Post-exposure prophylaxis in resource-poor settings: review and recommendations for pre-departure risk assessment and planning for expatriate healthcare workers
Corresponding Author Nidhi Vaid, Department of Acute Medicine, The Royal London Hospital, Whitechapel, London E1 1BB. UK. Tel.: +44-20-7377 7000; E-mail: email@example.com
It is estimated that more than 3 million healthcare workers worldwide suffer needlestick and splash injuries whilst at work resulting in the potential transmission of blood-borne pathogens via exposure to bodily fluids. Under-reporting and the subsequent management of occupational injuries is a problem both in the United Kingdom and abroad. Many expatriate health care workers will work in low resource settings where the risk of transmission is greatest but in contrast to wealthier countries such as the United Kingdom, there is often a lack of effective systems for its safe management. This article provides important information about this risk and how to minimise it. The reasons for an increased risk in transmission, its subsequent management and pre-departure planning are discussed, together with the evidence for initiation of post-exposure prophylaxis; current National and International guidelines as well as the urgent need for International standardisation of these is also discussed.
Il est estimé que plus de 3 millions d'agents de la santé dans le monde souffrent de blessures par piqûres d'aiguilles et par éclaboussures durant leur travail, entraînant la transmission potentielle de pathogènes hématogènes par l'exposition à des fluides corporels. La sous déclaration et la prise en charge ultérieure des accidents du travail sont un problème autant au Royaume-Uni et à l’étranger. De nombreux agents de la santé expatriés travaillent dans des milieux à faibles ressources où le risque de transmission est le plus élevé, mais contrairement aux pays plus riches comme le Royaume-Uni, il y a souvent un manque de système efficace pour la gestion de la sécurité. Cet article fournit des informations importantes sur ce risque et comment le minimiser. Les raisons pour un risque accru de transmission, sa prise en charge ultérieure et la planification avant le départ des agents sont discutées ainsi que les preuves sur l'initiation de la prophylaxie post-exposition; les directives nationales et internationales actuelles ainsi que le besoin urgent de standardisation internationale de ces dernières sont également discutés.
Se calcula que más de 3 millones de trabajadores sanitarios sufren, a nivel mundial, heridas por agujas y salpicaduras mientras trabajan, con el riesgo de contagio de patógenos transmitidos por la sangre al exponerse a fluidos corporales. La falta de información y por lo tanto el manejo subsecuente de heridas ocupacionales es un problema tanto en el Reino Unido como en el exterior. Muchos trabajadores sanitarios expatriados trabajarán en emplazamientos con pocos recursos en donde el riesgo de transmisión es mayor, pero a diferencia de lo que sucede en países más ricos como el Reino Unido, hay a menudo una falta de sistemas efectivos para su manejo seguro. Este artículo provee importante información sobre dicho riesgo y como minimizarlo. Se discuten las razones para un mayor riesgo de transmisión, su manejo subsecuente y la planeación antes del viaje, junto con la evidencia para iniciar profilaxis post-exposición; las guías nacionales e internacionales vigentes, así como la necesidad urgente de una estandarización internacional de las mismas.
Blood-borne pathogens may be transmitted through percutaneous or mucocutaneous exposure to bodily fluids especially via needlestick injuries (NSIs) and splash injuries (Sepkowitz 1996). The average risk of transmission of human immunodeficiency virus (HIV) from a positive source is estimated to be 0.3% from a single percutaneous exposure and 0.09% from mucous membrane exposure (Panlilio et al. 2005), 6–24% for hepatitis B virus (HBV) (Shapiro 1995) and 1–10% for hepatitis C virus (HCV) (Yazdanpanah et al. 2005).
It is estimated that more than 3 million healthcare workers (HCWs) worldwide suffer an NSI from a contaminated sharp each year, resulting in approximately 1000 HIV, 66 000 HBV and 16 000 HCV new infections annually (Pruss-Ustun et al. 2005). There is widespread under-reporting in the United Kingdom (Elder & Paterson 2006); this is a much greater problem in low-resource settings, which often lack formal surveillance systems. Of the 14 possible cases of HIV transmission reported in UK healthcare workers (HCWs) in 2003, 13 had previously worked in high-prevalence countries (HIV & STI Division Communicable Disease Surveillance Centre & Collaborators 2005). WHO estimates that the annual number of HIV infections in HCWs due to occupational exposure in sub-Saharan Africa is 620 and 6200 for hepatitis B infections (Pruss-Ustun et al. 2005).
Why is there a greater risk in low-resource settings?
HIV affected an estimated 34 million people worldwide at the end of 2010, 68% of whom lived in Sub-Saharan Africa (Joint United Nations Programme ON HIV/AIDS (UNAIDS) 2011). In areas of Africa and Asia where infection with hepatitis B is often acquired in childhood, HBsAg carrier rates may be as high as 10–15% (Mahoney and Kane 1999). The worldwide prevalence of hepatitis C is approximately 3%, but is much higher in some countries, such as Egypt, which has a prevalence of 15–20% (Alter 2007).
Several studies have investigated occupational injuries in resource-poor settings. Lack of universal precautions and eye protection together with unsafe sharp practices, such as recapping needles and improper disposal, account for a large proportion of injuries (Gounden & Moodley 2000; Doebbeling et al. 2003; Kermode et al. 2005; Rapparini et al. 2007; Jayanth et al. 2009; Chakravarthy et al. 2010; Foster et al. 2010; Salelkar et al. 2010). Equipment is often reused without adequate sterilisation (Hutin et al. 2003).
NSIs and splash injuries are commonplace in low-resource settings. A Ugandan survey revealed that more than half of nurses and midwives had experienced at least 1 NSI in the last year and more than 80% had experienced at least one in their career (Nsubuga & Jaakkola 2005). The main predictor of occurrence was lack of training in NSI prevention, and worryingly, most respondents were unaware of a hospital policy regarding NSIs even if there was one (Nsubuga & Jaakkola 2005). An alarmingly high proportion of Nigerian surgeons (72.1%) took no action when they were exposed (Nwankwo & Aniebue 2011), a finding replicated in other countries (Wig 2003; Salelkar et al. 2010; Vaz et al. 2010). Poor knowledge is not limited to resource-poor settings. A study of European medical students found that 34% did not report NSIs (Salzer et al. 2011) and only 18% of London doctors sought advice regarding post-exposure prophylaxis despite over three-quarters reporting occupational injury (Chen et al. 2001); lack of time, training and knowledge were cited as reasons for not seeking further advice (Chen et al. 2001; Chacko & Isaac 2007).
High viral prevalence, a lack of universal precautions and inadequate knowledge of both prevention and management of occupational exposure increase the risk of occupational transmission of blood-borne viruses in low-resource settings.
What should happen when you have an occupational exposure to a blood-borne virus?
Immediately after exposure, the site of injury should be washed with soap or a mild disinfectant [Joint WHO/ILO Expert Consultation for the Development of Policy and Guidelines on Occupational and Nonoccupational HIV Post-Exposure Prophylaxis (PEP) (2007)]. A full risk assessment should be carried out, and if possible, the source patient should be tested for HIV, HBV and HCV. The exposed HCW should also have blood taken for a baseline test for HCV antibody, HIV antibody and hepatitis B surface antibody (HbSAb).
Reporting and documentation of occupational exposure are important and are invaluable in guiding prevention efforts. The incident should be reported to the local healthcare facility as well as the individual's sponsoring agency. If no formal reporting systems are in place, the Exposure Prevention Information Network (EPINet), developed at the University of Virginia, is a valuable resource. It has free, downloadable reporting forms that are available in 21 languages and currently used in 83 countries (US Epinet Sharps Injury & Blood & Body Fluid Exposure Surveillance Research Group 2012).
Hepatitis B vaccination is highly recommended for HCWs going to resource-poor settings, prior to travelling. HBV is the only blood-borne virus for which there is a safe, efficacious vaccine. Hence, it is also recommended by all international guidelines for HCWs both at home and abroad. Three hepatitis B vaccinations over 6 months give protective immunity to 95% of those vaccinated (Zajac et al. 1986; Andre 1989). Table 1 outlines post-exposure management for hepatitis B (Centers for Disease Control & Prevention 2001a).
Table 1. Recommended post-exposure prophylaxis for exposure to hepatitis B virus (Centers for Disease Control & Prevention 2001b)
|Unvaccinated||HBIGc × 1 and initiate Hepatitis B vaccine series||Initiate HB vaccine series||Initiate HB vaccine series|
| Known respondere||No treatment||No treatment||No treatment|
| Known non-responderf||HBIG × 1 and initiate revaccination or HBIG × 2g||No treatment||If known high-risk source, treat as if source was HBsAg positive|
| Unknown|| |
Test exposed person for anti-HBsd
1. If adequate,eno treatment is necessary.
2. If inadequate,f administer HBIG × 1 and vaccine booster.
|No treatment|| |
Test exposed person for anti-HBs
1. If adequate,e no treatment is necessary.
2. If inadequate,f administer vaccine booster and recheck titre in 1-2 months.
Those without a documented antibody response to vaccination and undetectable Hepatitis B surface antibody (anti-HBs) at the time of exposure should receive a single booster vaccine, with non-immunes receiving hepatitis B immunoglobulin (HBIG) if available; even if HBIG is given, active vaccine should also be administered within 24 h.
There is no vaccine and no specific PEP for hepatitis C. Upon exposure, close follow-up is required. Detectable viraemia usually occurs within 2 weeks, but HCV antibodies can take 2–6 months to develop (Gerlach et al. 2003). Testing for HCV RNA at 4–6 weeks allows earlier detection, and efficacious antiviral drug therapy is available (Gerlach et al. 2003), although neither is usually accessible in low-resource settings.
The UK Department of Health (DoH) issued guidelines regarding HIV PEP in 2008 (Department of Health 2008). An initial risk assessment of the source patient including prompt HIV testing, injury type and 24-h availability of PEP was recommended. Whilst relatively straightforward in the UK, management in a low-resource setting may be problematic.
Although antiretroviral (ARV) drugs have certainly become more readily available in high-prevalence countries, personnel may be in remote or conflict areas where access to all but the most basic healthcare is difficult. In 2000, a survey of NGOs in the UK revealed that many did not check hepatitis B immunity of staff prior to departure, the majority did not supply PEP, and referral to a travel clinic was not routine (Gent & Zuckerman 2003). A survey of US-based health organisations in 2002 found that only 35% had a formal policy for protection of workers from blood and body fluids (Edler et al. 2002). This rate may be higher now, as ARV therapy is more readily available, but there are no recent data (Edler et al. 2002).
Availability of rapid HIV testing whereby specimens are tested by an initial, highly sensitive test and if reactive, retested by a second assay (The Centers for Disease Control and Prevention (Cdc) and the African Regional Office of the World Health Organization (WHO/AFRO) 2001) is highly variable. Quality assurance processes can be difficult, and some rapid tests require refrigeration of the kits or reagents, which are not always possible. PEP is also more difficult in the low-resource setting. Source patient testing may be unavailable or unreliable, and ARVs may not be available. Management of drug side effects is also challenging because access to further investigations may be limited. Specialist advisors are unlikely to be readily accessible; therefore, pre-travel planning is imperative. The importance of universal precautions and reporting of all occupational injuries must be stressed, and the UK Department of Health suggests that medical schools should provide information regarding PEP, as well as possible provision of PEP starter packs to travelling students.
Evidence for PEP
In animal models, HIV replicates in dendritic cells of skin and mucosae before eventually spreading systemically (Centers for Disease Control & Prevention 2001b). These observations form the principles underlying ARV PEP, which aims to inhibit initial replication and subsequent establishment of HIV infection (Centers for Disease Control & Prevention 2001b).
A case–control, multicountry study of the effects of PEP on HIV seroconversion (Cardo et al. 1997) found that the use of zidovudine significantly diminished the risk of HIV seroconversion. It had an efficacy of 81% (OR 0.19, 95% CI 0.06–0.52). Ethical constraints have prevented further studies evaluating multidrug therapy or different regimens; because combination therapies are more efficacious in HIV-infected patients, it is theorised that a combination of drugs would enhance the effectiveness of PEP (Parkin et al. 2000; Centers for Disease Control & Prevention 2001b).
UK guidelines recommend 3-drug therapy for PEP (Department of Health 2008). This differs from the CDC guidelines, which recommend 2-drug therapy for most HIV exposures (Panlilio et al. 2005). A third drug is advised if the exposure is high risk (large volume of blood, deep injuries and detectable viral load in a source patient currently on treatment) (HIV & STI Division Communicable Disease Surveillance Centre & Collaborators 2005; Panlilio et al. 2005; Young et al. 2007). Due to toxicity, nevirapine, abacavir and zalcitabine are generally not recommended for use as PEP (Panlilio et al. 2005). Cases where the source patient is already on ARV therapy and/or has a virus with known antiretroviral resistance, mutations need special consideration. In low-resource settings, viral load and resistance testing are usually only performed in research facilities; therefore, standard PEP is recommended whilst treatment history is acquired.
In animal models, PEP is most effective when administered within hours of initial exposure (Bottiger et al. 1997; Tsai et al. 1998). It should be given as soon as possible, ideally within an hour but certainly within 24 h. However, it is still recommended up to 72 h post-exposure (Panlilio et al. 2005). CDC has recommended PEP regimes, which are outlined in Table 2 (adapted from (Panlilio et al. 2005; Uslan & Virk 2005). However, these guidelines were written prior to the availability of newer agents, for example, alternative newer protease inhibitor (PI) regimens such as darunavir boosted with ritonavir. A new formulation of ritonavir, which does not require refrigeration, means that boosted protease inhibitors (PIs) such as atazanavir and darunavir are now more suitable for use in a low-resource setting. Raltegravir is a highly efficacious ARV agent, and there are emerging data of its efficacy and safety for PEP in the non-occupational setting (Mayer et al. 2012). It is especially attractive due to its favourable side effect profile but its disadvantage is rapid development of resistance if improperly taken.
Box 1. Key questions to consider before working in a low-resource setting
What is the prevalence of HBV, HCV and HIV in your destination?
Attendance at a pre-departure clinic is highly recommended. This may be a travel clinic or provided as part of the induction process with large organisations. Many hospitals have their own occupational health departments, which provide advice.
Does the organisation have occupational exposure guidelines?
Obtain the details of the contact person and guidelines in case of injury or exposure to a blood-borne virus.
What is your hepatitis B vaccination status?
Three hepatitis B vaccinations are strongly advised (95% protective immunity).
Do you know your immunity status?
Yes: Documented titre >10 IU after three vaccinations. You should take a copy of this with you when you travel.
No: Can be checked with a simple blood test at your occupational clinic, travel clinic or GP.
What is the reporting system if a blood or body fluid exposure occurs?
Is there a 24-h contact number for advice?
Is PEP available at your destination? If yes, what drugs and duration?
Usually fixed dose combination therapy is used. The following are standard three drug combinations:
Zidovudine/lamivudine (Combivir 300/150 mg; one tablet twice daily) +lopinavir/ritonavir (Kaletra 400/100 mg; one tablet twice daily)
Tenofovir/emtracitabine (Truvada 300/200 mg; one tablet daily (nocte)) +lopinavir/ritonavir (Kaletra 400/100 mg; one tablet twice daily).
If PEP is not available at your destination, do you need to bring PEP with you and does your organisation provide it?
What follow-up is required if a blood-borne virus exposure occurs?
|HBV (Centers for Disease Control and Prevention, 2001b)||HCV (Charles et al. 2003)||HIV (Panlilio et al. 2005)|
|Baseline: anti-HBs if vaccinated and antibody response unknown||Baseline: HCV Ab test||Baseline: HIV Ab test|
|If receives HBV vaccine; 4–8 weeks after last vaccine: anti-HBs||4 weeks: HCV Ab test, ALT, HCV PCR||6 weeks: HIV test|
| ||8 weeks: HCV Ab test if source known positive||12 weeks: HIV test|
| ||12 weeks: HCV Ab test||26 weeks: HIV test|
| ||26 weeks: HCV Ab test|| |
Does your organisation and/or personal travel insurance provide for repatriation, should a significant exposure occur?
Table 2. Centers for Disease Control and Prevention (CDC) recommendations for antiretroviral post-exposure prophylaxis regimens [adapted from (Panlilio et al. 2005; Uslan & Virk 2005)]
|Zidovudine (ZDV) + lamivudine (3TC) available as Combivir||200/150 mg twice daily||Lopinavir/ritonavir available as Kaletra||400/100 mg twice daily|
|Zidovudine (ZDV) + emtricitabine (FTC)||ZDV 300 mg twice daily FTC 200 mg once daily||Alternate|| |
|Tenofovir (TDF) + lamivudine (3TC)||TDF 300 mg once daily + 3TC 300 mg once daily (or 150 mg twice daily)||Atazanavir (ATV) (NB: if using tenofovir, ATV should be boosted with ritonavir (RTV)||ATV 400 mg once daily (+RTV 100 mg once daily)|
|Tenofovir (TDF) + emtricitabine (FTC) available as Truvada||300/200 mg once daily|| || |
| Alternate |
|Lamivudine (3TC) + stavudine (d4T)||3TC 300 mg once daily (or 150 mg twice daily) + T 40 mg twice daily (or 30 mg twice daily if <60 kg)||Atazanavir (ATV) (NB: if using tenofovir, ATV should be boosted with ritonavir (RTV).||ATV 400 mg once daily (+RTV 100 mg once daily)|
|Lamivudine (3TC) + stavudine (d4T)||3TC||Fosamprenavir (FOSAPV) ± ritonavir (RTV)||FOSAPV 1400 mg twice daily or FOSAPV 1400 mg once daily + RTV 200 mg once daily or FOSAPV 700 mg twice daily + RTV 100 mg twice daily|
|Indinavir (IDV) ± ritonavir (RTV)||IDV 800 mg + RTV 100 mg twice daily or IDV 800 mg every 8 h on an empty stomach|
|Saquinavir (SQV) + ritonavir (RTV)||SQV 1000 mg + RTV 100 mg twice daily|
|Nelfinavir (NFV)||NFV 1250 mg twice daily|
|Efavirenz (EFV)||EFV 600 mg once daily|
Side effects of PEP include gastrointestinal upset particularly with nucleoside reverse transcriptase inhibitors and PIs (Parkin et al. 2000), the latter also having serious drug interactions owing to inhibition of Cyp3A4. These are both contributory factors to non-adherence. The UK Health Protection Agency Centre for Infections has reported 24 cases of HIV seroconversion up to 2002, despite early PEP consisting mainly of zidovudine alone or as combination therapy (HIV & STI Division Communicable Disease Surveillance Centre & Collaborators 2005). PEP failure may be due to drug-resistant HIV strains, delayed initiation, a large inoculum, short duration of treatment or various host factors (Panlilio et al. 2005).
PEP is often not started in patients with exposure to a HIV-positive source. Data from the Health Protection Agency indicate that 1 in 5 exposed healthcare workers in the UK did not take up PEP (Zenner et al. 2009). There was a significant association between PEP uptake and visible blood on the source device (P < 0.0001) and a linear relationship with increasing injury depth (P < 0.0001). In a study of 130 Argentinean HCWs, the majority (53%) were lost to follow-up and there was only partial adherence in a further 33% (Miceli et al. 2005). In a Malawian PEP programme, just 25.2% of HCW who began PEP attended the first follow-up visit and only 1.9% completed all four visits (van Der Maaten et al. 2010). Unfortunately, follow-up in low-resource settings is often hampered by poor logistics, lack of awareness, unclear procedures and stigma (van Oosterhout et al. 2007); a coordinated approach is required.
Pre-departure planning before working in a low-resource setting
Currently, there are no standardised international guidelines that specifically address the issues of risk assessment and recommended procedures for PEP and occupational exposure in low-resource settings. Such a guideline would be helpful for both employers and HCWs. Visiting HCWs may turn to guidelines from their country of origin but these may be difficult to apply; hence, pre-departure risk assessments are essential. EU and national occupational regulations as well as the joint WHO and ILO guideline (World Health Organization, International Labour Organization 2007) indicate that PEP, amongst other pre- and post-exposure measures, is the responsibility of the employer. Prior to travel, a risk assessment should take place in the respective contractual framework of the HCW travelling abroad. Key questions for this risk assessment are listed in Box 1. This should include consideration that the travelling HCW may not have access to local services for HIV testing and treatment or local services may be insufficient. Ideally, the contact details of a local clinician with appropriate expertise should be sought prior to travel in case of more complex situations. Alternatively, emergency contact details for a willing clinician in the HCWs home country or host institution may be required. Input from local specialists familiar with regimens and resistance patterns may be needed. Financial and clinical responsibility must be defined pre-departure, and the importance of follow-up in either the host or home country must be emphasised.
The guideline would have to cover a variety of settings and scenarios and would have to allow for differing contractual arrangements for travelling HCWs. All responsible employers, organisations and individuals should follow the principle that there is a standard of care for pre- and post-exposure prophylaxis that must be observed regardless of the setting. Standardised guidelines that can be easily adopted and replicated in resource-poor settings (Mohan et al. 2010) are needed and would be invaluable to all stakeholders within the global health community. Guys, Kings and St Thomas' medical schools in London, UK, are an example of good practice: they provide access to advisors, PEP starter packs and gloves to students carrying out electives in high HIV-prevalence areas. There is a need for further work on strategies to increase risk awareness amongst travelling HCWs as current data indicate this is inadequate.
Exposure to blood-borne viruses can have profound psychological, physical and financial consequences for both the affected individual and their organisation. As the number of people working in low-resource settings increases, the global health community has a duty to respond with urgency to this very real occupational hazard. Standardised international guidelines are urgently needed.