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HIV Protease Inhibitors

The fact that hyperglycemia, new-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and diabetic ketoacidosis have occurred in HIV-infected individuals receiving HIV protease inhibitors should be considered when these drugs are used during pregnancy. Because pregnancy is itself a risk factor for hyperglycemia and it is not known whether use of an HIV protease inhibitor exacerbates this risk, glucose concentrations should be monitored closely in pregnant women receiving these drugs and these women should be advised about the warning signs of hyperglycemia and diabetes (e.g., increased thirst and hunger, unexplained weight loss, increased urination, fatigue, dry or itchy skin).

HIV Protease Inhibitors

Because hyperbilirubinemia (generally reported as an increase in indirect bilirubin) has been reported in nonpregnant individuals receiving indinavir, there is a theoretical concern that use of indinavir during late pregnancy, especially near the time of labor, potentially could exacerbate physiologic hyperbilirubinemia in the neonate

Because hyperbilirubinemia has been reported in individuals receiving atazanavir sulfate, the possibility exists that use of the drug in pregnant women could exacerbate physiological hyperbilirubinemia resulting in kernicterus in the neonate and young infant.

The liquid formulation of amprenavir contains propylene glycol (550 mg/mL); amprenavir oral solution should not be used in pregnant women.

Nonnucleoside Reverse Transcriptase Inhibitors

Efavirenz has been associated with teratogenic effects in primates at drug exposures similar to the recommended human dosage, and the drug should not be used in women of childbearing potential unless pregnancy has been excluded and appropriate measures are taken to avoid pregnancy.

HIV Protease Inhibitors

Nevirapine has been used in pregnant HIV-infected women for prevention of maternal-fetal transmission of HIV without unusual adverse effects to the woman or fetus.

Percutaneous Exposure

Based on analysis of data pooled from several prospective studies, the risk of HIV transmission following a percutaneous injury has been estimated to average about 03% (range: 0.1-0.5%). The risk appears to be greatest for percutaneous exposures involving a large blood volume and/or a source patient with advanced disease. Data from a retrospective case-control study using information reported to national surveillance systems in the US, France, and United Kingdom concerning health-care workers with documented occupational percutaneous exposure to HIV-infected blood (i.e., needlestick injury or cut with a sharp object such as a scalpel or lancet) and no other concurrent exposure to HIV indicate that the risk of transmission is greatest for percutaneous exposures involving a deep injury and is increased for exposures with visible blood on the device causing the injury, injury involving a device previously placed in the source patient's vein or artery (e.g., a phlebotomy needle), or an injury involving a source patient whose death occurred within 60 days after the incident as a result of AIDS.

Mucous-membrane Exposure

The risk of HIV transmission for each episode of mucous membrane exposure to HIV-positive blood is probably too low to measure accurately, but has been estimated to be about 0.09%. In documented cases of HIV transmission following mucous membrane exposure, factors that appeared to contribute to transmission of the virus included a large volume of blood and prolonged duration of contact.

Skin Exposure

The risk of transmission following nonintact skin exposures to HIV-positive blood has not been precisely quantified, but is estimated to be less than that following mucous membrane exposures. There have been documented episodes of HIV transmission from nonintact skin exposures. Compared with exposures that involve intact skin, the risk of HIV transmission presumably would be increased for skin exposures involving an area where skin integrity is visibly compromised.

Options for Postexposure Prophylaxis

While initial recommendations for PEP involved zidovudine monotherapy, the CDC and most clinicians currently recommend the use of multiple-drug regimens that include 2 or 3 antiretroviral agents for occupational exposures associated with a risk of HIV transmission. The recommendation for use of 2 or 3 antiretroviral agents for PEP is based on evidence that regimens that include at least 2 agents have been more effective than zidovudine monotherapy for the treatment of HIV infection and the fact that it is highly likely that occupational exposures to HIV-positive materials will involve resistant strains of HIV. There are documented cases when use of zidovudine alone failed to prevent HIV infection following occupational exposure to the virus.

For most situations when PEP is warranted because of a recognized risk of transmission of HIV, the CDC recommends use of a basic 2-drug oral regimen of zidovudine and lamivudine or, alternatively, lamivudine and stavudine or didanosine and stavudine given for 4 weeks. For occupational exposures associated with an increased risk for HIV transmission, the CDC recommends addition of third antiretroviral agent (usually indinavir, nelfinavir, efavirenz, or abacavir). While this highly potent 3-drug expanded regimen may be justified for exposures associated with an increased risk for HIV transmission or when the source is known or suspected to be infected with HIV strains resistant to the drugs used in the basic regimen, whether the potential added toxicity of a third drug is justified for lower risk exposures is uncertain.

The CDC acknowledges that recommendations regarding which drugs to include in the PEP regimen are largely empiric. Although the commercially available fixed combination preparation containing zidovudine and lamivudine (Combivir®) is convenient for use in the basic 2-drug regimen, recent data suggest that mutations associated with zidovudine and lamivudine resistance are common in some areas and individual clinicians might prefer other NRTIs or combinations based on local knowledge and experience in treating HIV infection and disease. The CDC states that ritonavir, saquinavir (given as liquid-filled [soft gelatin] capsules) amprenavir, delavirdine, or the fixed combination of lopinavir and ritonavir should be used for PEP only with expert consultation; however, use of nevirapine in such regimens is notrecommended.

Since strains of HIV resistant to each of the currently available antiretroviral agents have been reported and horizontal or vertical transmission of resistant strains can occur, consideration can be given to whether the HIV source is known or suspected to be infected with resistant HIV. Recent studies have demonstrated an emergence of drug-resistant HIV among source individuals involved in occupational exposures, and transmission of resistant HIV, despite PEP with a multiple-drug regimen has been reported. Resistance should be suspected in source individuals experiencing clinical progression of disease or a persistently increasing viral load and/or decline in CD4+ T-cell count despite antiretroviral therapy or lack of virologic response to therapy. However, resistance testing of the source virus at the time of an exposure is not practical because results will not be available in time to influence the choice of the initial PEP regimen. In addition, data are insufficient to date to determine whether modifications to the recommended regimens are necessary or will influence the outcome of PEP. No data exist to suggest that modification of the PEP regimen after receiving results of resistance testing (usually a minimum of 1-2 weeks) improves efficacy of the regimen.

To assist with the initial management of an HIV exposure, health-care facilities should have drugs for an initial PEP regimen selected and available for use. Whenever possible, regimens for PEP should be implemented in consultation with experts in antiretroviral treatment and HIV transmission.

HIV Protease Inhibitors

Safety and Efficacy of Postexposure Prophylaxis

Efficacy of PEP has been difficult to determine because of the low incidence of occupational exposures to HIV and the low seroconversion rate following such exposure Results of a retrospective case-control study suggest that the risk for HIV infection in health-care workers who received zidovudine monotherapy for PEP following percutaneous exposure to HIV-positive blood was reduced by approximately 81%. This study included data reported to national surveillance systems in the US, France, and United Kingdom on health-care workers who had documented occupational percutaneous exposure to HIV-infected blood (i.e., needlestick injury or cut with a sharp object such as a scalpel or lancet) and no other concurrent exposure to HIV.

Although data are not available from prospective or retrospective studies evaluating efficacy of zidovudine used in conjunction with other antiretrovirals for PEP in exposed health-care workers, there is substantial evidence involving the treatment of HIV infection that indicates that regimens that include zidovudine and 1 or 2 other antiretroviral agents are more effective than zidovudine monotherapy, have increased antiretroviral activity compared with use of zidovudine alone, and are active against many zidovudine-resistant strains of HIV.

Prophylaxis Failures

Despite indications that zidovudine prophylaxis can decrease the risk of HIV transmission following occupational exposure, there have been documented cases where PEP with zidovudine monotherapy failed to prevent transmission of HIV in health-care workers or others exposed to the virus. Although zidovudine prophylaxis was initiated within 0.5-12 hours in most of these individuals, most experienced an acute retroviral illness 13-75 days (median: 22 days) after exposure and seroconverted within 6 months. The CDC states that there have been at least 21 cases of failure of PEP in health-care workers (16 received zidovudine alone, 2 received zidovudine and didanosine, 3 received at least 3 antiretroviral agents). Some of these cases may have involved resistant HIV; other factors that may have contributed to these apparent failures might include a high viral load and/or large inoculum exposure, delayed initiation of PEP and/or short duration of prophylaxis, and factors related to the host (e.g., cellular immune system responsiveness) and/or the source individual's HIV (e.g., presence of syncytia-forming strains).

There has been at least one report of prophylaxis failure in a health-care worker who received a 6-week multiple-drug PEP regimen (zidovudine, lamivudine, indinavir, and didanosine) initiated within 40 minutes following a needle-stick injury that occurred while drawing blood from a parenteral drug abuser who was infected with HIV and hepatitis C virus (HCV). The health-care worker became HIV-positive and HCV-positive about 6 weeks after PEP was finished; HIV isolated from the health-care worker had a mutation associated with low-level zidovudine resistance and HIV isolated from the source patient had a mutation associated with lamivudine resistance but not the one associated with low-level zidovudine resistance. There have been 2 other reports of health-care workers allegedly seroconverting despite PEP with a multiple-drug regimen after occupational exposure to HIV; however, epidemiologic investigations and viral sequence comparisons indicated that HIV transmission in these 2 cases did not occur as a result of the reported occupational exposure.

Adverse Effects of Postexposure Prophylaxis

Although there is no evidence to date that any unusual adverse effects occur when antiretrovirals are used in healthy individuals for PEP, multiple-drug regimens currently recommended for PEP in health-care workers can be associated with a high incidence of adverse effects and these effects may adversely affect compliance with the regimens. In addition, serious adverse effects (e.g., nephrolithiasis, hepatitis, pancytopenia) have been reported rarely in health-care workers receiving antiretroviral regimens for PEP. There is some evidence that adverse effects and discontinuance of PEP are more common among health-care workers taking a 3-drug PEP regimen than among those taking a 2-drug regimen.

Information regarding tolerability of multiple-drug regimens used for PEP in health-care workers following occupational exposure to HIV is available from the Human Immunodeficiency Virus Postexposure Prophylaxis (HIV PEP) Registry, a prospective surveillance project that collected data from October 17, 1996 through March 31, 1999 and was sponsored by the CDC and 2 antiretroviral agent manufacturers. The registry (now closed) included data on 492 US health-care workers (71% female, median age: 37 years) who received PEP following an occupational exposure to HIV (63% received a regimen containing 3 or more antiretroviral agents). Overall, 76% of health-care workers for whom 4- to 6-week follow-up was available reported some symptom or adverse effect. The most frequent adverse effects were nausea (57%), fatigue/malaise (38%), headache (18%), vomiting (16%), and diarrhea (14%) and these effects generally were evident within 3-4 days after initiation of the PEP regimen. Of those who discontinued all drugs before completion of the PEP regimen, 50% did so because of adverse effects. A variety of PEP regimens were used (e.g., zidovudine monotherapy; zidovudine and lamivudine with or without indinavir; zidovudine, lamivudine, and saquinavir), and it was not possible to correlate toxicity with any particular drug. Although there were no reports of unusual adverse effects, serious adverse effects requiring dosage reduction or discontinuance of the PEP regimen (high fever and rash; adverse renal effects such as renal calculi, flank pain, and hematuria; adverse GI effects such as intractable vomiting or nausea; involuntary muscle movements or adverse ophthalmic effects) were reported in 6 health-care workers. All reported adverse effects resolved following completion or discontinuance of PEP.

Additional information regarding adverse effects reported in health-care workers who received multiple-drug regimens for PEP is available from individual case reports or small prospective and retrospective studies in individual health-care facilities. In one facility, 68 health-care workers received PEP (zidovudine and lamivudine with or without indinavir) and 75% reported at least one adverse effect; adverse effects were more frequent in those receiving the 3-drug regimen and many failed to complete the 28-day regimen because of adverse effects. In a small retrospective study, most individuals who discontinued or modified their PEP regimens did so because of intolerable adverse effects that appeared to be related to indinavir (e.g., uncontrollable vomiting, nausea, or reflux; urticaria; galactorrhea with hyperprolactinemia). In a prospective study in France that evaluated adverse effects reported with a PEP regimen of zidovudine, lamivudine, and nelfinavir, 85% experienced at least one adverse effect (diarrhea, nausea, and vomiting were reported most frequently) and 25% discontinued nelfinavir from the regimen because of adverse effects.

Severe reactions, consisting of pruritic rash on the abdomen, back, and extremities with fever, nausea, headache, vomiting, lymphocytopenia, and elevated liver enzymes have been reported in at least 2 otherwise healthy adults receiving zidovudine in conjunction with zalcitabine for PEP of HIV following occupational exposure to the virus. Serious adverse effects, including hepatotoxicity (e.g., end-stage liver failure requiring transplantation, clinical hepatitis, and elevated serum ALT and AST concentrations without clinical hepatitis), skin reaction, and/or rhabdomyolysis, have been reported in individuals who received multiple-drug PEP regimens that included nevirapine. The CDC recommends that nevirapine not be included in regimens for HIV PEP.

Because a high incidence of adverse effects has been reported in health-care workers receiving PEP following occupational exposure to HIV, careful counseling about such effects may be necessary to improve compliance. It has been suggested that many healthcare-workers who fail to complete the recommended 4-week regimen for PEP often discontinue the regimen because of GI effects (e.g., nausea, diarrhea) and that these effects often can be managed without changing the regimen by using antimotility and antiemetic agents or other drugs that target the specific symptoms.

Management of Occupational Exposure to HIV

Each health-care facility should develop an institutional policy for management of occupational exposures that put health-care workers and others at risk of HIV infection. This policy should include appropriate procedures for documenting and reporting such exposures, recommendations for determining the HIV status of the source patient, recommendations for immediate postexposure care and counseling for the exposed health-care worker, and follow-up medical evaluation and counseling for the worker.

The exposure report should include the date and time of exposure; details of the procedure being performed at the time of exposure (including where and how the exposure occurred; if it was related to a sharp device, the type and brand of device and how and when in the course of handling the device the exposure occurred); details of the exposure (including type and amount of fluid or material and severity of the exposure); details about the exposure source (including whether the source material contained HIV or other bloodborne pathogens, the HIV status of the source individual including their stage of disease, viral load, history of antiretroviral therapy, antiretroviral resistance information); details about the exposed individual; and details about counseling, postexposure management, and follow-up.

Treatment of the Exposure Site

Although there are no data demonstrating that immediate cleansing and decontamination of the exposure site reduces the risk of transmission of HIV, laboratory studies with HIV support the use of these procedures and they are strongly recommended as soon as possible after accidental exposures to blood or other potentially infectious fluids or tissue. Wounds and skin sites that have been in contact with blood or body fluids should be washed with soap and water; mucous membranes should be flushed with water. There is no evidence that use of antiseptics for wound care or expressing fluid by squeezing the wound further reduces the risk for HIV transmission; however, use of antiseptics is not contraindicated. The application of caustic agents (e.g., bleach) or the injection of antiseptics or disinfectants into the wound is not recommended.

Assessment of Infection Risk

An assessment of the likelihood of HIV transmission from the exposure should be made, taking into consideration information about the HIV source and the type of exposure.

The exposure should be evaluated for potential to transmit HIV based on the type of body substance involved and the route and severity of the exposure. Exposure to blood, fluid containing visible blood, or other potentially infectious fluid (e.g., semen, vaginal secretions, CSF, and synovial, pleural, peritoneal, pericardial, amniotic fluids) or tissue through a percutaneous injury (i.e., needlestick or other penetrating event) or through contact with a mucous membrane are situations that pose a risk for bloodborne transmission and require further evaluation. In addition, any direct contact (i.e., health-care worker did not use protective equipment or the equipment was ineffective in protecting skin or mucous membranes) with concentrated HIV in a research laboratory or production facility is considered an exposure that requires clinical evaluation to assess the need for PEP.

For skin exposures, follow-up is indicated only if direct contact with a potentially infectious body fluid occurred and there is evidence of compromised skin integrity (e.g., abrasion, open wound, dermatitis).

For human bites, the clinical evaluation must consider possible exposure of both the bite recipient and the person who inflicted the bite. While HIV transmission only rarely has been reported by this route, postexposure follow-up (including consideration of PEP) may be indicated if a bite results in blood exposure to either person involved.

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