the results do raise the need for further investigation and education for those taking PrEP about maintaining good bone health.

Nurses’ roles in PrEP

As PrEP use becomes more wide-spread in Australia, nurses have an important role to play (Table 15).  Adherence to the dosing schedule is crucial to PrEP efficacy.  Those who most need PrEP may well be those who most struggle to maintain these high levels of adherence. They will be men who have sex with men (or others) with significant alcohol or other drug issues or significant mental health problems. Rather than exclude these vulnerable groups from PrEP access, because of fears about poor engagement and adherence, ways should be found to support the adherence required.  In the IDU Bangkok PrEP study, participants received Truvada by directly observed therapy (DOT) 86% (SD 25%) of the time and were compensated for travel and the time required by the study procedures.213 Nurses can and ought to have a pivotal role in exploring and providing innovative methods of PrEP engagement medication adherence support in marginalised, vulnerable populations which could include DOT, other forms of highly supported therapy and the provision of financial incentives. 

Table 15: The nurse’s role in pre-exposure prophylaxis (PrEP)

  • Providing a nurse-led PrEP service
  • Ensuring that those at risk know about PrEP and current pathways to access in Australia
  • Referring onwards to providers who can facilitate PrEP access
  • Adherence education and support
    • The need for a high level of adherence to the regimen and dosing schedule
    • Choosing the optimum dosing time based on the client’s routine work and leisure patterns including discussion around the dosing window – a rigid, fixed time to dose sets clients up to miss a dose and fail
    • Strategies to assist adherence – teaching cueing (the act of associating pill taking with a habitual behaviour), visual and electronic reminders, pill boxes, preparing for the unexpected: keeping a supply at work, in the car, in a bag, at a friend’s house
    • What to do if a dose is missed particularly in the 24-hour period before a risk event – transition to NPEP might be required
    • For vulnerable groups, intensive support, case management, directly administered or observed therapy (DOT), partial-DOT, financial incentives.
  • Education about maintaining healthy bones
  • How to access help if unexpected side-effects occur
    • The nurse can provide the first port of call and access to help by encouraging re-presentation and providing telephone access and support

Conclusion

Antiretroviral therapy as prevention is currently front and centre stage. Nurses have a key role in service provision, education, support and innovative research as NPEP and now PrEP assume a more prominent role in HIV prevention.

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