Nevirapine is a nonnucleoside reverse transcriptase inhibitor proven effective as a part of highly active antiretroviral therapies for HIV infection and for prevention of placental transfer of HIV. 1 Nevirapine does not require phosphorylation to an active metabolite, 2 and it has a high oral bioavailability with a long half-life. 3 HIV viral load undetectability occurs shortly after the initiation of nevirapine-containing HIV regimens in HIV-1–positive patients. 4 Major adverse reactions, including skin rashes and hepatotoxicity, occur in <1% of HIV-infected individuals. 5 Review of 4 randomized clinical trials, which included 2700 subjects on either nevirapine or placebo, identified a 3.4% 1-year rate of hepatitis or related hepatic events. Higher rates of hepatic toxicity were observed among persons who had higher CD4+ levels. 6
The pharmacokinetic properties of nevirapine are theoretically advantageous in the setting of postexposure prophylaxis (PEP). Enthusiasm for this use diminished when reports appeared of non–HIV-infected health care workers (HCWs) and sexual contacts who developed hepatotoxicity following use of a nevirapine-containing PEP regimen. 7–11 As with all new agents, however, a comprehensive safety assessment requires diligent postmarketing surveillance. Safety considerations are especially important when pharmaceutic agents are used “off label” in the clinical setting. Based on reports of severe hepatotoxicity in PEP patients and the absence of supportive clinical trials in this population, the Centers for Disease Control and Prevention (CDC) cautioned against the use of nevirapine for PEP. 9 Herein, we describe the clinical and laboratory findings of cutaneous or hepatic toxicity that occurred when non–HIV-infected individuals received short-term nevirapine therapy.
Individual case histories of nevirapine-associated cutaneous or hepatic toxicity occurring among non–HIV-infected individuals were obtained from MedWatch, the US Food and Drug Administration's (FDA) passive reporting system (n = 19), 7 queries of HIV specialists (n = 6), the pharmaceutic supplier of nevirapine (n = 8), and published reports (n = 9). 10–16 Severe hepatotoxicity was characterized as Eastern Cooperative Oncology Group (ECOG) grade 3 or 4 (>5 times normal elevations in hepatic transaminases: alanine aminotransferase [ALT] or aspartate aminotransferase [AST], alkaline phosphatase [Alk Phos], and/or >1.5 times normal elevation in total bilirubin). Severe cutaneous toxicity was characterized as ECOG grade 3 or 4 (generalized symptomatic macular, papular, or vesicular eruption; exfoliative dermatitis; or ulcerating dermatitis). A serious adverse event was operationally described as an event that resulted in hospitalization, resulted in loss of time from work, was permanently or severely disabling, resulted in death or liver transplantation, and/or required emergency medical attention. Liver biopsies were reviewed by 2 experienced hepatologists for 2 non–HIV-infected HCWs who developed severe hepatic toxicities. The rates of nevirapine-associated cutaneous and hepatic toxicities were obtained from 2 sources: an unpublished phase 1 trial, where 41 non–HIV-infected volunteers received nevirapine (Maureen Oakes, Pharm D, Boehringer-Ingelheim, personal communication, December 13, 2000), and a survey of 5 occupational health programs in Chicago that prescribed nevirapine-containing PEP regimens after occupational exposures to HIV-infected blood or body fluids. 16
Nevirapine-associated ECOG grade 3 or 4 cutaneous toxicity without hepatic involvement was noted in 12 non–HIV-infected individuals (7 HCWs, 1 child, and 4 other adults) at a median of 9 days after initiation of PEP (range: 7–12 days) (Table 1). Exposure occurred via a needlestick (7 cases), fluid splash (1 case), and unknown route (4 cases). PEP was taken for a median duration of 13 days (range: 6–30 days). The recommended lead-in nevirapine dose of 200 mg once daily for 2 weeks prior to the 200-mg twice-daily schedule was used for 75% of the cases. Extracutaneous symptoms included fever (5 cases) and rhabdomyolysis (1 case). Three patients developed Stevens-Johnson syndrome. Four individuals were hospitalized for cutaneous toxicity events. After discontinuation of nevirapine, all the affected individuals rapidly improved.
Thirty non–HIV-infected individuals (12 HCWs, 3 sexual contacts of HIV-infected individuals, 8 clinical trial participants, and 7 other individuals) developed hepatotoxicity after a median of 20.5 days (range: 8–35 days) of nevirapine treatment (Table 2). Findings included grade 3 or 4 hepatotoxicity (n = 14), fevers (n = 11), skin rashes (n = 8), eosinophilia (n = 6), and fulminant hepatic necrosis requiring an orthotopic liver transplant (n = 1). No other causes for rashes or severe hepatotoxicity were identified. After discontinuation of nevirapine, all but 2 of these non–HIV-infected individuals improved within a median of 21.5 days (range: 14–60 days). Hepatotoxicity persisted in 1 HCW for 2 months after discontinuation of the nevirapine-containing PEP regimen; at that time, a course of corticosteroids was initiated, and 2 months later, the hepatotoxicity resolved. One HCW developed fulminant hepatic necrosis and coma and received a liver transplant 14 days after discontinuation of the nevirapine-containing PEP regimen. None of the non–HIV-infected individuals developed a positive serologic test for HIV or hepatitis C infection. Liver biopsy material showed extensive hemorrhagic central zonal necrosis, portal tract eosinophils, and lymphocytes in 1 non–HIV-infected HCW who developed fulminant hepatic necrosis (patient 15, see Table 2) and central zonal cholestasis with bile canalicular plugs, mild portal tract eosinophils, and no hepatocyte necrosis in 1 non–HIV-infected HCW who developed gradual but progressive jaundice that improved with 2 months of corticosteroids and discontinuation of nevirapine (patient 17, see Table 2).
Some information was available that allowed for rate estimation of severe nevirapine-associated hepatic or cutaneous toxicity in the setting of non–HIV-infected individuals. During a phase 1 trial with 41 non–HIV-infected volunteers who received between 6 and 15 days of nevirapine, 4 individuals developed nevirapine-associated grade 1 or 2 hepatotoxicity (10%) and 4 developed grade 3 or 4 hepatotoxicity (10%) (Maureen Oakes, Pharm D, Boehringer-Ingelheim, personal communication, December 13, 2000). The hepatic toxicity reversed rapidly with drug discontinuation. Among 8 HCWs in Chicago who received nevirapine-containing PEP regimens, 5 (62%) developed grade 3 or 4 hepatotoxicity.
Nevirapine is a potent nonnucleoside inhibitor of HIV-1 reverse transcriptase. When used in combination with nucleoside analogue reverse transcriptase inhibitors, it produces significant and sustained reductions in HIV viremia. In this study, we have described the clinical and laboratory findings of cutaneous or hepatic toxicity that occurred in 42 non–HIV-infected individuals who received nevirapine-containing antiretroviral therapies. Cutaneous toxicity and hepatic toxicity were not always linked, and severe life-threatening reactions such as Stevens-Johnson syndrome and fulminant hepatic failure were seen in different individuals. In interpreting our findings, several factors should be considered.
First, attribution of the cause of hepatotoxicity can be difficult. 17 Stavudine, a nonnucleoside HIV-1 reverse transcriptase inhibitor used by the majority of the patients with PEP in our series, is the most commonly reported agent causing mitochondrial toxicity and hepatitis, but this toxicity has also been seen with lamivudine, zidovudine, and didanosine. 18 The manifestations of mitochondrial toxicity may include fulminant hepatitis without fever and eosinophilia. Lactic acid levels that are usually markedly elevated with mitochondrial toxicity were only mildly elevated when measured for several cases in our study. Also, the histologic hallmark of mitochondrial toxicity, microvesicular hepatic steatosis, was not identified in liver biopsy materials obtained from 2 individuals in this study. In some cases, hepatic toxicity can result in an immune-mediated liver injury, in which neoantigens are generated as a consequence of a reaction between liver proteins and reactive drug metabolites. 19
Second, our study raises concern that individuals without immunodeficiency are at greater risk for the development of nevirapine-associated hepatotoxicity, which may occur in conjunction with rash and eosinophilia. An unpublished phase 1 clinical trial and a survey of occupational health programs identified high rates of nevirapine-associated toxicity among non–HIV-infected individuals. 16 A study from London identified a 20% rate of grade 3 or 4 hepatotoxicity among 49 non–HIV-infected HCWs or sexual contacts who received nevirapine-containing PEP regimens. 11 Hypersensitivity reactions consisting of rash, peripheral eosinophilia, constitutional symptoms, and hepatic dysfunction have been reported among HIV-infected individuals, typically within the first 2 months of treatment. 20–22 If the hypersensitivity reactions were mediated by CD4 lymphocytes, this could account for the occurrence of hepatotoxicity among non–HIV-infected individuals.
The primary treatment of hypersensitivity syndromes is removal of the causative agent. Although corticosteroid administration is controversial, this therapy has been used when symptoms are severe. 22,23 There are case reports where corticosteroids have been useful for the treatment of the nevirapine-associated hepatic toxicity that occurs in conjunction with hypersensitivity reactions. 24–29 Of the non–HIV-infected HCWs with severe hepatic toxicity after use of a nevirapine-containing PEP regimen described in this report, 2 did not improve until high-dose prednisone was administered. In contrast, randomized clinical trials have shown that corticosteroids do not prevent the development of nevirapine-associated cutaneous toxicity. 30,31
It is important to note that our findings do not apply to single-dose nevirapine use for the prevention of perinatal HIV transmission. To date, no serious toxicity has been reported among mother–infant pairs who receive single-dose nevirapine prophylaxis regimens, and nevirapine has been proven to be one of the most effective agents in this setting.
Third, identifying rare but serious adverse drug reactions infrequently occurs during clinical testing. Three methods exist for identifying adverse drug reactions in the postmarket approval period. 27,28 The first is the MedWatch program, in which health care professionals are encouraged on a voluntary basis to submit details of serious events that may have been caused by any FDA-regulated product. Although reports can be transmitted by telephone, telefax, mail, or the Internet, only 1% to 10% of serious events that might represent an adverse drug reaction are reported. 27 Less than half of the cases in this study were included in MedWatch reports. The second method, postmarketing cohort studies, is unlikely to provide information about nevirapine toxicity in non–HIV-infected individuals, because no clinical studies in the setting of PEP have been initiated. The third method, conducting active surveillance, is often the best method for identifying toxicities of drugs. Active surveillance in this study included obtaining case histories from physicians who directed employee health programs in our local area. Previously, we used similar methods to identify cases of another rare but potentially fatal adverse drug reaction, ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura. 29,32
In conclusion, nevirapine is commonly used for the treatment of HIV-infected individuals and for prevention of perinatal transmission of HIV. Non–HIV-infected individuals who receive nevirapine are at risk for the development of severe and potentially life-threatening cutaneous and hepatic toxicity. Although precise estimates of the risk for severe hepatotoxicity are not available, the risk appears to be higher than in HIV-infected persons and may be associated with higher CD4 counts. Therefore non–HIV-infected individuals should not receive PEP or other prophylaxis regimens that include multiple doses of nevirapine.
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