Occupational exposure to HIV and the use of post-exposure prophylaxis
Department of Sexual Health and HIV, Kings College Hospital, London SE5 9RS, UK
Correspondence to: Elizabeth Hamlyn, Caldecot Centre, Kings College Hospital, London SE5 9RS, UK. Tel: +44 787 066 5620; fax: +44 207 346 3486; e-mail: elizabeth.hamlyn{at}kingsch.nhs.uk
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Abstract |
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 Top Abstract IntroductionPrevention of occupational...Evidence for PEPRisk assessment and immediate...Prescription of PEPSide-effects, safety and...Other blood-borne virusesFollow-upConclusionConflicts of interestReferences |
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Abstract The use of antiretroviral therapy as post-exposure prophylaxis against human immunodeficiency virus (HIV) is now routine following high-risk exposure to the HIV virus. This article summarizes the management of health care workers and others exposed to HIV in an occupational setting, and the evidence behind it.
Keywords HIV; occupational exposure; post-exposure prophylaxis
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Introduction |
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TopAbstractIntroductionPrevention of occupational...Evidence for PEPRisk assessment and immediate...Prescription of PEPSide-effects, safety and...Other blood-borne virusesFollow-upConclusionConflicts of interestReferences |
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Occupational exposure to human immunodeficiency virus (HIV) in either a hospital or community setting presents a low but potential risk of infection. Exposures may also occur in other non-health care situations, for example, those working in the police [1] or for aid agencies [2]. The prescription of antiretroviral therapy as post-exposure prophylaxis (PEP) following significant potential exposure to HIV has now become routine and it is important that individuals with potential risk of exposure are aware of the procedures to follow and where their first point of contact should be if an incident occurs. This article summarizes the current evidence base underpinning the current recommended approach to risk assessment and management of those potentially exposed to HIV.
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Prevention of occupational exposures |
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TopAbstractIntroductionPrevention of occupational...Evidence for PEPRisk assessment and immediate...Prescription of PEPSide-effects, safety and...Other blood-borne virusesFollow-upConclusionConflicts of interestReferences |
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The widespread adoption of standard universal precaution guidelines [3], which include the provision of adequate sharps containers, the training of workers in the risks and prevention of transmission of blood-borne viruses and the use of personal protective equipment such as gloves and eye wear, together with the more recent use of safer devices such as needles that sheath or retract after use, has led to a significant reduction in needlestick and other injuries over the last two decades [4].
Despite these precautions, occupational exposures still occur and are underreported. A report published by the World Health Organization aimed at estimating the global burden of disease resulting from sharps injuries identifies a number of factors which may contribute to their occurrence including the use of unnecessary needles, the lack of availability of safer needle devices and sharps disposal containers, the lack of access to or failure to use sharps containers immediately after a procedure and the continued recapping of needles after use. Globally, the report estimates that 0.5% of health care workers are exposed to HIV annually, corresponding to an expected 1000 new HIV infections from occupational exposure [5]. A study of 526 African nurses and midwives indicated that the most important risk factors for needlestick injuries were lack of training (OR 5.72, 95% CI 3.41–9.62), long working hours of >40 h/week (OR 1.90, 95% CI 1.20–3.31), recapping of needles (OR 1.78, 95% CI 1.11–2.86) and not using gloves when handling needles (OR 1.91, 95% CI 1.10–3.32) [6]. There is evidence that adherence to standard precautions is often suboptimal, and that the occurrence of percutaneous injury and mucocutaneous blood exposure is inversely related to routine standard precaution compliance [7].
Awareness of the importance of reporting a potential exposure to HIV or other blood-borne viruses is essential for clinical and medicolegal reasons. Many doctors have inadequate knowledge about PEP despite being at risk of needlestick injury. A survey of 273 junior doctors at two London teaching hospitals found that although 76% had experienced high-risk exposure to potentially infective material during their careers, only one-third had knowledge of the recommended time period for giving PEP and <20% had sought advice following the incident [8]. A retrospective review of patients presenting to an Accident and Emergency department with needlestick injuries found that among non-health care workers, there was an average delay of 23 h from the time of an incident to presentation to hospital for advice, compared to a delay of <2 h in health care workers. The average wait for assessment after presentation was an additional 90 min [9]. These studies indicate a clear need for the training and education of doctors, the other health care workers and the general public on the use and availability of PEP. Lack of knowledge of the availability of PEP on the part of the care provider may translate to missed opportunities for its prescription and lead to an increased risk of seroconversion [10].
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Evidence for PEP |
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TopAbstractIntroductionPrevention of occupational...Evidence for PEPRisk assessment and immediate...Prescription of PEPSide-effects, safety and...Other blood-borne virusesFollow-upConclusionConflicts of interestReferences |
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No large prospective randomized controlled trials have been performed to determine the efficacy of occupational PEP, and indeed the practical, medicolegal and ethical issues involved in conducting such trials make it unlikely that they will occur in the future. A number of animal studies provide support for the use of PEP in preventing the transmission of the simian immunodeficiency virus (SIV) in primate models, where the administration of antiretroviral medication to macaques has prevented infection after intravenous, rectal and oral inoculation [11–15]. However, these studies provide information on the prevention of a different virus to HIV, and differences in drug metabolism between animals and humans should be taken into account. The results can therefore not be directly applied to humans.
Much of the evidence for prescribing PEP derives from a Center for Disease Control (CDC) case–control study of occupational exposure to HIV in health care workers. This retrospective study of 33 health care workers with occupationally acquired HIV, compared to 665 controls, demonstrated an 81% reduction in the risk of HIV infection in those who took zidovudine prophylactically for 28 days following exposure (95% CI 43–94). The study has some limitations including the relatively small number of cases compared to controls and the retrospective design making it difficult to control for known and unknown factors that contribute to HIV transmission [16].
Evidence that the prescription of antiretroviral medication can prevent human-to-human transmission of the HIV virus is supported by data from studies on vertical transmission of HIV. Numerous studies have shown that the prescription of antiretrovirals to mother and infant has been proven to significantly reduce mother-to-child transmission of HIV [17–20]. In the AIDS Clinical Treatment Group protocol 076, zidovudine administered to mothers before birth and during labour and delivery and to the newborns for 6 weeks after birth reduced the risk of vertical transmission by 67% [17]. Although a reduction in risk has been shown to correlate in part with the degree of suppression of HIV RNA in the mother's serum [18,19], studies also indicate that the prescription of antiretroviral medication to infants, even in the absence of the mother being treated, protects the infant from HIV acquisition [19,20]. A randomized study of zidovudine prophylaxis administered to babies in the first 48 h of life found that the rate of HIV transmission was 9% in those receiving zidovudine compared to 27% in the absence of antiretrovirals [20].
Finally, current and future prospective observational cohort studies on the use of PEP following sexual exposure (PEPSE) to HIV may provide evidence for its efficacy [21,22]. In a recent Brazilian study on the use of PEPSE in high-risk HIV seronegative homosexual men, those taking PEP had significantly fewer seroconversions to HIV than those who did not (0.6 versus 4.2%) [22]. However, results from PEPSE studies cannot be directly applied to occupational HIV exposure as there may be confounding factors related to the reasons why people do or do not receive PEP in these circumstances.
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Risk assessment and immediate management |
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TopAbstractIntroductionPrevention of occupational...Evidence for PEPRisk assessment and immediate...Prescription of PEPSide-effects, safety and...Other blood-borne virusesFollow-upConclusionConflicts of interestReferences |
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A significant risk exposure can be defined as a percutaneous injury or the contact of mucous membranes or non-intact skin with potentially infectious blood, body fluid or tissue. Body fluids that pose a risk of transmission of HIV virus are shown in Table 1. The risks of transmission of HIV vary with the type and severity of the exposure. A Health Protection Agency summary of published surveillance reports, looking at HIV transmission from occupational exposure to HIV, found that 22 of 6955 individuals with percutaneous exposure to HIV became infected, indicating a risk of
1 in 300 or 0.32% (95% CI 0.18–0.45). Of 2910 individuals with mucocutaneous exposure to HIV, there was one seroconversion indicating a risk of 1 in 3000 or 0.03% (95% CI 0.006–0.19) [23].
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In the CDC case–control study, Cardo et al. [16] demonstrated several factors that increase the likelihood of transmission from a percutaneous exposure to HIV (Table 2). These were the occurrence of a deep injury (OR 15, 95% CI 6–41), injury with devices that were visibly contaminated with blood (OR 6.2, 95% CI 2.2–21), injuries where the needle had been placed directly in the source patients vein or artery (OR 4.3, 95% CI 1.7–12) and injuries where there had been exposure to a source patient who died of the acquired immunodeficiency syndrome within 2 months after the injury (OR 5.6, 95% CI 2.0–16). In addition, where hollow bore needle were used, large-diameter needles were weakly associated with an increased risk of seroconversion.
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The high risk of seroconversion from injuries involving terminal HIV patients is likely to reflect high plasma HIV RNA viral load measurements in these patients. Although there is no definitive data on the effect of viral load in the occupational transmission of HIV, it has been shown that high plasma viral load is a risk factor in both sexual HIV transmission where each log increment in the viral load was associated with a rate ratio of 2.45 for seroconversion (95% CI 1.85–3.26) [24] and perinatal transmission where high maternal viral load has been shown to be a significant risk factor for transmission to the infant, with an odds ratio for transmission of 2.4 per log increment (95% CI 1.2–4.7) [18]. However, it should be noted that a low or undetectable viral load does not rule out the possibility of transmitting the infection.
Immediate first aid should be taken following any potential exposure, initially by gently washing the affected area with soap and water. Bleeding should be encouraged from puncture wounds and mucous membrane exposures irrigated with water, saline or sterile irrigants. The use of antiseptics and detergents should be avoided, as their effect on local host defences is unknown [25].
A full history of the incident should be documented including the time, type and circumstances of the exposure. Useful information includes the type of device causing the injury, the gauge of needle, the depth of the wound and whether gloves were worn. If the source is known to be HIV infected, it is important to gain details on their CD4 cell count and HIV RNA plasma viral load, current and previous antiretroviral medication and any known or likely resistance to antiretrovirals. Resistance should be suspected if there has been prolonged treatment with an antiretroviral drug associated with disease progression and/or a detectable viral load at that time. If necessary, the doctor managing the source patient's HIV should be consulted for this information.
If the source patient is of unknown HIV status, they should be approached and asked to agree to a test for HIV antibodies. UK Department of Health guidelines suggest a universal approach in asking all source patients to undergo an HIV test in the case of an exposure as this normalizes the process and avoids the appearance of discrimination or making judgements [25]. A full risk assessment should take place with appropriate pre-test counselling, informed consent and arrangement for obtaining the results. It is inappropriate for the exposed health care worker to be the person requesting an HIV test from the source patient and another competent health care worker should manage this. If the injury is considered to be high risk, it is appropriate to commence PEP while awaiting the source patients HIV test result, which can then be discontinued if the test is negative. Where available the use of rapid HIV tests, which can be processed at the bedside, can provide an immediate result to determine the HIV status of a source patient. These have been shown to reduce the need for unnecessary ingestion of PEP, thereby reducing the prescription of potentially toxic medication and producing a cost saving [26,27]. European guidelines recommend the use of such tests where available [28]. If the source is unknown or a known source patient refuses an HIV test, then the decision to start PEP should be based on the type and risk of the exposure and the wishes of the patient. The estimated risk of transmission in these circumstances can be calculated as the risk of HIV transmission resulting from the particular exposure multiplied by the likelihood of the source having HIV infection (Tables 3 and 4). Examples of calculating the risk of HIV transmission are shown in Table 5.
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Prescription of PEP |
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TopAbstractIntroductionPrevention of occupational...Evidence for PEPRisk assessment and immediate...Prescription of PEPSide-effects, safety and...Other blood-borne virusesFollow-upConclusionConflicts of interestReferences |
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A presentation for PEP should be considered to be an emergency. Animal studies and studies on vertical transmission studies indicate that earlier administration of antiretrovirals is beneficial in preventing HIV transmission. A study on macaques demonstrated that 100% of animals receiving PEP within 24 h of intravenous infection with SIV remained uninfected, but only 50% of the animals that received the first PEP dose 48 h after infection and 25% of those that received the first dose 72 h after infection were protected [13]. In perinatal transmission studies, zidovudine prophylaxis given within the first 48 h of life led to a 9% rate of HIV transmission compared to18% when given on Day 3 of life or later [20]. It is recommended that the first dose is taken within an hour of the exposure. The usual time frame for the prescription of PEP is within 72 h; however, following a high-risk incident and a delayed presentation, PEP can be considered at up to 5 days or longer with specialist advice.
Duration of treatment has also been shown to be important in animal studies. Macaques treated with (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) (tenofovir) for 28 days showed no evidence of viral replication following discontinuation of PMPA treatment, but only half of the macaques treated for 10 days, and none of those treated for 3 days, were completely protected [13]. UK guidelines recommend a combination of three antiretroviral medications to be prescribed for 28 days [25]. The importance of adhering to the medication and completing the full course of treatment should be emphasized at the initial time of prescription.
PEP against HIV should be advised following a significant exposure to HIV-infected blood or other bodily fluid, or when the source is suspected to be at high risk of HIV. It should be noted that currently no antiretrovirals are licensed for PEP and the patient should be made aware of this. A full medical history, including current medications, and risk of pregnancy if female, should be taken before prescribing PEP. Baseline blood tests including a full blood count and liver and renal function should be taken. A baseline HIV test, or serum sample for storage and later HIV testing if needed, should be encouraged.
Examples of regimens that may be used for PEP are shown in Table 6. The current UK recommendation for first-line treatment is a combination of two nucleoside reverse transcriptase inhibitors (NRTI) to be taken in conjunction with a protease inhibitor (PI). Until May 2007, the most commonly prescribed regimen was combivir (a fixed dose combination of the NRTI zidovudine and lamivudine) with the PI nelfinavir. However stocks of nelfinavir were abruptly withdrawn in June 2007 due to concerns over the finding of an unexpected genotoxic contaminant present in some batches of the drug. A regime of combivir with a fixed dose combination of lopinavir and ritonavir (Kaletra®) may be recommended as first line PEP. The use of the nucleotide reverse transcriptase inhibitor tenofovir may be considered as its efficacy in preventing seroconversion in SIV/macaque animal models has been well demonstrated [11–14].
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The medications prescribed may vary according to the characteristics of the exposure, the source patient's antiretroviral history including likely resistance to individual antiretrovirals and any underlying medical conditions in the exposed person.
Some authorities, such as the US public health service, recommend the use of a dual therapy (a combination of two antiretroviral drugs, as opposed to the three drug combinations used in the UK) for PEP in ‘low risk injuries’ in order to minimize side-effects and toxicities [29]. However, studies have demonstrated the emergence of drug-resistant HIV in source patients of occupational exposures and this raises concerns over the use of fewer medications. An observational study conducted in Brazil found that >41% of source patients had resistance-related mutations in reverse transcriptase, protease or both [30]. Another study of source patients to occupational exposure based in America also found an approximate 40% prevalence of mutations associated with resistance to reverse transcriptase and PIs [31]. The case report of a health care worker who became infected with HIV despite taking PEP describes how drug resistance was likely to be a major contributor to the failure of PEP [32]. Unfortunately, it is not practical to test source virus at the time of exposure for resistance as the results will not be able in time to influence the choice of medications. It is thought that three drug combinations will increase potency of the prophylaxis and reduce the risk of failure if there is viral resistance to one or more of the prescribed medication, and this is the current recommendation in the UK [25]. If the source patient has known drug resistance to individual antiretroviral medications or whole classes of drug, then the combination should be altered accordingly. Advice should be sought from an HIV physician in these circumstances.
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Side-effects, safety and tolerability |
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TopAbstractIntroductionPrevention of occupational...Evidence for PEPRisk assessment and immediate...Prescription of PEPSide-effects, safety and...Other blood-borne virusesFollow-upConclusionConflicts of interestReferences |
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Side-effects such as nausea and diarrhoea are common and patients should be warned that they are likely to occur and reassured that they are usually mild and reversible. Regimes containing indinavir have been shown to be poorly tolerated with high rates of discontinuation [33] and are now rarely used. A study comparing dual nucleoside analogue therapy to triple therapy regimes containing nelfinavir did not find a significant difference in the number of people experiencing side-effects overall, although those on nelfinavir did have more gastrointestinal manifestations [34]. If not managed properly, even minor side-effects can affect adherence and reduce the likelihood of completing the course of treatment. A study using a triple combination of lamivudine, stavudine and tenofovir found that it was significantly better tolerated than zidovudine and PI containing regimes, resulting in a higher completion rate of the PEP [35]. A prescription of antiemetics and antidiarrhoeals such as domperidone and loperamide may be given routinely alongside the initial antiretroviral prescription in order to reduce troublesome side-effects.
Studies have shown that HIV-negative subjects receiving antiretrovirals as PEP are more likely to experience side-effects than HIV-positive subjects taking the same medication for treatment of HIV [34,36]. The psychological morbidity associated with occupational needlestick injury may be substantial and has been reported to cause disabling long-term affects [37]. Those who experience occupational exposure to HIV should be offered psychological support and counselling if needed.
Severe side-effects are rare and tend to be reversible. Galactorrhoea with hyperprolactinaemia has been reported in relation to use of indinavir [33] and there have been case reports of cholestatic hepatitis occurring in patients taking nelfinavir [38]. Peripheral neuropathy may occur more frequently in PI containing regimes; one study demonstrated that 34% of those on nelfinavir containing regimes developed peripheral neuropathy compared to 13% on dual nucleoside regimes (P = 0.013) [34].
The use of the non-nucleoside transcriptase inhibitor nevirapine is not recommended for use in PEP as it has been reported to cause fulminant acute liver failure in health care workers [39]. The nucleoside reverse transcriptase inhibitor abacavir should also be avoided due to the risk of severe hypersensitivity reactions. Pregnancy should not prevent the use of PEP and the antiretrovirals zidovudine, lamivudine and Kaletra® are considered to be safe although the data are limited. Efavirenz should be avoided as it is has been shown to be teratogenic in animals. There is limited data on newer antiretroviral medications and updated information should be sought prior to prescribing them [40].
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Other blood-borne viruses |
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TopAbstractIntroductionPrevention of occupational...Evidence for PEPRisk assessment and immediate...Prescription of PEPSide-effects, safety and...Other blood-borne virusesFollow-upConclusionConflicts of interestReferences |
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Accidental blood and body fluid exposures pose a risk of other blood-borne viruses, in particular of hepatitis B and C. Health care workers should be vaccinated against hepatitis B with a standard vaccination schedule and hepatitis B surface antibody levels confirming response following completion of the vaccination course. Following an exposure to a potential hepatitis B carrier in a non-vaccinated person or non-responder to hepatitis vaccine, an accelerated schedule of hepatitis vaccine can be given. If the source is a confirmed hepatitis B carrier or deemed to be high risk, hepatitis B immune globulins can also be administered, preferably within 24 h from the exposure and no later than 1 week [41].
There is no current available PEP following exposure to hepatitis C virus. Post-exposure testing of the victim is however recommended though regimes vary. Exposed individuals can be tested for hepatitis C antibody at 3 and 6 months following an exposure, and recent European work suggests monitoring liver Alanine aminotransferase levels on a monthly basis in order to promptly recognize acute infection [41]. There is evidence that treating acute hepatitis C with pegylated interferon +/– ribavirin can prevent the development of chronic infection [42].
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Follow-up |
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TopAbstractIntroductionPrevention of occupational...Evidence for PEPRisk assessment and immediate...Prescription of PEPSide-effects, safety and...Other blood-borne virusesFollow-upConclusionConflicts of interestReferences |
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Routine follow-up should be organized in advance for all personnel who have had occupational exposures to HIV, regardless of whether or not they receive PEP. Those who are prescribed PEP are usually reviewed at 1–2 weeks in order to review side-effects, toxicity and adherence. Follow-up testing for HIV, and for other blood-borne viruses if necessary, should occur at 4–6 weeks, 3 months and 6 months. Although cases of delayed seroconversion have occurred, the vast majority of seroconversions will occur within 6 months [43] and this is now the standard follow-up interval. However, patients should be aware of the need to seek medical advice if they experience symptoms of primary HIV infection such as fever, rash, lymphadenopathy or flu-like symptoms.
There have been case reports of HIV seroconversion despite the correct use of PEP [43–45]. Health Protection Agency data to 2002 reports 24 cases of HIV seroconversion despite the prescription of PEP and in 83% of these cases, medication was commenced within 2 h of exposure. Twenty-one injuries were from percutaneous exposure, the remaining three from mucocutaneous exposure [45].
Advice should be given regarding safe sex during the follow-up period, and patients should not donate blood for transfusion during this time. It is considered safe for health care workers to continue performing exposure-prone procedures during the follow-up period as the risk of seroconversion is low and the risk of secondary onward transmission remote [25].
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Conclusion |
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TopAbstractIntroductionPrevention of occupational...Evidence for PEPRisk assessment and immediate...Prescription of PEPSide-effects, safety and...Other blood-borne virusesFollow-upConclusionConflicts of interestReferences |
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Although preventable, occupational exposures to HIV continue to occur presenting a very real risk of HIV infection. Worldwide, nurses and laboratory workers account for 69% of occupationally acquired HIV transmissions and 13% have occurred in doctors. Health Protection Agency statistics indicate that there have been 106 documented seroconversions worldwide following occupational exposure to HIV, with a further 238 cases of probable transmission. Five confirmed cases have occurred in the UK [45].
Despite the widespread availability of PEP, many health care workers remain ignorant about its correct use and the need for urgent assessment in the case of an exposure to HIV. This lack of awareness is more marked among non-health care workers and there is a need for the education of those who may be at risk including guidelines on how and where to seek medical advice should an incident occur. This is usually the local occupational health department, accident and emergency or genitourinary medicine clinic where a risk assessment and the prescription of necessary medication, if necessary in the form of a 3-day starter pack, can take place. The assessment of risk is not always straightforward, and in some cases, the HIV status of the source patient will remain unclear. As the prevalence of HIV in the UK continues to increase, the number of undiagnosed HIV-infected patients within hospitals enlarges, and the importance of appropriate source testing becomes increasingly apparent. In cases where the source status cannot be determined, a decision based on the type of exposure, likely risk factors of the source patient, and the wishes or concerns of the exposed worker need to be made. Triple drug antiretroviral combinations are recommended, with necessary consideration of possible viral resistance in the source patient, and medical conditions and concurrent medications in the exposed person. Follow-up is essential and should be arranged regardless of whether or not PEP is prescribed.
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Conflicts of interest |
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TopAbstractIntroductionPrevention of occupational...Evidence for PEPRisk assessment and immediate...Prescription of PEPSide-effects, safety and...Other blood-borne virusesFollow-upConclusionConflicts of interestReferences |
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None declared.
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