Nevirapine

“2024 liveborn infants [in Ethiopia, India and Uganda] randomised in the study had at least one specimen tested before 6 months of age…The modified intention-to-treat population included 986 infants in the single-dose [of Nevirapine] group and 901 in the extended-dose group…393 infants in the single-dose group and 346 in the extended-dose group experienced grade 3 or 4 serious adverse events during the study…Grade 3 and 4 serious adverse events were common. Overall, 1150 serious adverse events were reported in the first 6 months of life in 739 of the 1887 infants in the modified intention-to-treat population. However, the frequencies of specific serious adverse events were similar between groups. 521 (45%) of the serious adverse events were categorised as laboratory abnormalities. The next most frequent events were gastrointestinal conditions (n=184) and respiratory illnesses (n=158)”

“In a recent article, Mallet and colleagues reported a series of eight cases of nodular regenerative hyperplasia (NRH) of the liver as a new cause of chronic liver disease in HIV-infected patients. NRH is characterized ‘by the presence of diffuse rather small regenerative nodules in the absence of significant fibrosis’. All patients were treated with HAART and all received didanosine included in one of several lines of antiretroviral drugs they had before the diagnosis of NRH…Our case is very similar to those reported by Mallet et al and emphasizes the seriousness of this complication: the risk of variceal haemorrhage, indication for some patients of transplantation (three out of eight of the cases reported by Mallet et al). Only HIV infection and HAART have been identified as potential co-factors. Nevirapine toxicity is well known, has not been specifically incriminated in NRH pathogenesis, but was also taken by our patient as well as by eight patients reported by Mallet et al.”

“We studied the response to nevirapine-based antiretroviral treatment among women and infants who had previously been randomly assigned to a single, peripartum dose of nevirapine or placebo in a trial in Botswana…All women were treated with antenatal zidovudine [AZT]. The primary end point for mothers and infants was virologic failure by the 6-month visit after initiation of antiretroviral treatment…By the 6-month visit after the initiation of antiretroviral treatment, 5.0% of the women who had received placebo had virologic failure, as compared with 18.4% of those who had received a single dose of nevirapine…Among 60 women starting antiretroviral treatment within 6 months after receiving placebo or a single dose of nevirapine, no women in the placebo group and 41.7% in the nevirapine group had virologic failure. In contrast, virologic failure rates did not differ [statistically] significantly between the placebo group and the nevirapine group among 158 women starting antiretroviral treatment 6 months or more post partum (7.8% and 12.0%, respectively). Thirty infants also began antiretroviral treatment (15 in the placebo group and 15 in the nevirapine group). Virologic failure by the 6-month visit occurred in significantly more infants who had received a single dose of nevirapine than in infants who had received placebo.”

“Thirteen of the 49 patients studied developed a hypersensitive reaction to nevirapine within 3–60 days (median 12 and 25 days for reactions affecting the skin and liver, respectively). Five of these patients had extensive skin rash, five developed liver toxicity (grade III–IV) without cutaneous involvement, three had systemic reactions with skin rash and/or liver toxicity combined with fever (> 388C), myalgia, arthralgia and visceral impairment. In all 13 patients, nevirapine treatment had to be discontinued and the symptoms rapidly resolved after withdrawal of the drug.”

“A total of 123 women initiated nevirapine as part of combination antiretroviral therapy in the study period. Eight women developed significant hepatotoxicity, including two women who died from fulminant hepatitis. Women who experienced more severe hepatotoxicity had higher pretreatment CD4 counts”

“Of 202 patients, 95 (47%) and 69 (34.2%) developed a rash from all reasons and from NNRTI [the non-nucleoside reverse transcriptase inhibitors Efavirenz (EFV) and Nevirapine (NVP)], respectively. For NNRTI-related rash the incidences were EFV (20%), NVP BD [twice daily] (21%), NVP OD [once daily] (38%) and NVP + EFV (67%). The proportions of patients with grade I, II and III within the four treatment arms are as follows: EFV, 4.3, 13 and 2.9%; NVP BD, 2.3, 15.9 and 2.3%; NVP OD, 12.8, 19.1 and 6.4%; and NVP + EFV, 11.9, 47.6 and 7.1%…There were six patients (2.9%) who developed NNRTI related serious adverse events, as defined by hospitalization or death. Four were women and five were treated NVP: namely three taking NVP OD and two taking NVP BD. All patients were hospitalized and one died. Two patients had Stevens Johnson syndrome (one each in the NVP OD and NVP BD arms) and three had a serum sickness-like reaction with fever and rash (One each in the NVP OD, NVP BD and EFV arms). One patient with underlying congenital heart disease (ventral septal defect) died of heart failure during hospitalization for rash and severe liver toxicity from NVP. All the other patients on NVP except one were switched to EFV and did not have recurrent rash. The single patient on EFV did well after having EFV temporarily stopped.”

“During 1997--2000, a total of 22 severe adverse events in persons who had taken nevirapine-containing regimens for occupational or nonoccupational postexposure prophylaxis were reported to FDA [US Food and Drug Administration]. Severe hepatotoxicity [liver damage] occurred in 12 (one requiring liver transplantation), severe skin reactions in 14, and both hepatic and cutaneous manifestations occurred in four. Because the majority of occupational exposures do not lead to HIV infection, the risk for using a nevirapine-containing regimen for occupational PEP outweighs the potential benefits. The same rationale indicates that nevirapine should not be used for nPEP [non-occupational post-exposure prophylaxis, e.g. rape by a person suspected of being HIV-positive].”

“Both clinically symptomatic and asymptomatic liver toxicity are observed with long term use of nevirapine in combination with other HIV drugs. Asymptomatic liver toxicity is defined as increases in liver enzymes without any associated clinical signs or symptoms and is similar to that seen with other antiretroviral drugs. Symptomatic liver toxicity is more common with nevirapine compared to other antiretroviral drugs…Females and patients with higher CD4+ cell counts are at increased risk of liver toxicity. Females have a three fold higher risk of symptomatic nevirapine liver toxicity than males, and females with CD4+ cell counts > 250 cells/mm3 have a 12 fold higher risk of symptomatic liver toxicity than females with CD4+ cell counts < 250 (11% vs. 0.9%). Males with CD4+ cell counts > 400 cells/mm3 have a three fold higher risk of symptomatic liver toxicity than males with CD4+ cell counts < 400 (6.3% vs. 2.3%). Nevirapine-related deaths due to symptomatic liver toxicity, including some in HIV-infected pregnant women, have been reported to FDA’s Medwatch program. Serious and fatal liver toxicity has not been reported after single doses of nevirapine.”

“We implemented the nevirapine regimen in a real-life situation in Kenya. The perinatal HIV-1 transmission rate at 14 weeks was 18.1%, similar to the 21.7% before the intervention [not a statistically significant difference].”

“Antiretroviral therapy with nevirapine or efavirenz showed similar efficacy, so triple-drug regiments with either NNRTI [Non-Nucleoside Reverse Transcriptase Inhibitor] are valid for first-line treatment. There are, however, differences in safety profiles…The study was investigator initiated and financially supported by Boehringer-Ingelheim [the manufacturer of Nevirapine]. The sponsor had a non-binding input on issues of study design and analyses…One patient assigned nevirapine twice daily…developed fulminant hepatitis, attributed to the use of nevirapine, as well as pancreatitis [pancreas failure] and renal failure 32 days after the start of treatment; this patient died a week later. Another patient assigned nevirapine twice daily developed Stevens-Johnson syndrome, attributed to the use of nevirapine, 39 days after the start of treatment…and died after 8 days…11 deaths were related to HIV-1 disease…Nevirapine plus efavirenz [another non-nucleoside reverse transcriptase inhibitor] was associated with the highest frequency of clinical adverse events, and nevirapine once daily with significantly more hepatobilliary [liver and bile duct] laboratory toxicities than efavirenz. Of 25 observed deaths, two were attributed to nevirapine.”

“HAART regimens including nevirapine are associated with faster liver fibrosis ['scar' tissue] progression in HIV-infected patients with chronic hepatitis C.”

“Women with CD4+ counts >250 cells/mm3, including pregnant women receiving chronic treatment for HIV infection, are at considerably higher risk (12 fold) of hepatotoxicity. Some of these events have been fatal…The greatest risk of severe and potentially fatal hepatic events (often associated with rash) occurs in the first 6 weeks of VIRAMUNE [nevirapine] treatment. However, the risk continues after this time and patients should be monitored closely for the first 18 weeks of treatment with VIRAMUNE…In some cases hepatic injury progresses despite discontinuation of treatment. [Boehringer Ingelheim is the manufacturer of Nevirapine]”

“Twelve non-HIV-infected individuals developed severe cutaneous toxicity, including 3 with Stevens-Johnson syndrome, after 7 to 12 days of nevirapine-containing PEP regimens. Thirty non-HIV-infected individuals developed hepatotoxicity after 8 to 35 days of single-agent nevirapine (n = 8) or a nevirapine-containing PEP regimen (n = 22). Findings included ECOG 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). Rates of severe hepatotoxicity (grade 3 or 4) in non-HIV-infected individuals ranged from 10% (4/41) to 62% (5/8). Liver biopsy material from 2 individuals was consistent with a hypersensitivity syndrome.”

“HIV clinicians are well aware of the potential toxicities associated with nevirapine (NVP) therapy, including rash and hepatic injury, both of which appear in the FDA-mandated NVP black box warning. In the vast majority of patients in whom they develop, these complications are mild to moderate; however, in some patients, they can be severe and life-threatening…there is a significant risk of NVP-associated hepatotoxicity in pregnant women, especially those with high CD4 +cell counts, and that the progression to severe hepatotoxicity may be explosive in nature and not predicted by the patient's liver enzyme level determinations obtained before and during NVP therapy”

“VIRAMUNE [nevirapine] is not approved for multiple-dose postexposure prophylaxis. Serious hepatotoxicity, including hepatic failure, has occurred in this setting…Severe, life-threatening, and in some cases fatal, hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure, has been reported in patients treated with VIRAMUNE. In some cases, patients presented with nonspecific prodromal signs or symptoms of hepatitis and progressed to hepatic failure. Patients with signs and symptoms of hepatitis must seek medical evaluation immediately and should be advised to discontinue VIRAMUNE.”

“Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with VIRAMUNE. These have included severe cases of SJS [Stevens-Johnson syndrome], TEN [Toxic Epidermal Necrosis (skin death)], and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Patients developing signs and symptoms of severe skin reactions or hypersensitivity reactions must discontinue VIRAMUNE as soon as possible.”

“The US National Clinicians’ Post-Exposure Prophylaxis Hotline has received more than 19,000 calls. We recommend nevirapine for post-exposure prophylaxis only under extraordinary circumstances…If these criteria are met, the risks and benefits of nevirapine…should be explained to HCWs [health care workers]…The HCW should be monitored carefully for toxic effects; nevirapine should be stopped if adverse events develop or are suspected.”

“The cases of 2 patients with nevirapine-associated hepatotoxicity [liver damage] in conjunction with rash and eosinophilia [increase in eosinophil blood cells, common in allergic reactions] are reported here. Both patients' conditions improved following withdrawal of nevirapine. Previous case reports have described a variety of interventions other than drug withdrawal that might have contributed to resolution of drug-induced hepatitis. Until a better understanding of the clinical spectrum and pathophysiology of nevirapine-associated hepatotoxicity is realized, treatment will remain largely empiric [translation: we are not too sure what we are doing, but we never like to take a drug away from a patient]”

“The existing sections [of the product label for Nevirapine/Viramune] have been updated to provide additional warning information about the risk of severe, life-threatening and in some cases, fatal hepatotoxicity [liver damage] that have been reported in patients treated with Viramune. Although clinical presentation varied among patients, frequently occurring features included non-specific prodromal [early] signs and symptoms of fatigue, malaise, anorexia and nausea, with or without abnormal serum transaminase levels. In these reports, symptoms progressed to jaundice, hepatomegaly [enlarged liver], elevation of transaminase levels and hepatic [liver] failure over several days.”

“Of the 906 adult NVP-treated patients whose data were included in the investigational trials database, 51.5% (467/906) experienced at least one drug-related adverse event. The most frequently observed (>2%) drug-related adverse events were rash (19.8%) ['Includes rash, allergic reaction with rash, erthyematous rash, maculopapular rash, postular rash, urticaria, and Stevens-Johnson syndrome'], nausea (11.1%), fatigue (8.5%), fever (8.4%), headache (7.7%), somnolence (6.0%), and abnormal values on liver function tests (6.0%). Severe rash (grade 3 or greater) occurred in 4.0% (36/906) of patients [and if the events judged not to be due to Nevirapine are not excluded, the rate of these adverse events go up significantly, e.g. 32% had rash]…[In pediatric users of Nevirapine] The most common (>5%) drug-related adverse events were rash (24%), granulocytopenia (16%), vomiting (14%), fatigue (11%), nausea (11%), and dizziness, headache, nervousness, and somnolence (8% each)…Based on prescription data, approximately 50,000 patients in the United States have been treated with marketed NVP [nevirapine] from its first marketing in August 1996 through July 1998. During these two years, three deaths have been reported [which probably says more about the extremely low reporting rate of adverse events than about the safety of nevirapine]”

“[In a letter to the Canadian Minister of Health from the Deputy Minister] With respect to the antiretroviral Viramune (nevirapine), this drug has indeed been approved in several countries. Viramune was approved by the US FDA under the Accelerated Approval process...Approval of Viramune by the EMA [European Agency...]was associated with post-approval commitments for further clinical study…The review of the new drug submission for Viramune did not reveal any conclusive effects on clinical end points nor on surrogate marker end points [e.g. CD4 counts/Viral load] to support the benefit of Viramune in treating patients with HIV disease. The efficacy of Viramune was not clinically significant when evaluated against internationally recognized standards of efficacy for drugs used in the treatment of HIV. There are, in addition, safety concerns associated with Viramune use in clinical trials. On March 6, 1997, a Notice of non-compliance (NON) was issued by the Therapeutic Products Programme. On July 2, 1997, the manufacturer filed a response to the NON. In the absence of scientific evidence of efficacy and concerns relating to safety, the data available for Viramune are judged to be inadequate to support the clinical benefit of the drug. [Canada, under considerable political pressure, later approved the drug]”