Standard-dose efavirenz vs. standard-dose ... - Wiley Online Library

DOI: 10.1111/j.1468-1293.2008.00563.x HIV Medicine (2008), 9, 294–299

r

2008 British HIV Association

ORIGINAL RESEARCH

Standard-dose efavirenz vs. standard-dose nevirapine in antiretroviral regimens among HIV-1 and tuberculosis co-infected patients who received rifampicin W Manosuthi,1,2 W Mankatitham,1 A Lueangniyomkul,1 S Chimsuntorn1 and S Sungkanuparph2 1 Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Nonthaburi, Thailand and 2Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand Background

There is limited comparative data between efavirenz (EFV) 600 mg/day and nevirapine (NVP) 400 mg/day-based antiretroviral therapy (ART) among HIV-1 patients with tuberculosis (TB) and receiving rifampicin. Methods

A retrospective cohort study was conducted in all ART-naı¨ve patients who were receiving rifampicin between January 2002 and December 2005. Results

Of 188 patients, 77 and 111 patients were initiated on EFV-based ART (EFV group) and NVP-based ART (NVP group), respectively. Overall, median [interquartile range (IQR)] CD4 count was 36 (15–77) cells/mL and median (IQR) viral load was 5.6 (5.2–5.9) HIV-1 RNA log copies/mL. At 48 weeks, 77.9% (60/77) in the EFV group and 67.6% (75/111) in the NVP group achieved HIV-1 RNA o50 copies/mL (P 5 0.140, odds ratio 5 0.590, 95% confidence interval 5 0.302–1.153). At 24 and 48 weeks, respective median CD4 counts were 174 and 254 cells/mL in the EFV group and 156 and 218 cells/mL in the NVP group (P40.05). By binary logistic regression, treatment group was not associated with HIV-1 RNA o50 copies/mL (P40.05). No patient in the EFV group and eight (7.2%) patients in the NVP group discontinued ART because of adverse reactions (P 5 0.084). Conclusions

For HIV–TB co-infected patients who receive rifampicin, efficacy of 600 mg EFV-based and 400 mg NVP-based ART may be similar, although adverse events tend to be higher in NVP-based ART. Keywords: efavirenz, HIV, nevirapine, standard dose, tuberculosis Received: 23 November 2007, accepted 1 February 2008 inhibitors (NNRTIs) is a widely used regimen, particularly in resource-limited countries [5,6]. In most patients, CD4 cell counts rise with immune recovery after ART. Besides the appropriate timing of ART initiation, pill burdens, patients’ adherence and overlapping toxicities, drug–drug interactions are also a major concern for treatment in HIV-1-infected patients with active TB [7]. To date, rifamycins are still the key drug class needed in the treatment of TB. Rifabutin is a weak cytochrome P450 enzyme inducer. Unfortunately, this drug is not available in many resource-limited countries, including Thailand. Therefore, rifampicin, a potent cytochrome P450 enzyme inducer, is still a key drug used for treatment of TB in these countries [8]. Moreover, current evidence shows clearly that relapse of TB in HIV-1-infected patients is minimized by a regimen containing rifampicin throughout the course of treatment [9].

Introduction Tuberculosis (TB) and HIV-1 are the two leading causes of infectious disease-associated mortality worldwide. The accessibility of effective combined antiretroviral therapy (ART) has been associated with dramatic declines in the incidence of new AIDS cases and various opportunistic infections (OIs) among HIV-1-infected patients in many countries [1–4]. ART based on non-nucleoside reverse transcriptase

The abstract of this study was presented at the 11th European AIDS Conference, Madrid, October 2007 [Abstract P17.1/38]. Correspondence: Weerawat Manosuthi, Department of Medicine, Bamrasnaradura Infectious Diseases Institute, Tiwanon Road, Nonthaburi 11000, Thailand. Tel: 66 2 590 3408; fax: 66 2 590 3411; e-mail: [email protected]

294

Standard-dose efavirenz vs. nevirapine 295

The drug–drug interactions of rifampicin and either NNRTIs or protease inhibitors (PIs) cause decreased plasma concentrations of NNRTIs and PIs, potentially leading to a loss of antiviral efficacy and subsequent accumulation of resistance mutations [10,11]. Nonetheless, a number of previous studies demonstrated that the standard dose of efavirenz (EFV) and nevirapine (NVP) in ART was associated with favourable outcomes in patients who were concomitantly receiving these NNRTIs with rifampicin [12–16]. On the other hand, there are few interactions with rifampicin and nucleoside reverse transcriptase inhibitors (NRTIs) but no specific changes of NRTIs’ dosage are needed. To date, comparative data are still lacking regarding efficacy, safety and tolerability between EFVbased and NVP-based ART among HIV-1-infected patients who were diagnosed with active TB and received rifampicin-containing anti-tuberculous regimens.

Patients and methods A retrospective cohort study was conducted among ARTnaı¨ve HIV-1-infected patients who were diagnosed with active TB and were subsequently initiated on ART between January 2002 and December 2005 at Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Nonthaburi, Thailand. This institute is a tertiary care referral centre for HIV-1-infected patients from Nonthaburi province and the northwestern part of Bangkok. The patients’ identification numbers were obtained from the annual database of the institute. Data were extracted from medical records. Inclusion criteria were as follows: (i) HIV1-infected patients 415 years of age; (ii) naı¨ve to ART prior to the diagnosis of TB; (iii) diagnosed with active TB by clinical features, positive acid fast stain and/or positive culture for Mycobacterium tuberculosis; (iv) receiving rifampicin-containing anti-tuberculous regimens o4 months prior to initiation of ART; (v) initiated with ART based on EFV 600 mg/day or NVP 400 mg/day (divided to twice a day); and (vi) received ART over at least two clinic visits. Patients were excluded if they had baseline serum creatinine 42.0 mg/dL. All eligible patients were followed until 48 weeks after ART initiation except those who were lost to follow-up, transferred out or deceased. They were categorized into two groups according to their antiretroviral regimens: EFV-based regimen (EFV group) and NVPbased regimen (NVP group). All patients were cared for and followed up every 6–8 weeks to monitor clinical response and adverse reactions, as per standard of care in our institute. The final decision regarding whether the relevant adverse events developed was determined by the attending investigator. In routine clinical practice, uncomplicated TB is treated by using standard therapy of 6-month anti-

r

2008 British HIV Association HIV Medicine (2008) 9, 294–299

tuberculous regimen of isoniazid, rifampicin, pyrazinamide and ethambutol. If the therapeutic response is delayed, the consolidation phase of therapy is extended and the total duration of anti-tuberculous therapy is extended to 9–12 months, based on individual clinical response. The primary outcomes of interest were virological success after 48 weeks of ART and the definition of the factor that related to virological success. Virological success was defined as achieving plasma viral load o50 HIV-1 RNA copies/mL. The secondary objectives were: (i) to compare immunological responses after 24 and 48 weeks of ART between the two groups; (ii) to compare adverse drug reactions between the two groups; and (iii) to study overall treatment outcomes of TB after 48 weeks of ART. TB treatment outcome (cure, treatment completed or treatment failure) was evaluated using definitions from the World Health Organization and the European Region of the International Union Against Tuberculosis and Lung Disease [17]. Possible factors, along with other data collected, were studied and compared between the two groups. This included patients’ demographic information, previous OIs, baseline CD4 cell counts, baseline log plasma HIV-1 RNA and timing from TB diagnosis to ART initiation. CD4 cell counts were measured by flow cytometry. Plasma HIV-1 RNA levels were monitored by reverse transcription polymerase chain reaction (COBAS AMPLICOR HIV-1 monitor version 1.5; Roche Diagnostics GmbH, Mannheim, Germany). HIV-1 RNA levels were expressed as copies/mL of plasma; the lower detection limit of the assay was 50 copies/mL. Mean [ standard deviation (SD)], median [interquartile range, (IQR)] and frequencies (%) were used to describe patients’ characteristics in each group. The w2 test and Mann–Whitney U-test were used to compare categorical variables and continuous variables between the two groups, respectively. The proportions of patients with plasma HIV-1 RNA o50 copies/mL after 48 weeks of ART were analysed as intention-to-treat. Missing data on plasma HIV-1 RNA levels were taken to be 450 copies/mL. The increments of CD4 cell counts between the two groups were compared by Mann–Whitney U-test. The binary logistic regression model was used to determine the factors associated with achieving plasma HIV-1 RNA o50 copies/mL after 48 weeks of ART and the factors associated with cure/complete treatment of TB. The odds ratio (OR) and its 95% confidence interval (CI) were estimated. All analyses were performed using SPSS version 11.5 (SPSS, Chicago, IL, USA). A P-value o 0.05 was considered statistically significant. The study was reviewed and approved by the institute review board and ethics committee of the Department of Disease Control, Ministry of Public Health.

296 W Manosuthi et al.

Table 1 Baseline characteristics of patients in the efavirenz (EFV) and nevirapine (NVP) groups Baseline characteristics

EFV group (n 5 77)

NVP group (n 5 111)

P-value

Age (years), mean SD Male gender, n (%) Body weight (kg), mean SD Previous major OIs, n (%) Median CD4 count (cells/mL) (IQR) Median % CD4 (IQR) Baseline plasma HIV-1 RNA copies/mL, median (IQR) Baseline log HIV-1 RNA, median (IQR) Duration from TB diagnosis to ART initiation (months), median (IQR) Site of TB, n (%) Pulmonary TB Extrapulmonary/disseminated TB Duration of concurrent TB treatment and ART (months), median (IQR) Baseline ALP (mg/dL), median (IQR) Baseline AST (U/L), median (IQR) Baseline ALT (U/L), median (IQR)

35.8 6.8 54 (70.1) 52.8 8.4 14 (18.2) 36 (12–78) 4 (2–8) 372 000 (104 750–750 000) 5.6 (5.0–5.9) 2.6 (1.9–3.8)

35.1 6.8 82 (73.9) 53.7 8.7 24 (21.6) 36 (17–76) 4 (2–8) 451 500 (195 500–750 000) 5.7 (5.0–5.9) 1.4 (1.0–2.1)

0.501 0.620 0.478 0.470 0.639 0.761 0.539 0.464 o 0.001 0.138

44 (57.1) 33 (42.9) 5.5 (4.0–6.9)

50 (45.0) 61 (55.0) 5.6 (4.7–7.3)

144.5 (87.8–251.3) 38.0 (24.8–65.3) 26.0 (18.0–48.3)

0.083

111.0 (75.0–186.0) 34.5 (23.8–50.0) 24.5 (17.0–41.5)

0.088 0.436 0.544

ALP, alkaline phosphatase; ALT, alanine aminotransferase; ART, antiretroviral therapy; AST, aspartate aminotransferase; IQR, interquartile range; OI, opportunistic infection; SD, standard deviation; TB, tuberculosis.

Results In total, 188 patients met the inclusion criteria and medical records were retrieved and reviewed. Overall, mean SD age was 36 8 years; 72% were male. Median (IQR) baseline CD4 count was 36 (15–77) cells/mL and median (IQR) plasma HIV-1 RNA was 5.6 (5.2–5.9) log copies/mL. We compared the patients’ characteristics in the two groups, as shown in Table 1. Median (IQR) duration from TB treatment to ART initiation was 2.6 (1.9–3.8) months in the EFV group and 1.4 (1.0–2.1) months in the NVP group (Po0.001). Other baseline characteristics were not different between the two groups (P40.05). Regarding backbone regimens, all patients in the EFV group received stavudine (d4T) and lamivudine (3TC). Of the 111 patients in the NVP group, 91 (82.0%) patients received d4T and 3TC and 20 (18.0%) patients received zidovudine and 3TC. The virological responses at week 24 and week 48 were compared as shown in Table 2. At 48 weeks, 60 of 77 (77.9%) patients in the EFV group and 75 of 111 (67.6%) patients in the NVP group achieved plasma HIV-1 RNA o50 copies/mL (P 5 0.140, OR 5 0.590, 95% CI 5 0.302– 1.153). By binary logistic regression analysis, none of the possible factors was associated with plasma HIV-1 RNA o50 copies/mL at week 48 after adjusting for group of ART, gender, baseline CD4 cell counts, plasma HIV-1 RNA o50 copies/mL at week 12 and timing from diagnosis of TB to ART initiation (P40.05). After 24 and 48 weeks of ART, respective median CD4 counts were 174 and 254 cells/ mL in the EFV group and 156 and 218 cells/mL in the NVP group (P40.05). At week 48 of ART, four patients in both groups had no results of plasma HIV-1 RNA. No patient in the EFV group and eight (7.2%) patients in the NVP group

Table 2 Proportions of patients who achieved undetectable plasma HIV-1 RNA after 24 and 48 weeks of antiretroviral therapy

Plasma HIV-1 RNA Week 24 o400 copies/mL o50 copies/mL Week 48 o400 copies/mL o50 copies/mL

EFV group (n 5 77)

NVP group (n 5 111)

P-value

OR, 95% CI

67 (87.0%) 66 (85.7%)

84 (75.7%) 89 (80.2%)

0.601 0.816

0.674, 0.306–1.487 0.816, 0.405–1.645

60 (77.9%) 60 (77.9%)

75 (67.6%) 75 (67.6%)

0.140 0.140

0.590, 0.302–1.153 0.590, 0.302–1.153

CI, confidence interval; EFV, efavirenz; NVP, nevirapine; OR, odds ratio.

Table 3 Reasons for discontinuation of antiretroviral therapy in the efavirenz (EFV) and nevirapine (NVP) groups

Outcomes

EFV group (n 5 77)

NVP group (n 5 111)

P-value

Drug allergy Lost to follow-up Died Treatment failure Transferred care

0 10 1 2 0

8 6 7 9 2

0.084 0.108 0.144 0.204 1.000

(0%) (12.9%) (1.3%) (2.6%) (0%)

(7.2%) (5.4%) (6.3%) (8.1%) (1.8%)

had to discontinue ART prematurely because of adverse reactions (P 5 0.084). All causes of NVP discontinuation were related to skin reactions grade II–III, and all developed within the first 12 weeks after commencing NVP. NVP was substituted for EFV among these patients. All patients could tolerate EFV well. The reasons for ART discontinuation between the two groups are shown in Table 3. The causes of death of seven patients in the NVP group were: five TB-related events, one disseminated

r



Mycobacterium avium complex infection and one hepatocellular carcinoma. One patient in the EFV group died from tuberculous meningitis. After 48 weeks of ART, 144 (76.6%), 21 (11.2%), 11 (5.8%), seven (3.7%) and five (2.7%) patients were cured/completed treatment, lost to follow-up, transferred care, died or were receiving TB treatment (recurrent or drug-resistant), respectively. Four of seven (57.1%) causes of death were related to TB; one of these was related to TB immune reconstitution inflammatory syndrome (IRIS). One patient died from IRIS caused by increased intracranial pressure.

Discussion TB is an important illness that enters into HIV/AIDS care and is also the most frequent major OI in HIV-1-infected patients in resource-limited countries – including Thailand, where the prevalence of TB is high [18,19]. Thus, the clinical data of ART in the patients undergoing treatment for TB is required urgently. From our best knowledge, the present study is the first that attempts to compare efficacy and tolerability between standard doses of EFV-based and NVP-based ART, while the results from the prospective randomized control trial are not yet available. In resource-limited countries, HIV-1-infected patients often present late with advanced AIDS and major OIs [19]. In the present study, three-quarters of patients had baseline CD4 counts of o75 cells/mL. The results from the present study have demonstrated that the proportions of patients who achieved undetectable plasma HIV-1 RNA at both week 24 and week 48 of ART were not different between the EFV and NVP groups, either in univariate or multivariate analyses. Our results of virological success rates are concordant with a previous study comparing EFV-based and NVP-based ART in patients without TB by van Leth et al. [6], which demonstrated that 70% of patients who received NVP twice daily and 65.4% of patients who received EFV achieved plasma HIV-1 RNA o50 copies/mL. Furthermore, immunological outcomes are comparable between the two groups. Regarding adverse drug reactions leading to discontinuation of ART, it appears that the patients who received NVPbased ART have a higher tendency of ART discontinuation because of adverse drug reactions compared to the other group (7.2% vs. 0%). All skin reactions resolved after discontinuation of NVP. The rate of NVP-associated skin rash is comparable to previous studies conducted in those who concurrently received NVP and rifampicin [12]. Symptomatic, serious and even fatal liver toxicities were not observed in this cohort. A 12-fold higher incidence of symptomatic events was seen in women with CD4 counts 4250 cells/mL at the time of NVP initiation compared to

r


women with CD4 counts 250 cells/mL (11.0% vs. 0.9%). An increased risk was also seen in men with baseline CD4 counts 4400 cells/mL compared to baseline CD4 counts 400 cells/mL (6.3% vs. 1.2%) [20–23]. The other established risk factors for symptomatic hepatic adverse events included elevated pretreated aspartate aminotransferase (AST) value and hepatitis B virus (HBV) and/or hepatitis C virus (HCV) co-infection [24,25]. In the present study, most patients had no impairment of baseline liver function and had very low baseline CD4 cell count. This may be the reason why the rate of liver toxicity is very low. Current recommendations for the treatment of HIV-1 associated TB are the same as those for the treatment of TB in HIV-1 uninfected adults [26]. Consensus exists that TB treatment regimens containing rifampicin for the entire treatment period have better outcomes than do those including rifampicin only for the initial 2 months [26]. Previous studies of co-infected HIV-1 and TB patients with a 6-month duration of treatment with rifampicin-containing anti-tuberculous regimens showed cure rates of 59–97% [27]. In the present study, over three-quarters of our patients had cured and complete treatment of TB – this rate is considered favourable. Immune restoration from effective ART initiation, combined with completion of TB treatment, contributed to the successful treatment of TB. However, long-term follow-up of relapse rate should be further evaluated. There are some limitations in the present study. First, it is the nature of retrospective study that detail of patients’ clinical condition, such as adherence to ART and frequency of clinic visits, may be underestimated. Second, sample size may not be enough to detect a difference of efficacy between the two groups. Third, some patients may have co-infection with HBV or HCV. Most of our patients were not tested routinely for HBsAg and antibody to HCV. Therefore, we lack these factors in the multivariate analysis. However, our previous study showed that the prevalence rates of HBV or HCV co-infection with HIV-1 were about 9% and 8%, respectively, in HIV-1 infected Thai patients [28]. Fourth, the average baseline body weight of patients in this study is 53 kg and the SD value is 8 kg. Therefore, the result may not be applicable to the patients with body weight 460 kg. Fifth, patients should be monitored for a longer time in order to assess treatment outcomes of TB, such as 2-year relapse rate. Ultimately, based on the number of patients in the study, the statistical power to detect the difference is limited. A well-designed prospective trial should be conducted in future to confirm this result. In summary, HIV-1 and TB co-infected patients who receive rifampicin-containing anti-tuberculous regimens, antiretroviral regimens with standard doses of 600 mg EFV or 400 mg NVP are not different in terms of efficacy.

298 W Manosuthi et al.

Adverse events tend to be higher in HIV-1-infected patients who concomitantly received NVP-based ART and rifampicin. Treatment outcome of TB is favourable among these patients. However, a prospective randomized control study of standard doses of 600 mg EFV and 400 mg NVP for longterm antiviral efficacy is needed to confirm this finding.

Acknowledgements The authors would like to thank all the attending staff and physicians in the Department of Medicine at Bamrasnaradura Infectious Diseases Institute for their support. This study was supported by a research grant from the Bamrasnaradura Infectious Diseases Institute.

Council tuberculosis units, 1946–1986, with relevant subsequent publications. Int J Tuberc Lung Dis 1999; 3 (Suppl.): 231–279. 10 Gonzalez de Requena D, Bonora S, Garazzino S et al. Nevirapine plasma exposure affects both durability of viral suppression and selection of nevirapine primary resistance mutations in a clinical setting. Antimicrob Agents Chemother 2005; 49: 3966–3969. 11 Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 2001; 15: 71–75. 12 Manosuthi W, Sungkanuparph S, Thakkinstian A et al. Plasma nevirapine levels and 24-week efficacy in HIV-infected patients receiving nevirapine-based highly active antiretroviral therapy with or without rifampicin. Clin Infect Dis 2006; 43:

References 1 Egger M, Hirschel B, Francioli P et al. Impact of new

253–255. 13 Manosuthi W, Sungkanuparph S, Thakkinstian A et al.

antiretroviral combination therapies in HIV-infected patients in

Efavirenz levels and 24-week efficacy in HIV-infected patients

Switzerland: prospective multicentre study. Swiss HIV Cohort

with tuberculosis receiving highly active antiretroviral therapy and rifampicin. AIDS 2005; 19: 1481–1486.

Study. BMJ 1997; 315: 1194–1199. 2 Ledergerber B, Egger M, Opravil M et al. Clinical progression and virological failure on highly active antiretroviral therapy

14 Dean GL, Back DJ, de Ruiter A. Effect of tuberculosis therapy on nevirapine trough plasma concentrations. AIDS 1999; 13: 2489–2490.

in HIV-1 patients: a prospective cohort study. Swiss HIV Cohort Study. Lancet 1999; 353: 863–868.

15 Ribera E, Pou L, Lopez RM et al. Pharmacokinetic interaction between nevirapine and rifampicin in HIV-infected patients

3 Palella FJ Jr, Delaney KM, Moorman AC et al. Declining morbidity and mortality among patients with advanced human

with tuberculosis. J Acquir Immune Defic Syndr 2001; 28:

immunodeficiency virus infection. HIV Outpatient Study

450–453.

Investigators. N Engl J Med 1998; 338: 853–860.

16 Oliva J, Moreno S, Sanz J et al. Co-administration of rifampin and nevirapine in HIV-infected patients with tuberculosis. AIDS 2003; 17: 637–638.

4 Manosuthi W, Chottanapand S, Thongyen S, Chaovavanich A, Sungkanuparph S. Survival rate and risk factors of mortality among HIV/tuberculosis-coinfected patients with and without

17 Veen J, Raviglione M, Rieder HL et al. Standardized

antiretroviral therapy. J Acquir Immune Defic Syndr 2006; 43:

tuberculosis treatment outcome monitoring in Europe.

42–46.

Recommendations of a Working Group of the World Health Organization (WHO) and the European Region of the

5 Hammer SM, Saag MS, Schechter M et al. Treatment for adult HIV infection: 2006 recommendations of the International

International Union Against Tuberculosis and Lung Disease

AIDS Society – USA Panel. JAMA 2006; 296: 827–843.

(IUATLD) for uniform reporting by cohort analysis of treatment outcome in tuberculosis patients. Eur Respir J 1998; 12: 505–510.

6 van Leth F, Phanuphak P, Ruxrungtham K et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and

18 Nunn P, Reid A, De Cock KM. Tuberculosis and HIV infection: the global setting. J Infect Dis 2007; 196 (Suppl. 1):

lamivudine: a randomised open-label trial, the 2NN Study.

5–14.

Lancet 2004; 363: 1253–1263. 7 McIlleron H, Meintjes G, Burman WJ, Maartens G.

19 Ruxrungtham K, Phanuphak P. Update on HIV/AIDS in Thailand. J Med Assoc Thai 2001; 84 (Suppl. 1): 1–17.

Complications of antiretroviral therapy in patients with tuberculosis: drug interactions, toxicity, and immune

20 Baylor MS, Johann-Liang R. Hepatotoxicity associated with nevirapine use. J Acquir Immune Defic Syndr 2004; 35: 538–539.

reconstitution inflammatory syndrome. J Infect Dis 2007; 196 (Suppl. 1): 63–75. 8 Finch CK, Chrisman CR, Baciewicz AM, Self TH. Rifampin and

21 Sanne I, Mommeja-Marin H, Hinkle J et al. Severe hepatotoxicity associated with nevirapine use in HIV-infected

rifabutin drug interactions: an update. Arch Intern Med 2002;

subjects. J Infect Dis 2005; 191: 825–829.

162: 985–992. 9 Fox W, Ellard GA, Mitchison DA. Studies on the treatment of

22 Reisler K. High hepatotoxicity rate seen among HAART patients. AIDS Alert 2001; 16: 118–119.

tuberculosis undertaken by the British Medical Research

r



23 Stern JO, Robinson PA, Love J, Lanes S, Imperiale MS, Mayers

HIV-associated tuberculosis. J Infect Dis 2007; 196 (Suppl. 1):

different populations of HIV-infected patients. J Acquir

35–45.

Immune Defic Syndr 2003; 34 (Suppl. 1): 21–33. 24 Ena J, Amador C, Benito C, Fenoll V, Pasquau F. Risk and determinants of developing severe liver toxicity during therapy with nevirapine- and efavirenz-containing regimens in HIV-infected patients. Int J STD AIDS 2003; 14: 776–781. 25 Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD.

r

26 Onyebujoh PC, Ribeiro I, Whalen CC. Treatment options for

DL. A comprehensive hepatic safety analysis of nevirapine in

27 El-Sadr WM, Perlman DC, Denning E, Matts JP, Cohn DL. A review of efficacy studies of 6-month short-course therapy for tuberculosis among patients infected with human immunodeficiency virus: differences in study outcomes. Clin Infect Dis 2001; 32: 623–632. 28 Sungkanuparph S, Vibhagool A, Manosuthi W et al. Prevalence

Hepatotoxicity associated with nevirapine or efavirenz-

of hepatitis B virus and hepatitis C virus co-infection with

containing antiretroviral therapy: role of hepatitis C and B

human immunodeficiency virus in Thai patients: a tertiary-

infections. Hepatology 2002; 35: 182–189.

care-based study. J Med Assoc Thai 2004; 87: 1349–1354.
