Management of HIV Exposure

 

Chinese Version

Eric S. Daar, M.D.

Chief, Division of HIV Medicine

Harbor-UCLA Medical Center

Professor of Medicine

David Geffen School of Medicine at UCLA

1124 W, Carson St, N-24, Torrance, CA 90502

Phone: (310) 222-2467, Fax: (310) 533-0447

E-mail: EDaar@LABioMed.org

 

               Transmission of human immunodeficiency virus type 1 (HIV-1) occurs primarily as a result of sexual or blood exposures, or from an infected mother to her newborn. Prospective randomized trials of post-exposure prophylaxis (PEP) are not practical because the risk of transmission in most settings is low. Consequently, recommendations for PEP are based on limited data from a single case-control study as well as extrapolation from animal models and studies designed to prevent vertical transmission. Guidelines have emerged that suggest how PEP might be utilized in the event of an occupational exposure to HIV-1. These recommendations balance the potential risk of infection occurring after a specific exposure with the likely benefits and adverse effects related to the use of select antiretroviral agents. More recently the Center for Disease Control has updated guidelines for the use of PEP in the setting of non-occupational exposures to HIV-1.

Stürmer M, et al. Is transmission of HIV-1 in non-viraemic serodiscordant couples possible?  Antivir Ther 2008;13:729-732.

Timing and Determinants of HIV Infection

               HIV transmission occurs when virus-containing fluids such as blood, semen, vaginal secretions, cerebrospinal fluid, or amniotic fluid contact mucous membranes or breaks in the skin. The likelihood of transmission is expected to be closely related to the concentration of virus in the fluid and extent of exposure. Transmission rates vary from greater than 90% for transfusion of blood from an infected person (12), 25-35% for vertical transmission from an untreated infected woman to her newborn (8), 0.1-3% for receptive anal intercourse, to 0.1-0.2% for receptive vaginal intercourse (14, 20, 24, 31, 39). The risk of transmission as a result of oral sex is likely to be even lower (30). Transmission from blood occurs most often among intravenous drug users and healthcare workers. The risk of transmission after a single exposure in these populations is estimated to be approximately 0.5% and depends on the type of exposure (13, 19, 34).

               The interval between HIV-1 exposure and the onset of viremia has been studied in the simian immunodeficiency virus (SIV) primate model. Spira and colleagues demonstrated that dendritic cells are infected within hours of a mucosal SIV challenge, viral spread to regional lymph nodes occurs within 24 to 48 hours, and viremia is usually detectable within 5 days (33), While these types of studies are not possible in humans, the time frame for HIV-1 infection is probably similar (10). Together, the data from animals and humans suggests that if antiretroviral therapy is to prevent infection it is best initiated within the first few hours of exposure in order to halt the spread to regional lymph nodes and subsequent dissemination.

Review Article:  Landovitz RJ, Jagannathan P, Bhatt A, Roland ME.  Preventing HIV Infection After a Potential Sexual Exposure. Infect in Med 2007;24:239-246.

Risk of Infection Following Occupational Exposure and Rationale for PEP

               A case-control surveillance study previously showed that the use of open-label zidovudine (ZDV) resulted in an 81% reduction in transmission among occupationally exposed healthcare workers from France, Italy, United Kingdom and the United States (1). The study also showed that the risk of HIV-1 transmission was significantly increased when the injuries were deep, when there was visible blood on the surface of the transmitting instrument, when the instrument had been previously inserted in the vein or artery of an infected person, and when the source patient died of AIDS within two months of the exposure. All of these factors are likely to be surrogates for exposure to larger amounts of infectious fluid and/or the presence of higher concentrations of virus.

               Despite the promising reduction in transmission seen in this case-control study, it is important that clinicians counseling exposed individuals are aware that early experiences with ZDV alone were associated with a high frequency of side effects and early termination of therapy (11, 17, 25, 34). In addition, the efficacy data from this study is limited to only 33 cases, often taken from a different cohort than the 665 control subjects and unlike the prospectively collected data from the control group, some cases were reported retrospectively. Finally, the reported 81% efficacy of PEP is bracketed by wide 95% confidence intervals (48% - 94%) (16). Despite the limitations of the available data statistical models have shown that occupational PEP is potentially cost effective (26), and this management strategy is widely endorsed by the Centers for Disease Control and Prevention (CDC) (7).

Evaluation of an Exposed Healthcare Worker

               In the event of exposure to potentially infectious material, healthcare workers should seek immediate medical attention from clinicians experienced in assessing occupational exposures and in the use of antiretroviral drugs. Those exposed should be questioned as to the circumstances, timing and type of exposure, as well as what is known of the HIV-1 infection status of the source person. Exposed individuals should also undergo hepatitis B virus (HBV) post-exposure management.

               The risk of infection is expected to correlate with the type and volume of potentially infectious fluid that the healthcare worker is exposed to and the nature of the exposure. If the exposure was to blood, the degree of infectivity may be inferred from the source patient's viral load. For example, if percutaneous exposure occurs with a solid bore needle or other sharp instrument the actual amount of infectious material inoculated is relatively small, in contrast to the larger inoculums delivered by a hollow bore needle. Similarly, exposure to intact skin poses relatively little risk compared to abraded skin. The risk of transmission after exposure of mucous membranes is less well defined but is a recognized alternate route of occupational HIV-1 transmission (6).

Evaluation of Source Person

               The source person of an occupational exposure should be evaluated for epidemiological, clinical, and laboratory evidence of HIV-1, HBV, and hepatitis C virus (HCV) infection (4, 7). The source person's overall risk of being infected with HIV-1 should also include the possibility of a recent exposure history or the presence of a syndrome consistent with primary HIV-1 infection (9, 38). The presence of such symptoms in an HIV-antibody-negative source person may require further testing, such as with a p24 antigen or plasma HIV-1 RNA assay, with the continuation of PEP for the healthcare worker. If the source’s HIV status is unknown, rapid HIV-antibody testing should be performed on the source, if possible, in order to minimize the duration of unnecessary antiretroviral therapy (32). The source should also be evaluated for the likelihood of harboring drug-resistant HIV-1. There is strong evidence that drug resistant virus is transmitted by sexual exposure and is likely to also occur in the setting of an occupational exposure (21, 40). Therefore, whenever possible the source should be questioned about previous antiretroviral therapy as well as known pre-existing drug resistance.

Recommendations for PEP Following Occupational Exposure

               The CDC provides guidelines for PEP in cases of percutaneous injuries (Table 1) and exposures to mucous membrane and non-intact skin (Table 2) (7). Whether or not to institute therapy depends on the significance of the exposure, whereas decisions about the type of drug therapy generally depends on the severity of the exposure, such as the amount of infectious fluids the person is exposed to, the amount of virus in the fluids, such as viral load in blood, and the likelihood of drug resistance in the source. The type of antiretroviral therapy recommended in guidelines is based upon the goal of balancing the risk of toxicity with the potential benefit. Assistance in decision-making is also available through a direct consultation 24-hours-per-day from PEPLine, a joint program of the University of California San Francisco and San Francisco General Hospital Community Provider AIDS Training Project and Epidemiology and Prevention Interventions Center at 1-888-HIV-4911 (Table 3).

               Recommended therapeutic options for occupational PEP include a basic regimen of 2 nucleoside reverse transcriptase inhibitors (NRTIs) for relatively low-risk exposures and an expanded regimen of three drugs for higher-risk exposures. Based upon recent guidelines for PEP along with extrapolation from current treatment recommendations for chronically HIV-1-infected adolescents and adults the basic regimen should generally be one that would include lamivudine (3TC, EpivirTM) or emtricitabine (FTC, EmtrivaTM) in combination with zidovudine (ZDV, RetrovirTM), stavudine (d4T, ZeritTM) or tenofovir DF (TDF, VireadTM) (3, 7). Although most recent PEP guidelines have not specifically included TDF, this agent is now one of the preferred choices for the treatment of chronically HIV-1-infected individuals, as well as being highly efficacious in SIV models of PEP. In fact, in theory it may act more quickly than other NRTIs because it requires the addition of only two, rather than three phosphates to become activated (36, 37). In contrast, the most recent PEP guidelines have included d4T and didanosine (ddI, VidexTM) as an options (7) which has more recently been proven to be associated with increased toxicity and is generally no longer recommended as a treatment option for HIV infection (3).

               Recommended “expanded regimens” can be created by adding a protease inhibitor (PI) or a nonnucleoside analogue reverse transcriptase inhibitor (NNRTI) to the dual NRTI regimens outlined above. Recommended PIs have included indinavir (IDV, Crixivan®) or nelfinavir (NFV, ViraceptTM) but in the current era the use of other agents frequently suggested for the treatment of chronically infected individuals can be considered (3). Many experts would also recommend a ritonavir (RTV, NorvirTM)-boosted PI regimen to achieve higher PI drug levels, particularly if drug resistance is a concern. NNRTI-containing PEP regimens are potent, fast acting, easy to administer, and have yielded promising results in animal models (15). They also do not require intracellular phosphorylation to become active. However, it is important to note that nevirapine (NVP, ViramueTM) is not recommended in this situation due to reports of severe hepatotoxicity and skin reactions in persons taking this agent as part of a PEP regimen (5). Due to the teratogenicity of efavirenz (EFV, SustivaTM), it should be used with caution in those of child-bearing potential.

               Regardless of the regimen used treatment should be initiated as soon as possible after an exposure and be continued for 4 weeks with appropriate follow-up, although this duration is based on limited animal data (36). The CDC guidelines list several situations for which expert consultation for HIV-1 PEP is advised: (i) delayed presentation (i.e., more than 24-36 hours post exposure), (ii) an unknown source, (iii) known or suspected pregnancy in the exposed person, (iv) documented or suspected antiretroviral drug resistant virus in the source person, and (v) toxicity of the initial PEP regimen (7).

Follow-up of HIV-1-Exposed Individuals

               Healthcare workers exposed to potentially infectious material should be offered psychological counseling and support. If PEP is started the exposed individual should return in two weeks to have a complete blood count and hepatic enzyme measurements. Following completion of prophylaxis they should return for hepatic transaminase levels and HIV antibody testing 6, 12, and 24 weeks after exposure. Exposed individuals should also be advised to use precautions to prevent secondary transmission throughout the follow-up period. Furthermore, they should be counseled as to the symptoms of primary HIV-1 infection and the need to return immediately for HIV antibody and virologic testing if they develop such symptoms. However, unless primary infection is being considered, virologic testing such as measures of plasma HIV-1 RNA should be discouraged because of the potential for false positives (9, 29). To reduce psychological stress during the course of follow-up, individuals should also be told that most seroconversions occur during the first 6 weeks after an exposure, and that the likelihood of infection declines with time.

Non-Occupational Exposure

               The clinical data supporting PEP for non-occupational exposures are scarce and most evidence is derived from studies of experimental mucosal and intravenous challenges in primates using NRTIs. One of the few studies demonstrating protection was in a macaque model using SIV and TDF with optimal protection occurring when therapy was started within 24 hours of exposure (36, 37). Although studies in humans of occupational exposure and vertical transmission suggest potential benefits of PEP, individuals need to recognize the limitations of extrapolating these experiences to PEP in the non-occupational setting. Nevertheless, updated guidelines have recently been released by the Department of Health and Human Services in the United States that provide guidance for those managing these exposed individuals (2). Although definitive efficacy trials are unlikely to ever exist, pilot data has demonstrated the feasibility of providing non-occupational PEP in the community (18). Moreover, modeling has suggested that such treatment may be cost-effective when the source is known to be HIV1-infected or after high risk exposures, such as unprotected receptive anal intercourse with a homosexual or bisexual man of unknown serostatus (27).

               Individuals who present for care after a potential sexual, percutaneous, or other non-occupational exposure should be interviewed as to the type of their exposure, and counseled as to the potential risks and benefits of PEP in this setting, as well as ways to prevent future exposures. Underlying depression and/or substance abuse that may contribute to people repeatedly placing them at risk should be identified and individuals referred to community resources to assist in dealing with these underlying problems.

Non-Occupational Exposure: Evaluation of Source Person and Type of Exposure

               The risk of infection during sex is likely to be related to several factors, including the partner's viral load, type of bodily fluid to which the exposure occurred, and presence of genital inflammation (20, 28, 39). The risk of transmission will also vary based upon the type of sexual exposure. The greatest risk is associated with receptive anal intercourse (0.1-3%) and vaginal intercourse (0.1-0.2%) (24, 39). There is a lower but real risk associated with oral sexual exposures (30). The risk of transmission may be further increased if sexual exposure is to blood, such as during menses in HIV-infected women or with associated trauma. Moreover, the presence of genital ulcer disease or inflammatory genital lesions may further increase the risk of transmission. Needle sharing is also associated with an estimated 0.67% chance of infection, approximating that seen with percutaneous exposures in occupational settings (19, 34). An assessment of the source should include their history of antiretroviral therapy use in order to estimate the potential that the person may harbor drug-resistant virus. This assessment is generally done by history since treatment decisions need to occur long before resistance testing could be made available.

Considerations for Treatment

               Those who present after a non-occupational exposure should be interviewed as to the circumstances and timing of the exposure. Animal data supports initiation of PEP within the first two hours with diminished value after 24-36 hours. Current guidelines recommend PEP in those presenting within 72 hours of a substantial exposure to a source partner known to be HIV-infected. Substantial risk is defined as exposure of vagina, rectum, eye, mouth or other mucous membranes, as well as to non-intact skin or percutaneously to potentially infectious material such as blood, semen, vaginal secretions, rectal secretions, breast milk or other body fluids that are visibly contaminated with blood. In the case where the source partner is not known the decision to start PEP should be individualized based upon the type of exposure and what is known of the potential risk factors of the source person. In contrast, those presenting more than 72 hours after such an exposure should not necessarily be offered such treatment (2). Recommendations further support the use of PEP in those victims of assault that include substantial exposure to potentially infectious fluids.

               Subjects should be informed of the experimental nature of PEP in this setting, as well as the risks and benefits of therapy as outlined in the sections related to occupational exposures. They should also be offered follow-up testing and counseling regarding behavior modification, adherence to antiretroviral therapy, and the symptoms of acute HIV-1 infection. There have also been concerns raised as to whether the availability of PEP may lead to increased risk-taking behavior (22). While this concern emphasizes the need for behavioral counseling, reassurance comes from studies showing that the provision of non-occupational PEP has not resulted in increased high-risk behavior (23). Finally, those younger than age 16 should be evaluated, prior to initiation of therapy by a pediatrician or family physician familiar with the use of antiretroviral therapy in children and adolescents. This initial evaluation might include investigation of possible child abuse and deal with issues of consent for medical care of minors.

Antiretroviral Therapy for Non-Occupational PEP

               The administration of antiretroviral therapy after non-occupational exposure to HIV-1 is of unproven efficacy, many clinicians are routinely asked to provide such treatment. As outlined in recent guidelines, therapeutic options largely parallel those of current recommendations for treatment of chronically HIV-1-infected adolescents and adults (2). Although it is acknowledged that in this setting there is no evidence that three drug regimens are better than two, preferred options include PI-based treatment with lopinavir/ritonavir (LPV/r, KaletraTM) and ZDV with either 3TC or FTC, or these NRTIs with one of several alternative PIs. Another preferred option includes EFV with either ZDV or TDF along with either 3TC or FTC, remembering that EFV should be used with caution in women of child-bearing potential. As with occupational PEP, NVP should be avoided in this setting. In addition, exposed individuals should be assessed for sexually transmitted diseases and the need for emergency contraception (35). Finally, as described for occupational PEP follow-up should be performed to assure that infection by HIV, HBV and HCV does not occur as well as for drug-related toxicity.

Conclusion

               There are animal and human data that suggest the provision of antiretroviral therapy after occupational and non-occupational exposure may reduce the risk of HIV-1 transmission. Based upon these data the CDC and other agencies have developed guidelines for when therapy should be considered in each of these settings. Recommendations focus on providing treatment to those with a true risk of acquiring HIV-1-infection, and when there is believed to be potential benefit of such therapy, such as when initiated within 72 hours of the exposure. Since there are no randomized-controlled studies defining the utility of PEP, yet alone the optimal treatment regimen to use, guidelines have approximated those for the treatment of chronically HIV-1-infected adolescents and adults, although avoiding drugs with substantial short-term toxicity. Nevertheless, it remains important to counsel subjects as to the risks of such treatment. Moreover, the initial meeting with an exposed individual should be used as an opportunity to address behavioral changes, both in the work place and the community that might result in avoiding exposures in the future.

 

Tables

Table 1.  Recommended HIV Post-Exposure Prophylaxis (PEP) for Occupational Percutaneous Injuries  [Download PDF]

Table 2.  Recommended HIV Post-exposure Prophylaxis (PEP) for Mucous Membrane Exposures and Non-Intact Skin Exposures  [Download PDF]

Table 3. Occupational Exposure Management Resources

 

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