Occupational Transmission of HIV

Risk for Occupational Transmission of HIV

In prospective studies of HCP, the average risk of HIV transmission after a percutaneous exposure to HIV-infected blood has been estimated to be approximately 0.3% (95% confidence interval [CI] = 0.2%-0.5%) (94) and after a mucous membrane exposure, approximately 0.09% (95% CI = 0.006%-0.5%) (95). Although episodes of HIV transmission after nonintact skin exposure have been documented (96), the average risk for transmission by this route has not been precisely quantified but is estimated to be less than the risk for mucous membrane exposures (97). The risk for transmission after exposure to fluids or tissues other than HIV-infected blood also has not been quantified but is probably considerably lower than for blood exposures (98).

As of June 2000, CDC had received voluntary reports of 56 U.S. HCP with documented HIV seroconversion temporally associated with an occupational HIV exposure. An additional 138 episodes in HCP are considered possible occupational HIV transmissions. These workers had a history of occupational exposure to blood, other infectious body fluids, or laboratory solutions containing HIV, and no other risk for HIV infection was identified, but HIV seroconversion after a specific exposure was not documented (99).

Epidemiologic and laboratory studies suggest that several factors might affect the risk of HIV transmission after an occupational exposure. In a retrospective case-control study of HCP who had percutaneous exposure to HIV, the risk for HIV infection was found to be increased with exposure to a larger quantity of blood from the source person as indicated by a) a device visibly contaminated with the patient's blood, b) a procedure that involved a needle being placed directly in a vein or artery, or c) a deep injury (100). The risk also was increased for exposure to blood from source persons with terminal illness, possibly reflecting either the higher titer of HIV in blood late in the course of AIDS or other factors (e.g., the presence of syncytia-inducing strains of HIV). A laboratory study that demonstrated that more blood is transferred by deeper injuries and hollow-bore needles lends further support for the observed variation in risk related to blood quantity (101).

The use of source person viral load as a surrogate measure of viral titer for assessing transmission risk has not yet been established. Plasma viral load (e.g., HIV RNA) reflects only the level of cell-free virus in the peripheral blood; latently infected cells might trans-mit infection in the absence of viremia. Although a lower viral load (e.g., <1,500 RNA copies/mL) or one that is below the limits of detection probably indicates a lower titer exposure, it does not rule out the possibility of transmission.

Some evidence exists regarding host defenses possibly influencing the risk for HIV infection. A study of HIV-exposed but uninfected HCP demonstrated an HIV-specific cytotoxic T-lymphocyte (CTL) response when peripheral blood mononuclear cells were stimu-lated in vitro with HIV-specific antigens (102). Similar CTL responses have been observed in other groups who experienced repeated HIV exposure without resulting infection (103‚108). Among several possible explanations for this observation is that the host immune response sometimes might prevent establishment of HIV infection after a percutaneous exposure; another is that the CTL response simply might be a marker for exposure. In a study of 20 HCP with occupational exposure to HIV, a comparison was made of HCP treated with zidovudine (ZDV) PEP and those not treated. The findings from this study suggest that ZDV blunted the HIV-specific CTL response and that PEP might inhibit early HIV replication (109).

Rationale for HIV PEP

Considerations that influence the rationale and recommendations for PEP include

• the pathogenesis of HIV infection, particularly the time course of early infection;
• the biological plausibility that infection can be prevented or ameliorated by using antiretroviral drugs;
• direct or indirect evidence of the efficacy of specific agents used for prophylaxis; and
• the risk and benefit of PEP to exposed HCP.

The following discussion considers each of these concerns.

Role of Pathogenesis in Considering Antiretroviral Prophylaxis. Information about primary HIV infection indicates that systemic infection does not occur immediately, leaving a brief window of opportunity during which postexposure antiretroviral intervention might modify or prevent viral replication. In a primate model of simian immunodeficiency virus (SIV) infection, infection of dendritic-like cells occurred at the site of inoculation during the first 24 hours following mucosal exposure to cell-free virus. Over the subsequent 24‚48 hours, migration of these cells to regional lymph nodes occurred, and virus was detectable in the peripheral blood within 5 days (110). Theoretically, initiation of antiretroviral PEP soon after exposure might prevent or inhibit systemic infection by limiting the proliferation of virus in the initial target cells or lymph nodes.

Efficacy of Antiretrovirals for PEP in Animal Studies. Data from animal studies have been difficult to interpret, in part, because of problems identifying an animal model that is comparable to humans. In early studies, differences in controlled variables (e.g., choice of viral strain [based on the animal model used], inoculum size, route of inoculation, time of prophylaxis initiation, and drug regimen) made extrapolation of the results to humans difficult. Recently, refinements in methodology have facilitated more relevant studies; in particular, the viral inocula used in animal studies have been reduced to levels more analogous to human exposures but sufficient to cause infection in control animals (111‚ 113). These studies provide encouraging evidence of postexposure chemoprophylactic efficacy.

Studies among primates and in murine and feline animal models have demonstrated that larger viral inocula decrease prophylactic efficacy (114‚117). In addition, delaying initiation, shortening the duration, or decreasing the antiretroviral dose of PEP, individually or in combination, decreased prophylactic efficacy (113,118‚124). For example, when (R)-9-(2-phosphonylmethoxypropyl) adenine (tenofovir) was administered 48 hours before, 4 hours after, or 24 hours after intravenous SIV inoculation to long-tailed macaques, a 4-week regimen prevented infection in all treated animals (122). A subsequent study confirmed the efficacy of tenofovir PEP when administered 24 hours after intravenous inoculation of a dose of SIV that uniformly results in infection in untreated macaques. In the same study, protection was incomplete if the tenofovir administration was delayed to 48 or 72 hours postexposure or if the total duration of treatment was curtailed to 3 or 10 days (123).

Efficacy of Antiretrovirals for PEP in Human Studies. Little information exists from which the efficacy of PEP in humans can be assessed. Seroconversion is infrequent following an occupational exposure to HIV-infected blood; therefore, several thousands of exposed HCP would need to enroll in a prospective trial to achieve the statistical power necessary to directly demonstrate PEP efficacy (125).

In the retrospective case-control study of HCP, after controlling for other risk factors for HIV transmission, use of ZDV as PEP was associated with a reduction in the risk of HIV infection by approximately 81% (95% CI = 43%-94%) (100). Although the results of this study suggest PEP efficacy, its limitations include the small number of cases studied and the use of cases and controls from different cohorts.

In a multicenter trial in which ZDV was administered to HIV-infected pregnant women and their infants, the administration of ZDV during pregnancy, labor, and delivery and to the infant reduced transmission by 67% (126). Only part of the protective effect of ZDV was explained by reduction of the HIV viral load in the maternal blood, suggesting that ZDV prophylaxis, in part, involves a mechanism other than the reduction of maternal viral burden (127,128). Since 1998, studies have highlighted the importance of PEP for prevention of perinatal HIV transmission. In Africa, the use of ZDV in combination with lamivudine (3TC) decreased perinatal HIV transmission by 50% when administered dur-ing pregnancy, labor, and for 1 week postpartum, and by 37% when started at the onset of labor and continued for 1 week postpartum (129). Studies in the United States and Uganda also have demonstrated that rates of perinatal HIV transmission have been reduced with the use of abbreviated PEP regimens started intrapartum or during the first 48-72 hours of life (130‚132).

The limitations of all of these studies with animals and humans must be considered when reviewing evidence of PEP efficacy. The extent to which data from animal studies can be extrapolated to humans is largely unknown, and the exposure route for mother-to-infant HIV transmission is not similar to occupational exposures; therefore, these findings might not be directly applicable to PEP in HCP.

Reports of Failure of PEP. Failure of PEP to prevent HIV infection in HCP has been reported in at least 21 instances (78,133‚139). In 16 of the cases, ZDV was used alone as a single agent; in two cases, ZDV and didanosine (ddI) were used in combination (133,138); and in three cases, >3 drugs were used for PEP (137‚139). Thirteen of the source persons were known to have been treated with antiretroviral therapy before the exposure. Antiretroviral resistance testing of the virus from the source person was performed in seven instances, and in four, the HIV infection transmitted was found to have decreased sensitivity to ZDV and/or other drugs used for PEP. In addition to possible exposure to an antiretroviral-resistant strain of HIV, other factors that might have contributed to these apparent failures might include a high titer and/or large inoculum exposure, delayed initiation and/or short duration of PEP, and possible factors related to the host (e.g., cellular immune system responsiveness) and/or to the source person's virus (e.g., presence of syncytia-forming strains) (133). Details regarding the cases of PEP failure involving combinations of antiretroviral agents are included in this report (Table 1).

Antiretroviral Agents for PEP

Antiretroviral agents from three classes of drugs are available for the treatment of HIV infection. These agents include the nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). Only antiretroviral agents that have been approved by FDA for treatment of HIV infection are discussed in these guidelines.

Determining which agents and how many to use or when to alter a PEP regimen is largely empiric. Guidelines for the treatment of HIV infection, a condition usually involving a high total body burden of HIV, include recommendations for the use of three drugs (140); however, the applicability of these recommendations to PEP remains unknown. In HIV-infected patients, combination regimens have proved superior to monotherapy regimens in reducing HIV viral load, reducing the incidence of opportunistic infections and death, and delaying onset of drug resistance (141,142). A combination of drugs with activity at different stages in the viral replication cycle (e.g., nucleoside analogues with a PI) theoretically could offer an additional preventive effect in PEP, particularly for occupational exposures that pose an increased risk of transmission. Although the use of a three-drug regimen might be justified for exposures that pose an increased risk of transmission, whether the potential added toxicity of a third drug is justified for lower-risk exposures is uncertain. Therefore, the recommendations at the end of this document provide guidance for two- and three-drug PEP regimens that are based on the level of risk for HIV transmission represented by the exposure.

NRTI combinations that can be considered for PEP include ZDV and 3TC, 3TC and stavudine (d4T), and ddI and d4T. In previous PHS guidelines, a combination of ZDV and 3TC was considered the first choice for PEP regimens (3). Because ZDV and 3TC are available in a combination formulation (Combivir™, manufactured by Glaxo Wellcome, Inc., Research Triangle Park, NC), the use of this combination might be more convenient for HCP. However, recent data suggest that mutations associated with ZDV and 3TC resistance might be common in some areas (143). Thus, individual clinicians might prefer other NRTIs or combinations based on local knowledge and experience in treating HIV infection and disease.

The addition of a third drug for PEP following high-risk exposures is based on demonstrated effectiveness in reducing viral burden in HIV-infected persons. Previously, indinavir (IDV) or nelfinavir (NFV) were recommended as first-choice agents for inclusion in an expanded PEP regimen (5). Since the publication of the 1998 PEP guidelines, efavirenz (EFV), an NNRTI; abacavir (ABC), a potent NRTI; and Kaletra™, a PI, have been approved by FDA. Although side effects might be common with the NNRTIs, EFV might be considered for expanded PEP regimens, especially when resistance to PIs in the source person's virus is known or suspected. ABC has been associated with dangerous hypersensitivity reactions but, with careful monitoring, may be considered as a third drug for PEP. Kaletra, a combination of lopinavir and ritonavir, is a potent HIV inhibitor that, with expert consultation, may be considered in an expanded PEP regimen.

Toxicity and Drug Interactions of Antiretroviral Agents. When administering PEP, an important goal is completion of a 4-week PEP regimen when PEP is indicated. Therefore, the toxicity profile of antiretroviral agents, including the frequency, severity, duration, and reversibility of side effects, is a relevant consideration. All of the antiretroviral agents have been associated with side effects (Table 2). However, studies of adverse events have been conducted primarily with persons who have advanced disease (and longer treatment courses) and who therefore might not reflect the experience in persons who are uninfected (144).

Several primary side effects are associated with antiretroviral agents (Table 2). Side effects associated with many of the NRTIs are chiefly gastrointestinal (e.g., nausea or diarrhea); however, ddI has been associated with cases of fatal and nonfatal pancreatitis among HIV-infected patients treated for >4 weeks. The use of PIs has been associated with new onset diabetes mellitus, hyperglycemia, diabetic ketoacidosis, exacerbation of preexisting diabetes mellitus, and dyslipidemia (145‚147). Nephrolithiasis has been associated with IDV use; however, the incidence of this potential complication might be limited by drinking at least 48 ounces (1.5 L) of fluid per 24-hour period (e.g., six 8- ounce glasses of water throughout the day) (148). NFV has been associated with the development of diarrhea; however, this side effect might respond to treatment with antimotility agents that can be prescribed for use, if necessary, at the time the drug is recommended for PEP. The NNRTIs have been associated with severe skin reactions, including life-threatening cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hepa-totoxicity, including fatal hepatic necrosis, has occurred in patients treated with nevirapine (NVP); some episodes began during the first few weeks of therapy (FDA, unpublished data, 2000). EFV has been associated with central nervous system side effects, including dizziness, somnolence, insomnia, and abnormal dreaming.

All of the approved antiretroviral agents might have potentially serious drug interac-tions when used with certain other drugs (Appendix C). Careful evaluation of concomi-tant medications used by an exposed person is required before PEP is prescribed, and close monitoring for toxicity is also needed. Further information about potential drug interactions can be found in the manufacturer's package insert.

Toxicity Associated with PEP. Information from the National Surveillance System for Health Care Workers (NaSH) and the HIV Postexposure Registry indicates that nearly 50% of HCP experience adverse symptoms (e.g., nausea, malaise, headache, anorexia, and headache) while taking PEP and that approximately 33% stop taking PEP because of adverse signs and symptoms (6,7,10,11). Some studies have demonstrated that side effects and discontinuation of PEP are more common among HCP taking three-drug combination regimens for PEP compared with HCP taking two-drug combination regimens (7,10). Although similar rates of side effects were observed among persons who took PEP after sexual or drug use exposures to HIV in the San Francisco Post-Exposure Prevention Project, 80% completed 4 weeks of therapy (149). Participants in the San Francisco Project were followed at 1, 2, 4, 26, and 52 weeks postexposure and received medication adherence counseling; most participants took only two drugs for PEP.

Serious side effects, including nephrolithiasis, hepatitis, and pancytopenia have been reported with the use of combination drugs for PEP (6,7,150,151). One case of NVP-associated fulminant liver failure requiring liver transplantation and one case of hypersensitivity syndrome have been reported in HCP taking NVP for HIV PEP (152). Including these two cases, from March 1997 through September 2000, FDA received reports of 22 cases of serious adverse events related to NVP taken for PEP (153). These events included 12 cases of hepatotoxicity, 14 cases of skin reaction (including one documented and two possible cases of Stevens-Johnson syndrome), and one case of rhabdomyolysis; four cases involved both hepatotoxicty and skin reaction, and one case involved both rhabdomyolysis and skin reaction.

Resistance to Antiretroviral Agents. Known or suspected resistance of the source virus to antiretroviral agents, particularly to agents that might be included in a PEP regimen, is a concern for persons making decisions about PEP. Resistance to HIV infection occurs with all of the available antiretroviral agents, and cross-resistance within drug classes is frequent (154). Recent studies have demonstrated an emergence of drug-resistant HIV among source persons for occupational exposures (143,155). A study conducted at seven U.S. sites during 1998‚1999 found that 16 (39%) of 41 source persons whose virus was sequenced had primary genetic mutations associated with resistance to RTIs, and 4 (10%) had primary mutations associated with resistance to PIs (143). In addition, occupational transmission of resistant HIV strains, despite PEP with combination drug regimens, has been reported (137,139). In one case, a hospital worker became infected after an HIV exposure despite a PEP regimen that included ddI, d4T, and NVP (139). The transmitted HIV contained two primary genetic mutations associated with resistance to NNRTIs (the source person was taking EFV at the time of the exposure). Despite recent studies and case reports, the relevance of exposure to a resistant virus is still not well understood.

Empiric decisions about the presence of antiretroviral drug resistance are often difficult to make because patients generally take more than one antiretroviral agent. Resistance should be suspected in source persons when they are experiencing clinical progression of disease or a persistently increasing viral load, and/or decline in CD4 T-cell count, despite therapy or a lack of virologic response to therapy. However, resistance testing of the source virus at the time of an exposure is not practical because the results will not be available in time to influence the choice of the initial PEP regimen. Furthermore, in this situation, whether modification of the PEP regimen is necessary or will influence the outcome of an occupational exposure is unknown. No data exist to suggest that modification of a PEP regimen after receiving results from resistance testing (usually a minimum of 1-2 weeks) improves efficacy of PEP.

Antiretroviral Drugs During Pregnancy. Data are limited on the potential effects of antiretroviral drugs on the developing fetus or neonate (156). Carcinogenicity and/or mutagenicity is evident in several in vitro screening tests for ZDV and all other FDA-licensed NRTIs. The relevance of animal data to humans is unknown; however, because teratogenic effects were observed in primates at drug exposures similar to those representing human therapeutic exposure, the use of EFV should be avoided in pregnant women (140). IDV is associated with infrequent side effects in adults (i.e., hyperbilirubinemia and renal stones) that could be problematic for a newborn. Because the half-life of IDV in adults is short, these concerns might be relevant only if the drug is administered shortly before delivery.

In a recent study in France of perinatal HIV transmission, two cases of progressive neurologic disease and death were reported in uninfected infants exposed to ZDV and 3TC (157). Laboratory studies of these children suggested mitochondrial dysfunction. In a careful review of deaths in children followed in U.S. perinatal HIV cohorts, no deaths attributable to mitochondrial disease have been found (158).

Recent reports of fatal and nonfatal lactic acidosis in pregnant women treated throughout gestation with a combination of d4T and ddI have prompted warnings about use of these drugs during pregnancy (159). Although the case-patients were HIV-infected women taking the drugs for >4 weeks, pregnant women and their providers should be advised to consider d4T and ddI only when the benefits of their use outweigh the risks.

PEP Use in Hospitals in the United States. Analysis of data from NaSH provides information on the use of PEP following occupational exposures in 47 hospitals in the United States. A total of 11,784 exposures to blood and body fluids was reported from June 1996 through November 2000 (CDC, unpublished data, 2001). For all exposures with known sources, 6% were to HIV-positive sources, 74% to HIV-negative sources, and 20% to sources with an unknown HIV status. Sixty-three percent of HCP exposed to a known HIV-positive source started PEP, and 54% of HCP took it for at least 20 days, whereas 14% of HCP exposed to a source person subsequently found to be HIV-negative initiated PEP, and 3% of those took it for at least 20 days. Information recorded about HIV exposures in NaSH indicates that 46% of exposures involving an HIV-positive source warranted only a two-drug PEP regimen (i.e., the exposure was to mucous membranes or skin or was a superficial percutaneous injury and the source person did not have end-stage AIDS or acute HIV illness); however, 53% of these exposed HCP took >3 drugs (CDC, unpublished data, 2000). Similarly, the National Clinicians' Post-Exposure Prophylaxis Hotline (PEPline) reported that PEPline staff recommended stopping or not starting PEP for approximately one half of the HCP who consulted them about exposures (D. Bangsberg, San Francisco General Hospital, unpublished data, September 1999). The observation that some HCP exposed to HIV-negative source persons take PEP from several days to weeks following their exposures suggests that strategies be employed such as the use of a rapid HIV antibody assay, which could minimize exposure to unnecessary PEP (11). A recent study demonstrated that use of a rapid HIV test for evaluation of source persons after occupational exposures not only resulted in decreased use of PEP, but also was cost-effective compared with use of the standard enzyme immunoassay (EIA) test for source persons subsequently found to be HIV-negative (160).