Nevirapine belongs to the class of the non-nucleoside reverse transcriptase inhibitors and, when used in combination therapy, has proven to be equally effective in the treatment of HIV-infection when compared to protease inhibitor-containing regimens [1,2]. Overall, nevirapine has a favorable safety profile, and thereby provides an attractive option when a protease inhibitor-sparing regimen is preferred . The most common and limiting toxicities of nevirapine are rash and increases in liver transaminases . Usually, these adverse effects occur during the first 12 weeks of treatment requiring discontinuation of nevirapine in 2–7% of the patients [5–7], although late onset hepatitis associated with nevirapine therapy has also been described . Martinez et al.  reported clinical hepatitis with an incidence of 1.1% in an unselected sample of HIV-1-infected individuals. Underlying factors such as chronic hepatitis C infection (HCV) and other hepatotoxic agents may, however, have played a part in these individuals.
Besides several case reports [7,9–11], we are aware of only two studies reporting on acute clinical hepatitis in an unselected outpatient population [6,12]. In contrast with these two studies, however, we observed a higher incidence of acute clinical hepatitis in our outpatient population. In addition, patients developed acute clinical hepatitis in a shorter period after start of nevirapine  but recovered in a shorter period of time than reported earlier . We, therefore, wanted to evaluate the characteristics of these patients who developed acute clinical hepatitis in this unselected outpatient population.
Subjects were selected from a cohort of patients with HIV-1 infection referred to the Department of Internal Medicine of the Slotervaart Hospital, Amsterdam, where they were treated by an infectious disease specialist. Patients who started a nevirapine-containing regimen in the period January 1999 to February 2001 and presented with clinical symptoms in accordance with increased transaminase values (higher than the upper limit of normal) within 12 weeks of initiation of nevirapine were considered possible cases of clinical hepatotoxicity. According to standard procedures, each HIV-1-infected patient is tested at the first visit to the outpatient clinic for the presence of hepatitis B surface antigen, anti-hepatitis A antibodies, and anti-hepatitis C antibodies. Patient characteristics, medication, HIV-1 RNA levels, and clinical chemistry parameters were collected from outpatient medical records and clinical medical records.
During the study period, 306 patients started a nevirapine-containing regimen; eight of these developed acute hepatitis (incidence 2.6%). Table 1 presents the characteristics of these eight patients at baseline (before starting the nevirapine-containing regimen). All patients were Caucasian, two were female and the median age was 37 years. Four patients had an undetectable plasma HIV-1 RNA at baseline due to successful prior therapy with a protease inhibitor-containing regimen and four patients were antiretroviral naive. All patients had normal transaminase levels at baseline except patients 3 and 8 (Table 1, Fig, 1).
Overall, patients reported clinical symptoms that were interpreted as a hepatic reaction after the introduction of their new antiretroviral regimen in a median of 24 days [interquartile range (IQR), 20–25 days], whereas transaminases peaked at 28 days (IQR, 27–32 days) (Table 2, Fig, 1).
As shown in Table 2, the injury pattern is in general mixed-hepatocellular. Aspartate aminotransferase and/or alanine aminotransferase values (the highest of the two was used for grading) were graded according to the criteria of the AIDS Clinical Trial Group , yielding one patient with grade 2 toxicity, five patients with grade 3 toxicity, and two patients with grade 4 toxicity. Two patients (patients 3 and 7) experienced eosinophilia during the peak of the transaminases.
Clinical symptoms and signs of the acute hepatitis are outlined in Table 2. Rash occurred in conjunction with the hepatic reaction in five of the eight patients. These patients were treated with cetirizine plus prednisone (n = 4) or only prednisone (n = 1). Patients with only constitutional symptoms (without rash) were not treated, but their condition improved rapidly following withdrawal of the antiretroviral drugs including nevirapine.
Patients 3 and 4 were admitted to the hospital for 5 and 2 days, respectively. An abdominal ultrasound performed on patient 3 revealed a mild hepatomegaly with diffuse steatosis of the liver. Physical examination on patient 4 revealed no remarkable abnormalities.
Five patients discontinued nevirapine including the nucleosides. The other three patients discontinued only nevirapine (patients 2, 5 and 8). This resulted in a relatively rapid decrease in the transaminases in all patients (see Fig. 1), reaching normal values in a median time of 44.5 days (IQR, 28.8–46.3 days). Clinical symptoms revealed in seven patients within 15 days and in one patient (patient 1) in 37 days.
The patients in this case series all experienced an acute hepatitis with constitutional symptoms, sometimes including rash, within a maximum of 31 days after initiation of a new antiretroviral regimen including nevirapine. Two types of hepatotoxicity have been encountered in nevirapine-containing therapy. The first might represent an intrinsic toxic effect, as it does not involve other organs and has a delayed onset (> 12 weeks) [6,8]. The second involves elevations in transaminases, constitutional symptoms sometimes including skin reactions, and it develops quickly (< 12 weeks) after initiation of nevirapine-containing treatment, suggesting an immune-mediated mechanism [7,9,11]. Patients in our case series probably experienced the latter mechanism, because of the short onset, in some cases in conjunction with rash (n = 5) or eosinophilia (n = 2), and the observed clinical symptoms.
The observed delay in the peak of transaminase levels after onset of clinical symptoms was probably caused by the determination of transaminases as a consequence of the symptoms and, thus, in most cases performed after the occurrence of the symptoms. However, three patients (patients 1, 3 and 4) had two laboratory results after the occurrence of symptoms, of which the second showed the peak in transaminases.
All nucleosides have been associated with hepatic steatosis , but stavudine (d4T) is the drug that is typically related to this adverse event [15,16], especially in combination with nevirapine . Hepatic steatosis develops secondary to the ability of nucleosides to inhibit the mitochondrial DNA polymerase γ, the enzyme required for replication of mitochondrial DNA. Disease symptoms appear when the mitochondrial energy-generating capacity falls below the energetic threshold of an organ. Therefore, these toxicities generally emerge only in long-term antiretroviral therapy. The four antiretroviral naive patients received lamivudine (3TC) plus zidovudine (ZDV; n = 3) and 3TC plus d4T (n = 1) besides nevirapine, and just started their first antiretroviral regimen, probably excluding mitochondrial toxicity in these cases as the primary cause. The pretreated patients received 3TC plus d4T or 3TC plus ZDV as a backbone for at least 7.4 months (range, 7.4–21.3 months) without elevations of transaminases. Patient 8 had relatively high transaminases at baseline, but in the preceding period normal values were observed.
Seven of the eight patients have commenced antiretroviral treatment (without nevirapine) again after recovery of the hepatic reaction. No problems were encountered in these seven patients, except for one patient (patient 3) who had elevations in transaminases again after the introduction of d4T, 3TC, and abacavir, and the disturbances in transaminases persisted when therapy was changed to 3TC, ZDV and nelfinavir. In this case it is not certain if nevirapine was the culprit in the first hepatic reaction, because this patient already had elevated transaminases at baseline. However, the shortness of his therapy (24 days) before the development of symptoms, makes d4T as the primary cause disputable.
One patient (patient 6) also had chronic hepatitis B infection (HBV), and increases in liver enzymes have been described in patients with HBV because of immune-restoration caused by highly active antiretroviral therapy (HAART) . This patient (patient 6), however, was pretreated with HAART and had high CD4 cell counts, making HBV less likely to be a contributor.
Several factors associated with an increased risk of developing hepatotoxicity during nevirapine-containing treatment have been described. These include HBV and HCV, baseline levels of transaminases, baseline CD4 cell count, concomitant use of other hepatotoxic agents, and duration of prior exposure to antiretroviral drugs [6,19–21]. Patients in our case series had CD4 cell counts ranging from 230 to 890 × 106 cells/l, and four were antiretroviral naive, one patient had HBV, no patients had HCV, and only two patients had elevated levels of transaminases at baseline. Thus, these patients differ greatly in their characteristics, and no specific risk factor applying to all patients could be identified.
At our hospital, nevirapine is a frequently prescribed antiretroviral drug, being part of HAART in both first- and second-line treatment. Compared to the incidence reported in the literature (1.1%) , the incidence observed at our institute is fairly high (2.6%). The reason for this is unclear.
In conclusion, the patients in this case series developed a hepatic reaction rapidly after introduction of a nevirapine-containing regimen. Nevirapine was probably the cause of this syndrome. Withdrawal of the antiretroviral agent led to rapid restoration in transaminases and resolution of clinical symptoms. The reason for developing this hepatic reaction is not clear in every case as no specific risk factor that applied to all of the patients in this group could be identified. However, increased transaminase levels accompanied the observed clinical symptoms in every patient. It is, therefore, very important to monitor closely transaminase levels of all patients starting a nevirapine-containing regimen, including patients with hitherto no specific characteristics that put them at risk. The rapid onset of the clinical symptoms suggests that determination of transaminase levels needs to be done in a very early stage (i.e., within 2 weeks of initiation) of the nevirapine-containing regimen.
We thank H. Paap for help with data collection.
Sponsorship: Supported by AGIS Health Insurances, Amsterdam, the Netherlands.
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