12-hydroxy nevirapine as a possible cause of nevirapine induced skin rashes

Nevirapine [NVP] is the first non-nucleoside reverse transcriptase inhibitor approved by the U.S. Food and Drug Administration [FDA] for use in combination therapy of HIV-1 infection. The favorable pharmacokinetic profile of NVP permits a simplified dosage and inexpensive regimen to prevent perinatal transmission, more especially in developing countries. Greater than 80% of administered NVP dose is transformed to glucuronidated conjugates of hydroxylated metabolites that are excreted in urine and only a small fraction of the dose [2.7%] was urinary excreted as the parent compound NVP. Adverse effects, mainly hypersensitivity skin reactions and hepatotoxicity, have emerged from NVP and hampered its use. Maculopapular rash and several cases of Stevens-Johnson syndrome have been reported in 17% of patients treated with NVP. 12-hydroxynevirapine has been proposed as a factor in nevirapine hepatocarcinogenicity and skin rashes. This work was conducted to explore the proposition that 12-hydroxy-NVP is the ultimate toxic metabolite responsible for the NVP induced side effects. Primary culture of skin fibroblasts of small female Brown Norway rats was utilized in this study, where the third and the fourth passaged cells were used. NVP, 12-hydroxy-NVP as well as 12-chloro-NVP [as surrogate for 12-hydroxy-NVP] were utilized for exploring the expression profiles of some genes as well as the cytotoxic potential of each of them. Also, the stability of 12-hydroxy and 12-chloro NVP in vitro was determined. Results showed that both of NVP and 12-hydroxy-NVP are free from any cytotoxic potential while 12-chloro-NVP exhibited cytotoxic effect in the third and the fourth passaged population. Each of NVP, 12-hydroxy-NVP or 12chloro-NVP caused some what similar gene expression profile. The stability study showed clear transformation of 12-chloro-NVP to more stable metabolite which is 12-hydroxy-NVP. As a conclusion obtained from the present work is that the main metabolite of NVP which is 12-hydroxy-NVP may not be the ultimate toxic metabolite responsible for NVP induced side effect. It is possible to propose that; 12-hydroxy-NVP may be further converted to ultra short lived ultimate toxic metabolite responsible for the adverse side effects. This suggested proposal need to be verified by more extensive and advanced works

Detección de hipotiroidismo en un programa de atención de VIH/SIDA en un hospital de Bogotá, Colombia / Mass screening for hypothyroidism in a cohort of HIV infected patients in a Bogotá hospital, Colombia

Objetivos: Evaluar la frecuencia de alteración tiroidea y los factores asociados en los pacientes con VIH/SIDA de un hospital universitario en Colombia. Pacientes y Métodos: Estudio tipo corte transversal de pacientes con VIH/SIDA durante el periodo de 2007 a 2008. Se registró niveles hormonales, inmunológicos, carga viral y tratamiento anti-retroviral. Resultados: En 636 pacientes la prevalencia de hipotiroidismo (TSH > 4,6 μUI/mL) fue de 15,5 por ciento (100/636). El análisis independiente demostró relación significativa para el uso de nevirapina (RR 1,6; IC 95 por ciento 1,1 - 2,3) y estavudina (RR 1,5; IC 95 por cientoo 1 - 2,3). Conclusiones: La prevalencia de hipotiroidismo fue alta y se relacionó con el uso de nevirapina.

Introduction: The objective of this study was to evaluate the frequency of thyroid function alterations and its associated factors in a group of patients from a university hospital in Colombia. Methods: From June 2007 through June 2008, 636 HIV patients were followed in order to assess the relation of thyroid function with the use of HAART. Results: The overall prevalence of hypothyroidism (TSH > 4.6 μUI/mL) was 15.5 percent (100/636). The association of hypothyroidism in the independent analysis showed significant relation only for the use of nevirapine (RR 1.6; CI 95 percent 1.1- 2.34) and stavudine (RR 1.5; CI 95 percent, 1 - 2.3). Conclusions: The prevalence of hypothyroidism was surprisingly high among the studied population.

Adverse drug reactions to antiretroviral therapy in AIDS patients at a tertiary care hospital in India: A prospective observational study.

Objectives: To identify the adverse drug reactions (ADRs) to antiretroviral therapy (ART) and to assess their impact on treatment compliance in patients with HIV/AIDS. Materials and Methods: Two hundred and thirty-five (235) AIDS patients who received ART were monitored for ADRs over a period of 6 months. The incidence and nature of ADRs occurring with different ART regimens were recorded. We also assessed the severity, causality as well as the impact of ADRs on the patients' compliance. Results: Of 235 patients receiving ART, 90.6% patients experienced ADRs. A total of 618 ADRs involving various systems were observed. A majority were related to gastrointestinal (42.39%) and central nervous (25.57%) system. 23.1% ADRs were severe in intensity. Severe ADRs occurred in 41 out of 235 (17.4%) patients necessitating drug withdrawal. A majority of the patients (87.8%) who complained of severe ADRs received combination of stavudine, lamivudine and nevirapine. Causality assessment revealed 6.63% ADRs were probable and 93.3% ADRs were possible. Non-compliance due to ADRs was observed in 28.9% patients. Conclusions: Myriad ADRs are associated with ART which leads to poor patient compliance. With the increasing access to ART in India, it is prudent that antiretroviral drugs are used judicially with regular monitoring of ADRs.

Incidence and risk factors of nevirapine-associated severe hepatitis among HIV-infected patients with CD4 cell counts less than 250 cells/microL.

OBJECTIVES: To determine incidence and risk factors of nevirapine (NVP)-associated severe hepatitis that led to NVP discontinuation among HIV-infected patients with CD4 < 250 cells/microL. MATERIAL AND METHOD: A retrospective cohort study was conducted among antiretroviral-naïve HIV-infected patients who had baseline CD4 < 250 cells/microL and were initiated NVP-based antiretroviral therapy (ART) between January 2003 and October 2005. All patients were categorized to group A: occurred clinical hepatitis and group B: did not occur clinical hepatitis. All were followed until 6 months after ART. RESULTS: There were 910 patients with a mean age of 35.4 years, 57% were males and median (IQR) CD4 cell count was 27 (9-80) cells/microL; contributing 5,006 person-months of observations. Ten (1.1%) patients were in group A and 900 (98.9%) patients were in group B. Incidence of clinical hepatitis was 2 per 1,000 person-months. Probabilities of clinical hepatitis at 0.5, 1, 2, 3 and 6 months after ART were 0.2%, 0.5%, 0.7%, 0.8% and 1.1%, respectively. By Cox regression analysis, baseline AST > or = 1.5 times of upper limit was associated with higher incidence of clinical hepatitis (p = 0.019, HR = 5.83, 95% CI = 1.33-25.51). CONCLUSION: Incidence of NVP-associated severe hepatitis that lead to NVP discontinuation among HIV-infected patients with baseline CD4 < 250 cells/microL is low. The higher baseline AST is also associated with a higher risk of severe hepatitis.

Avaliação dos efeitos colaterais da nevirapina em gestantes HIV positivo em Hospital Universitário do sul do Brasil / Evaluation of the adverse effects of nevirapine in HIV-infected pregnant women in a South Brazilian University Hospital

OBJETIVO: avaliar a freqüência de efeitos advesos com o uso da nevirapina e suas correlações em gestantes infectadas pelo vírus da imunodeficiência humana (HIV). MÉTODOS: estudo retrospectivo foi realizado entre janeiro de 2003 e dezembro de 2006, incluindo todas as mulheres que utilizaram nevirapina durante a gestação. Os critérios de exclusão foram: início da nevirapina antes da gestação; presença de enzimas hepáticas basais aumentadas e dados incompletos de bioquímica hepática no prontuário. Os parâmetros avaliados foram idade, duração de exposição à nevirapina, idade gestacional no início da medicação, semanas de seguimento, carga viral, contagem de CD4 e dosagens de transaminases. A incidência de efeitos adversos hepáticos e/ou cutâneos foi determinada e correlacionada com a contagem de CD4. As análises estatísticas foram realizadas utilizando o teste exato de Fisher e o teste t de Student quando apropriado. A significância estatística foi estabelecida quando p<"0,05. RESULTADOS: cento e cinqüenta e sete gestantes foram incluídas nos critérios estabelecidos. Trinta e uma mulheres (19,7 por cento) apresentaram toxicidade cutânea e/ou hepática. Rash cutâneo foi responsável por 77,4 por cento das toxicidades e anormalidade da função hepática por 22,6 por cento. Hepatotoxicidades graus 1, 2 e 3 foram observadas em 0,6, 2,5 e 1,3 por cento, respectivamente. Contagem de CD4, carga viral e dosagem de transaminases basais foram similares em gestantes com e sem reação induzida pela nevirapina. A contagem de CD4 média foi de 465,4 e 416,6 células/µL em mulheres com e sem efeitos colaterais, respectivamente (p=0,3). Todas as pacientes que apresentaram hepatotoxicidade apresentavam contagem de CD4 prévia ao tratamento superior a 250 células/µL. CONCLUSÕES: a incidência de eventos adversos com nevirapina em nosso estudo foi alta, mas a maioria deles foi cutâneo. Não houve correlação entre a alta contagem de CD4 e os eventos adversos quando se analisou conjuntamente as reações cutâneas e hepáticas; entretanto, a hepatotoxicidade ocorreu apenas em gestantes com contagem de CD4 > 250 células/µL.

PURPOSE: The aim of this article is to evaluate the use of nevirapine HIV-infected pregnant women in our service. METHODS: a retrospective study was performed between January 2003 and December 2006 analysing all women prescribed nevirapine in pregnancy. Exclusion criteria included: (1) women who started nevirapine before pregnancy, (2) patients with abnormal baseline liver enzymes, and (3) women with incomplete liver biochemistry data. Evaluated parameters included age, weeks of exposure to nevirapine, gestational age in the begginning of medication, weeks of follow-up, viral load, CD4 cells count and serum aminotransferase levels. The incidence of adverse hepatic and/or cutaneous effects was determined and correlated to the CD4 cells count. Statistical analysis were performed using Fisher’s exact test and t-Student test when appropriate, with a statistical significance level of p<0,05. RESULTS: one hundred fifty-seven women met the inclusion criteria. Thirty-one (19.7 percent) presented cutaneous and/or hepatic toxicity. Skin rash accounted for 77.4 percent of toxicities and liver function abnormalities were noted in 22.6 percent of women exhibiting toxicities. Grade 1, 2 and 3 hepatotoxicities were observed in 0.6, 2.5 and 1.3 percent, respectively. Baseline CD4 counts, viral loads and transaminases were similar in pregnant women with nevirapine adverse effects and those without reaction. Median absolute CD4 cell counts were 465.4 and 416.6 cells/µL in women with and without side effects, respectively (p=0.3). All patients who experienced hepatotoxicity had pretreatment CD4 counts superior to 250 cells/µL. CONCLUSIONS: The incidence of adverse events with nevirapine in our study was high, but most of them were cutaneous. There was no correlation between high CD4 counts and adverse events when analysing both cutaneous and hepatic reactions; nevertheless, hepatotoxicity occurred only in pregnant women with CD4 counts >250 cells/µL.

Nevirapine-induced side effects in pregnant women: experience of a brazilian university hospital

Nevirapine-based therapy is associated with increased frequency of adverse events among HIV-infected pregnant women. The aim of this article was to evaluate the incidence of adverse effects in HIV-infected women who started nevirapine during pregnancy. A retrospective study was performed in our center between January 2003 and December 2006 analyzing all women prescribed nevirapine during pregnancy. Women presenting any risk factor for hepatotoxicity were excluded from the analysis. Patients were divided into two groups according to the presence or absence of adverse effects, and a correlation to CD4 counts was performed. Liver function abnormality was graded according to the Division of AIDS toxicity guidelines. A total of 170 women initiated nevirapine during pregnancy, but only 133 were included in the study. Twenty-seven women (20.3 percent) presented adverse effects, skin rash accounting for 77.8 percent (21/27 women) and liver function abnormalities for 22.2 percent (6/27) of the cases. Baseline CD4 counts, viral loads and transaminases were similar in both groups. All nevirapine side effects were developed in less than seven weeks. Four of 31 women with CD4 counts <250 cells/µL (12.9 percent) and 23 of 102 women with CD4 counts ≥250 cells/µL (22.5 percent) developed adverse events. All patients who experienced hepatotoxicity had pretreatment CD4 counts >250cells/µL. The incidence of adverse events with nevirapine in our study was high, but most of them were cutaneous. There was no correlation between high CD4 counts and adverse events when analyzing both cutaneous and hepatic reactions; nevertheless, hepatotoxicity occurred only in pregnant women with CD4 counts ≥250cells/µL.

Predisposing factors for nevirapine toxicity among AIDS patients with low baseline CD4 count.

The objective of the study was to determine the predisposing factors and incidence of toxicity among AIDS patients treated with a nevirapine (NVP)-based regimen in clinical practice. A retrospective cohort study of representative samples of AIDS patients treated with a NVP-based regimen was performed. A total of 206 adult HIV/AIDS cases with median age (IQR) 33 years (range, 29-38 years), 51% male, treated between January 2004-December 2005, were included. Most (92.2%) of the patients were naïve to antiretroviral drug. The incidence of NVP toxicity was 1.09/100 person-months. The median onset time was 4 weeks post NVP initiation (2.57 weeks for skin toxicity and 12.43 weeks for hepatic toxicity). History of drug allergy and NVP toxicity were significantly associated (p = 0.006), as were sulfamethoxazole allergy and toxicity (p = 0.015). Regarding concomitant medication, concurrent anti-tuberculosis drugs significantly increased the risk of NVP associated liver toxicity (p = 0.001). Therefore, it is important to monitor adverse events from NVP, including liver function tests among HIV/AIDS patients with history of drug allergy, especially against sulfamethoxazole, and those concurrently treated with antituberculosis drugs.

Cryptococcal meningoradiculitis: an atypical presentation after initiation of antiretroviral therapy.

Atypical presentations of cryptococcal infection have been described as clinical manifestations of immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients following commence of antiretroviral therapy (ART). The authors describe a patient presenting with cryptococcal meningoradiculitis two weeks after initiation of ART. In patients with advanced HIV disease, immune reconstitution induced by ART can precipitate onset of atypical clinical manifestations in those patients with latent cryptococcal infection of the central nervous system.

Necrólisis epidérmica tóxica por nevirapine Una patología poco frecuente en un servicio de terapia intensiva / Toxic epidermal necrolysis by nevirapine A rare pathology in an intensive care service

La Necrólisis epidérmica tóxica (N.E.T), es un desorden poco frecuente, caracterizado por una muerte epidérmica extensa, producido por una reacción idiosincrática por drogas. Es una enfermedad grave que puede eventualmente ocasionar la muerte por complicaciones sépticas o fallo multiorgánico, en alrededor del 30 % de los pacientes. El caso clínico que se describe, se asocia con el uso de Nevirapine que es un fármaco antirretroviral inhibidor de la Transcriptasa inversa, no análogo de nucleosidos, esta droga se vincula a la aparición de N.E.T en el 1% de los tratamientos(AU)

Toxic epidermal necrolysis (TEN) is a very uncommon disorder, characterized by extensive epidermal death, produced by an idiosyncratic drug reaction. Is a severe disease that eventually can be lethal. Death may be caused by septic complications or multiorgan failure, in about 30% of patients. In this case report the disease is related to the use of Nevirapine. This antiretroviral drug is a nonnucleoside reverse transcriptase inhibitor that is supposed to cause TEN in 1% of the patients.(AU)

Nevirapine-induced fulminant hepatitis.

Nevirapine induced hepatotoxicity is known but fatality is rare. We report a case of a young individual who developed nevirapine (NVP) induced fatal hepatitis without apparent risk factors or preceding rash. Exacerbation of underlying silent chronic liver dysfunction possibly contributed to the fatal outcome. This case stresses the need for careful evaluation, regular monitoring and prompt omission of drug on suspicion of hepatotoxicity.

The efficacy and adverse effects of GPO-VIR (stavudine+lamivudine+nevirapine) in treatment-naïve adult HIV patients.

A descriptive, combined retrospective and prospective study was conducted at the Anonymous Clinic, Chon Buri Hospital, Chon Buri Province, Thailand from November 10, 2003 to January 4, 2004. A total of 83 adult HIV-treatment-naïve patients undergoing treatment with GPO-VIR (stavudine, lamivudine, and nevirapine) for at least one year were studied. The objectives of the study were to assess the efficacy of GPO-VIR by evaluating body weight changes, CD4 T-cell count changes, the occurrence of opportunistic infections, and long-term side effects, such as lipodystrophy, during treatment. Of 83 studied patients, approximately half (52.3%) of them had a body weight increase > 10% of pre-treatment body weight after 12 months treatment. After taking GPO-VIR, CD4 T-cell counts increased rapidly, by a median of 78 x 10(6) cells/l during the first three months. 39.5% of the patients attained median CD4 counts > 200 x 10(6) cells/I, and 11.6% achieved > 500 x 10(6) cells/l after 2 years of treatment. The occurrence of opportunistic infections was significantly lower after treatment with GPO-VIR (p = 0.001). Subjective assessment of lipodystrophy by physicians and patients showed that 16.8% had symptoms of lipodystrophy within 2 years of GPO-VIR treatment. There was a significant association between older age group (40-49 years) and occurrence of lipodystrophy (p = 0.043). GPO-VIR is an inexpensive and effective antiretroviral drug regimen for initiating treatment of naïve patients, but careful assessment for lipodystrophy is necessary, especially after one year of treatment.

Nevirapine-associated rash in a Jamaican child with HIV/AIDS

Nevirapine is one of the first line antiretroviral agents used in the treatment of HIV/AIDS as well as for prophylaxis against mother-to-child transmission of HIV As antiretroviral medication becomes more available it is important for physicians to recognize the major clinical toxicities of these medications. We report a HIV-infected infant who developed a rash with systemic symptoms in association with nevirapine administration