Safety and tolerability of nevirapine-based antiretroviral therapy in HIV-infected patients receiving fluconazole for cryptococcal prophylaxis: a retrospective cohort study
© Manosuthi et al; licensee BioMed Central Ltd. 2005
Received: 29 May 2005
Accepted: 24 August 2005
Published: 24 August 2005
To compare the adverse events after initiation of nevirapine-based ART among HIV-infected patients who did not receive fluconazole (group A), received fluconazole 400 mg/week (group B), and received fluconazole 200 mg/day (group C).
A retrospective cohort study was conducted among HIV-infected patients who began NVP-based ART between December 2003 and September 2004. Patients were followed up for 6 months. Clinical hepatitis, elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (> 3 times from baseline), and skin rashes were studied.
There were 686 patients; 225, 392, and 69 patients in group A, B, and C, respectively. Baseline characteristics including age, previous opportunistic infections, use of antituberculous drugs, and baseline aminotransferase levels among the three groups were similar. Group C had a higher proportion of men (p = 0.016). Baseline median (IQR) CD4 cell counts were 85 (21–159), 18 (7–48), and 16 (5–35) cell/mm3 in group A, B, and C, respectively (p < 0.001). Of 2/225 (0.9%), 4/392 (1.0%), and 0/69 (0%) patients in group A, B, and C developed clinical hepatitis (p = 0.705). There were no significant difference of elevated AST or ALT among the three groups (p > 0.05). By logistic regression, receiving fluconazole was not predictive of clinical hepatitis, elevated aminotransferase, or skin rashes. At 6 months after initiating NVP, 174 (77.3%) patients in group A, 309 (78.8%) patients in group B, and 58 (84.1%) patients in group C remained on NVP.
Initiation of NVP-based ART among Thais with advance HIV disease receiving fluconazole is safe and well-tolerated. nevirapine should not be contraindicated for patients receiving fluconazole for treatment or prophylaxis of cryptococcosis.
Highly active antiretroviral therapy (HAART) has been widely used for the treatment of human immunodeficiency virus (HIV) infected patients with successful immune restoration and reductions in morbidity and mortality [1, 2]. However, access to antiretroviral therapy for HIV-infected patients in resource-limited countries is still a major obstacle [3, 4]. HIV-infected patients in these areas often presented with advanced HIV disease. Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that has shown efficacy even in advanced HIV disease [5–8]. NVP-based HAART has been widely used in the resource-limited countries because of its efficacy, relative low cost, and availability. Additionally, NVP is part of two of the four World Health Organization-recommended generic combinations for the 3 × 5 program in resource-limited countries . NVP-related adverse events particularly skin rashes and hepatotoxicity have been well recognized as the limitation of NVP use [10–12]. NVP-associated skin rashes usually appear after one to four weeks of treatment . The risk of hepatotoxicity is greatest in the first six weeks of treatment and continues through 18 weeks of treatment .
Fluconazole is a commonly used for the prophylaxis and treatment of cryptococcosis in HIV-infected patients. Fluconazole 400 mg/day has been used as standard therapy for treatment of cryptocoocal meningitis after completion of two weeks of amphotericin B . Fluconazole 200 mg/day is used for secondary prophylaxis until immune reconstitution occurs with HAART . Fluconazole 400 mg/week is recommended for primary prophylaxis among HIV-infected patients with CD4 cell count <100 cells/mm3 in Thailand and some developing countries because of a high prevalence of cryptococcosis and the evidence of a survival benefit . Nonetheless, the potential drug-drug interaction between NVP and fluconazole is a major concern. Both drugs can induce cytochrome P450 isoenzymes in the liver [16–18]. Geel et al recently reported that fluconazole significantly raised plasma NVP levels and may cause serious hepatotoxicity . So far, there have not been enough data or any recommendations to adjust NVP dosage for the concomitant use of both drugs in order to avoiding adverse events. A previous study demonstrated that genetic disposition may play a role in NVP hypersensitivity reactions . There is little data of safety and tolerability for concurrent use of NVP and fluconazole in Asian populations. We therefore conducted this retrospective cohort study to compare the frequencies of hepatotoxicity and skin rashes among HIV-infected patients who received fluconazole and subsequently received NVP-based HAART regimens.
A retrospective cohort study was conducted among antiretroviral-naïve HIV-infected patients who began a NVP-based HAART regimens between December 2003 and September 2004 at Bamrasnaradura Institute, Ministry of Public Health, Nonthaburi, Thailand. Inclusion criteria were as follows: (1) HIV-infected patients > 15 years of age, (2) naïve to antiretroviral therapy, (3) began antiretroviral therapy with a NVP-based HAART regimen, (4) used NVP 200-mg once-daily lead-in dose, prior to escalation to 200 mg twice daily. Each eligible patient was classified into one of three groups according to whether he or she received fluconazole or not and the different dosages of fluconazole as follows: not received fluconazole (group A), received fluconazole 400 mg/week (group B), and received fluconazole 200 mg/day (group C). All patients were followed for 6 months after initiating NVP-based HAART. The primary objective was to compare the frequency of clinical hepatitis among the three groups. The secondary objectives of interest were to compare the frequencies of elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > three times from baseline at six months after initiation of NVP and to compare the frequencies skin rashes among the three groups.
The patients' clinical statuses including clinical hepatitis and skin rashes were assessed monthly by the attending physician. Liver functions test was performed at 6 months after initiating NVP in case of no evidence of hepatitis. Clinical hepatitis was defined as symptomatic hepatitis and either AST or ALT elevated > five times the upper limit of normal. Signs and symptoms of hepatitis may include anorexia, malaise, jaundice, nausea/vomiting, hepatomegaly, and hepatic tenderness. Skin rash was determined by medical record of skin reactions including diffuse erythematous or maculopapular rash, urticarial rash, serum sickness-like reaction, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
Mean (± standard deviation, SD), median (interquartile range, IQR) and frequencies (%) were used to describe patients' characteristics in each treatment groups. Chi-square test and Kruskal-Walis test were used to compare categorical and continuous variables among the treatment groups, respectively. Logistic regression was used to determine predicting factors for each adverse event of interest. The possible risk factors were entered into the model of binary logistic regression. Spearman correlation was use to study the relationship between skin rashes and clinical hepatitis, skin rashes and aminotransferase levels. All analyses were performed using SPSS program version 11.5. A P value less than 0.05 was considered statistically significant. The study was approved from the institute review board.
Baseline characteristic of 686 patients receiving NVP-based HAART.
Not receiving fluconazole
(n = 225)
400 mg/week (n = 392)
200 mg/day (n = 69)
Age, years, mean ± SD
36.0 ± 7.5
35.0 ± 7.4
34.7 ± 8.03
Weight, kg., mean ± SD
54.9 ± 10.6
52.3 ± 10.0
51.4 ± 8.7
Previous opportunistic infections, patients (%)
Any major opportunistic infections
Baseline CD4 cell count, cell/mm3, median (IQR)
Baseline % CD4, median (IQR)
Baseline plasma HIV RNA,
copies/ml, median (IQR)
Baseline AST, U/L, median (IQR)
Baseline ALT, U/L, median (IQR)
Baseline TB, mg/dl, median (IQR)
Frequency of adverse events among the three groups.
Not receiving fluconazole
(n = 225)
400 mg/week (n = 392)
200 mg/day (n = 69)
Elevated AST > 3 times from baseline
Elevated ALT > 3 times from baseline
Logistic regression of possible risk factors and clinical hepatitis
95% confidence interval
Baseline CD4 cell count
Receiving anti-tuberculous drugs
Logistic regression of possible risk factors and skin rashes.
95% confidence interval
Baseline CD4 cell count
Receiving anti-tuberculous drugs
Tolerability of NVP-based HAART among the three groups.
Not receiving fluconazole
(n = 225)
400 mg/week (n = 392)
200 mg/day (n = 69)
On NVP-based HAART at six months
Reasons of discontinuation
3 of 3 (100.0%)
Loss to follow-up
In the present study, we have shown that the prevalence of clinical hepatitis and AST and ALT elevation 6 months after initiating HAART among HIV-infected patients who concurrently received NVP and fluconazole were not different from those who received NVP- based HAART without fluconazole. These findings suggest that administration of NVP-based HAART regimens in HIV-infected patients who receive fluconazole dose not increase the risk of hepatotoxicity. The prevalence of clinical hepatitis and aminotransferase elevations in our study was lower than that reported in studies conducted in African HIV-infected patients [19, 20]. There may be several explanations for this discrepancy. First, the patients in this study had very low CD4 cell counts (i.e., 97% had CD4 cell counts < 200 cells/mm3 and 80% had CD4 cell counts < 100 cells/mm3). High CD4 cell count is a predictor of hepatotoxicity [11, 19]. Second, there was a higher proportion of men in our study than the previous studies [17, 18]. CD4 cell counts are more predictive of hepatotoxicity among men than women (i.e., men who have a CD4 cell counts > 400 cells/mm3 are at a greater risk of hepatitis than women with CD4 cell counts > 250 cells/mm3) [13, 21]. Third, our study included Asians, which was different from the previous study [11, 17, 18]. Sanne et al reported that African women may have an increased likelihood of hepatotoxicity . The previous studies demonstrate that there are differences in drug and alcohol metabolism that may be related to genetic or environmental factors (e.g., differences in diet and protein intake) [22–24]. There is little data on differences in NVP metabolism based on genetic disposition.
While logistic regression analyses in the present study show that receiving fluconazole was not predictive for any adverse events, receiving anti-tuberculous drugs was significantly predictive for both clinical hepatitis and skin rashes. The patients in our large cohort had overall 16% of concurrent tuberculosis and the results from the regression analyses can demonstrate this important issue. These findings point out that concurrent concomitant use of NVP and anti-tuberculous drugs may a cause of more concern. We suggest to closely monitoring liver function test in patients with concomitant use of NVP and anti-tuberculous drugs. Further well-designed prospective study is needed.
Regarding NVP-associated skin rashes, the overall prevalence in the present study was similar to previous study in Thai patients with advanced HIV disease . The incidence of NVP-associated skin rashes in the patients who received Fluconazole was lower than the other groups. This may be explained by the lower CD4 cells count in this group. As the previous studies have demonstrated that persons with a higher baseline CD4 cell counts are likely to develop rash from NVP . Given there was no correlation between skin rashes and clinical hepatitis or elevated aminotransferase, these two entities of adverse events may need different approaches for monitoring and management.
Overall about 80% of the patients in our cohort continued on NVP-based HAART at six months. Although all patients were initiated with NVP 200-mg once-daily lead-in dose prior to escalation to 200 mg twice daily, skin rash was still the major adverse event led to discontinuation of NVP-based HAART. The previous studies using short-course prednisolone were failed to prevent NVP-associated skin rashes [26, 27]. The further study to minimize this major limitation is needed.
NVP-based HAART is a common regimen which widely used for treatment of HIV-infected patients in resource-limited countries due to its affordability. Until the other options are more accessible, NVP-based HAART is still a key regimen to scale up treatment of HIV in resource-limited countries. Our study may provide the safety data of concomitant use of NVP and fluconazole and support the use of NVP in patients receiving fluconazole for treatment or prophylaxis of cryptococcal diseases.
The limitation of the present study is the nature of retrospective study that patients' clinical status may be underreported. First, not all patients had been checked for aminotransferase level during the first 6 months. Only 328 and 188 patients had been checked for AST and ALT levels, respectively. However, we had analyzed the demographics and adverse events between patients who had and did not have AST or ALT levels and found that there were no statistically significant differences. We did not have data of plasma NVP level in this cohort due to retrospective nature. However, Dailly et al reported that there was no association between plasma NVP level and hepatotoxicity . Ultimately, the present study did not assess patients who initiated NVP while received fluconazole 400 mg/day.
In summary, receiving of fluconazole for treatment or prophylaxis of cryptococcosis does not increase the risk of hepatotoxicity, elevated aminotransferase, or skin rashes from NVP. Initiation of NVP-based HAART among HIV-infected patients receiving fluconazole is safe and well-tolerated. Use of anti-tuberculous drugs is predictive of clinical hepatitis and skin rashes. Initiation of NVP-based HAART in HIV-infected patients receiving anti-tuberculous needs closely monitoring and prompt management.
List of abbreviations
Highly active anti-retroviral therapy, HIV: Human immunodeficiency virus, NVP: Nevirapine, NNRTI: Non-nucleoside reverse transcriptase inhibitor, AST: Aspartate aminotransferase, ALT: Alanine aminotransferase
We would like to thank all the study patients in this study and all the attending staffs in Department of Medicine, Bamrasnaradura Institute. The authors would like to thank Michael Martin for his comments.
- Hogg RS, Heath KV, Yip B, Craib KJ, O'Shaughnessy MV, Schechter MT, Montaner JS: Improved survival among HIV-infected individuals following initiation of antiretroviral therapy. Jama. 1998, 279: 450-454. 10.1001/jama.279.6.450.View ArticlePubMedGoogle Scholar
- Palella FJJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998, 338: 853-860. 10.1056/NEJM199803263381301.View ArticlePubMedGoogle Scholar
- Dionisio D, Esperti F, Messeri D, Vivarelli A: Priority strategies for sustainable fight against HIV/AIDS in low-income countries. Curr HIV Res. 2004, 2: 377-393. 10.2174/1570162043351057.View ArticlePubMedGoogle Scholar
- Vermund SH, Powderly WG: Developing a human immunodeficiency virus/acquired immunodeficiency syndrome therapeutic research agenda for resource-limited countries: a consensus statement. Clin Infect Dis. 2003, 37: S4-12. 10.1086/375367.View ArticlePubMedGoogle Scholar
- Floridia M, Bucciardini R, Ricciardulli D, Fragola V, Pirillo MF, Weimer LE, Tomino C, Giannini G, Galluzzo CM, Andreotti M, Cargnel A, Alberici F, De Rienzo B, Leoncini F, Fiaccadori F, Francisci D, Grillone W, Ortona L, Piazza M, Scalzini A, Nigra E, Tumietto F, Vella S: A randomized, double-blind trial on the use of a triple combination including nevirapine, a nonnucleoside reverse transcriptase HIV inhibitor, in antiretroviral-naive patients with advanced disease. J Acquir Immune Defic Syndr Hum Retrovirol. 1999, 20: 11-19.View ArticlePubMedGoogle Scholar
- Manosuthi W, Sungkanuparph S, Vibhagool A, Rattanasiri S, Thakkinstian A: Nevirapine- versus efavirenz-based highly active antiretroviral therapy regimens in antiretroviral-naive patients with advanced HIV infection. HIV Med. 2004, 5: 105-109. 10.1111/j.1468-1293.2004.00195.x.View ArticlePubMedGoogle Scholar
- Podzamczer D, Ferrer E, Consiglio E, Gatell JM, Perez P, Perez JL, Luna E, Gonzalez A, Pedrol E, Lozano L, Ocana I, Llibre JM, Casiro A, Aranda M, Barrufet P, Martinez-Lacasa J, Miro JM, Badia X, Casado A, Lupo S, Cahn P, Manos M, Estela J: A randomized clinical trial comparing nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients (the Combine Study). Antivir Ther. 2002, 7: 81-90.PubMedGoogle Scholar
- van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B, Cahn P, Lalloo UG, van der Westhuizen IP, Malan DR, Johnson MA, Santos BR, Mulcahy F, Wood R, Levi GC, Reboredo G, Squires K, Cassetti I, Petit D, Raffi F, Katlama C, Murphy RL, Horban A, Dam JP, Hassink E, van Leeuwen R, Robinson P, Wit FW, Lange JM: Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet. 2004, 363: 1253-1263. 10.1016/S0140-6736(04)15997-7.View ArticlePubMedGoogle Scholar
- Scaling up Antiretroviral Therapy in Resource-limited Settings: Treatment Guidelines for a public Health Approach. 2003, Geneva, Joint United Nations Programme on HIV/AIDS (UNAIDS) and World Health Organization (WHO)
- Milinkovic A, Martinez E: Nevirapine in the treatment of HIV. Expert Rev Anti Infect Ther. 2004, 2: 367-373. 10.1586/14787220.127.116.117.View ArticlePubMedGoogle Scholar
- Pollard RB, Robinson P, Dransfield K: Safety profile of nevirapine, a nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus infection. Clin Ther. 1998, 20: 1071-1092. 10.1016/S0149-2918(98)80105-7.View ArticlePubMedGoogle Scholar
- Knudtson E, Para M, Boswell H, Fan-Havard P: Drug rash with eosinophilia and systemic symptoms syndrome and renal toxicity with a nevirapine-containing regimen in a pregnant patient with human immunodeficiency virus. Obstet Gynecol. 2003, 101: 1094-1097. 10.1016/S0029-7844(02)02620-0.PubMedGoogle Scholar
- Stern JO, Robinson PA, Love J, Lanes S, Imperiale MS, Mayers DL: A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr. 2003, 34 Suppl 1: S21-33.View ArticlePubMedGoogle Scholar
- Saag MS, Graybill RJ, Larsen RA, Pappas PG, Perfect JR, Powderly WG, Sobel JD, Dismukes WE: Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis. 2000, 30: 710-718. 10.1086/313757.View ArticlePubMedGoogle Scholar
- Chetchotisakd P, Sungkanuparph S, Thinkhamrop B, Mootsikapun P, Boonyaprawit P: A multicentre, randomized, double-blind, placebo-controlled trial of primary cryptococcal meningitis prophylaxis in HIV-infected patients with severe immune deficiency. HIV Med. 2004, 5: 140-143. 10.1111/j.1468-1293.2004.00201.x.View ArticlePubMedGoogle Scholar
- Albengres E, Le Louet H, Tillement JP: Systemic antifungal agents. Drug interactions of clinical significance. Drug Saf. 1998, 18: 83-97.View ArticlePubMedGoogle Scholar
- Kuper JI, D'Aprile M: Drug-Drug interactions of clinical significance in the treatment of patients with Mycobacterium avium complex disease. Clin Pharmacokinet. 2000, 39: 203-214.View ArticlePubMedGoogle Scholar
- Joly V, Yeni P: [Non-nucleoside reverse transcriptase inhibitors]. Ann Med Interne (Paris). 2000, 151: 260-267.Google Scholar
- Geel J, Pitt J, Orrell CJ, Van Dyk M, Wood R: The effect of fluconazole on nevirapine pharmacokinetics: July 11-16; Bangkok. 2004, , 1: 369-Google Scholar
- Sanne I, Mommeja-Marin H, Hinkle J, Bartlett JA, Lederman MM, Maartens G, Wakeford C, Shaw A, Quinn J, Gish RG, Rousseau F: Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis. 2005, 191: 825-829. 10.1086/428093.View ArticlePubMedGoogle Scholar
- Reisler K: High hepatotoxicity rate seen among HAART patients. AIDS Alert. 2001, 16: 118-119.PubMedGoogle Scholar
- Stranges S, Freudenheim JL, Muti P, Farinaro E, Russell M, Nochajski TH, Trevisan M: Greater hepatic vulnerability after alcohol intake in African Americans compared with Caucasians: a population-based study. J Natl Med Assoc. 2004, 96: 1185-1192.PubMedPubMed CentralGoogle Scholar
- Ma B, Yeo W, Hui P, Ho WM, Johnson PJ: Acute toxicity of adjuvant doxorubicin and cyclophosphamide for early breast cancer -- a retrospective review of Chinese patients and comparison with an historic Western series. Radiother Oncol. 2002, 62: 185-189. 10.1016/S0167-8140(02)00003-8.View ArticlePubMedGoogle Scholar
- Critchley JA, Nimmo GR, Gregson CA, Woolhouse NM, Prescott LF: Inter-subject and ethnic differences in paracetamol metabolism. Br J Clin Pharmacol. 1986, 22: 649-657.View ArticlePubMedPubMed CentralGoogle Scholar
- Anekthananon T, Ratanasuwan W, Techasathit W, Sonjai A, Suwanagool S: Safety and efficacy of a simplified fixed-dose combination of stavudine, lamivudine and nevirapine (GPO-VIR) for the treatment of advanced HIV-infected patients: a 24-week study. J Med Assoc Thai. 2004, 87: 760-767.PubMedGoogle Scholar
- Montaner JS, Cahn P, Zala C, Casssetti LI, Losso M, Hall DB, Wruck J, McDonough M, Gigliotti M, Robinson PA: Randomized, controlled study of the effects of a short course of prednisone on the incidence of rash associated with nevirapine in patients infected with HIV-1. J Acquir Immune Defic Syndr. 2003, 33: 41-46.View ArticlePubMedGoogle Scholar
- Knobel H, Miro JM, Domingo P, Rivero A, Marquez M, Force L, Gonzalez A, De Miguel V, Sanz J, Boix V, Blanco JL, Locutura J: Failure of a short-term prednisone regimen to prevent nevirapine-associated rash: a double-blind placebo-controlled trial: the GESIDA 09/99 study. J Acquir Immune Defic Syndr. 2001, 28: 14-18.View ArticlePubMedGoogle Scholar
- Dailly E, Billaud E, Reliquet V, Breurec S, Perre P, Leautez S, Jolliet P, Bourin M, Raffi F: No relationship between high nevirapine plasma concentration and hepatotoxicity in HIV-1-infected patients naive of antiretroviral treatment or switched from protease inhibitors. Eur J Clin Pharmacol. 2004, 60: 343-348. 10.1007/s00228-004-0769-5.View ArticlePubMedGoogle Scholar
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