Nevirapine Levels after Discontinuation of Rifampicin Therapy and 60-Week Efficacy of Nevirapine-Based Antiretroviral Therapy in HIV-Infected Patients with Tuberculosis

The growing epidemic of HIV infection poses a serious public health problem worldwide. Combined antiretroviral therapy (ART) can reduce the risk of mortality among patients coinfected with HIV and tuberculosis (TB) [1]. Nevirapine (NVP) is a nonnucleoside reverse-transcriptase inhibitor that has shown effective antiretroviral efficacy [2]. TB is the most common AIDS-defining illness in HIV-infected patients [3]. The potential for drug-drug interactions is a major concern among HIV-infected patients concurrently receiving both HIV and TB treatments. Both NVP and rifampicin (RFP) can induce cytochrome P450 isoenzyme in the liver [4]. Our previous study [5] demonstrated that the NVP level is significantly lower in patients who are concurrently receiving RFPwith RFP. However, the short-term efficacy of ART was similar for HIV-infected patients who concurrently received RFP and HIV-infected patients who did not receive RFP. The results of long-term efficacy studies are needed. In addition, changes in NVP level after discontinuation of RFP therapy have not been established. Another concern is whether NVP-associated adverse events will develop after discontinuation of RFP therapy because of the increase in NVP level.

Herein, we continue the previously described prospective cohort study [5], with the objective being to (1) determine the trough plasma NVP levels after discontinuation of RFP therapy and compare those levels with NVP levels determined while the patients were receiving RFP, (2) compare the antiretroviral efficacy after 60 weeks of NVP-based ART between HIV-infected patients with TB receiving rifampicin and HIV-infected patients without TB, and (3) observe NVP-associated adverse events after discontinuation of RFP therapy.

Materials and methods. The study was designed as a prospective cohort study involving 140 HIV-infected patients at the Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health (Nonthaburi, Thailand). There were 70 patients who had TB and were receiving RFP (the TB group) and 70 patients who did not have TB (the control group). Enrollment criteria are described elsewhere [5]. The administered antiretroviral drugs were stavudine, lamivudine, and NVP. In the present study, the patients in the TB and control groups were followed up through 60 weeks, during which period they were assessed clinically and evaluated for adverse events. CD4⁺ cell count, HIV RNA level, and alanine aminotransferase (ALT) level were assessed at 36, 48, and 60 weeks of ART. The patients in the TB group were repeatedly tested to determine trough NVP levels after discontinuation of RFP therapy at 60 weeks of ART. Serum alkaline phosphatase (ALP) and ALT enzyme levels were measured before and after discontinuation of RFP therapy. The institutional ethics committees of Bamrasnaradura Infectious Diseases Institute and the Thai Ministry of Public Health approved the study.

The anti-TB regimen consisted of isoniazid, RFP, ethambutol, and pyrazinamide administered during the first 2 months of therapy, followed by isoniazid and RFP for the subsequent 4 months. 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 [6].

Power and Sample Size, version 1.01 (Dupont and Plummer), was used to calculate sample size, as described elsewhere [5]. Paired Student's t tests were used to compare plasma NVP levels, ALP levels, and ALT levels before and after discontinuation of RFP therapy. A χ² test was used to compare the number of patients who achieve undetectable HIV RNA levels between groups. A P value <.05 was considered to be statistically significant. All analyses were performed using SPSS software, version 11.5 (SPSS).

Results. A total of 140 patients were initially enrolled in the study. Seventy patients each were in the TB group and the control group. The patients' baseline demographic and clinical characteristics are summarized in table 1. The median duration of concomitant receipt of NVP and RFP in the TB group was 5.8 months.

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Figure 1

Distribution of mean plasma nevirapine (NVP) levels (±;SD) at weeks 8 and 12 (with rifampicin [RFP] therapy) and at week 60 (without RFP therapy) in the tuberculosis group.

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Table 1

Baseline characteristics of 140 HIV-infected patients.

Of 70 patients in the TB group, 31 (44.3%), 20 (28.6%), 14 (20%), 3 (4.3%), and 2 (2.9%) of the patients received diagnoses of pulmonary TB, disseminated TB, cervical TB lymphadenitis, gastrointestinal TB, and TB meningitis, respectively. Sixty (86%) of the patients were cured or completed treatment, 5 were lost to follow-up, 3 died (1 each from Mycobacterium avium complex infection, TB paradoxical reaction, and severe wasting), and 2 experienced treatment failure.

The distribution of plasma NVP levels after discontinuation of RFP therapy for the patients in TB group, compared with the mean level at weeks 8 and 12 (when the patients were receiving RFP) are shown in figure 1. After discontinuation of RFP therapy, the patients had an increase in mean (±;SD) NVP level to 6.4 ±; 3.4 mg/L, and this was higher than the mean (±;SD) NVP level for weeks 8 and 12 (5.40 ±; 3.53 mg/L; P = .047). There were no differences in mean (±;SD) serum ALP level (101.0 ±; 51.7 vs. 100.3 ±; 42.2; P = .851) and ALT level (49.9 ±; 66.0 vs. 39.6 ±; 41.2; P = .166) before and after discontinuation of RFP therapy. There was 1 male patient who had an elevated ALT level >5 time of upper limit of normal value within 3 months after RFP therapy discontinuation. Mean (±;SD) ALT levels at week 60 were 37.2 ±; 28.9 U/L in the TB group and 34.0 ±; 27.9 U/L in the control group (P = .575). No patients developed NVP-related adverse events.

At 60 weeks of ART, the proportion of patients who achieved plasma HIV RNA loads of <50 copies/mL did not differ between the TB and control groups with respect to intention-to-treat analysis (68.8% vs. 68.8%; P = 1.000) and the on-treatment analysis (85.7% vs. 87.3%; P = 1.000). Median CD4⁺ cell counts at 60 weeks of ART were 234 cells/mL (interquartile range, 171–402 cells/mL) in the TB group and 274 cells/mL (interquartile range, 162–356 cells/mL) in the control group, and there were no differences with respect to changes in CD4⁺ cell count between the 2 groups (P = .385).

Discussion. In the present study, we have shown that the mean trough plasma NVP level of patients in the TB group increased by 16.7% after discontinuation of RFP therapy, compared with during the period of concomitant administration of NVP and RFP. This difference is considered to be relatively low, compared with the findings of previous studies [7, 8]. This discrepancy may be partly explained by the fact that our study was conducted in Thailand, unlike the previous report. Kappelhoff et al. [9] have demonstrated that individuals from Thailand have lower clearance of NVP, compared with persons of other ethnicities. The increase in NVP level raises concern regarding NVP toxicity when RFP therapy is discontinued in patients receiving NVP-based ART. Liver toxicity has been reported to correlate with either hypersensitivity reaction during the early period of receiving NVP or a dose-dependent mechanism [10]. Consequently, the CD4⁺ cell counts of the patients increased over time while they were receiving antiretroviral drugs. A high incidence of nonnucleoside reverse-transcriptase inhibitor—related hepatotoxicity has been reported in patients with high CD4⁺ cell counts [11, 12]. Nevertheless, no patients in the TB group experienced adverse events after discontinuation of RFP therapy. Serum ALP and ALT levels did not differ before and after discontinuation of RFP therapy.

To date, there are a number of pharmacokinetic studies of concomitant administration of both drugs [7, 13, 14]. However, a prospective cohort study regarding the correlation of NVP level and long-term outcomes is still limited. The present study has demonstrated the long-term virological and immunological outcomes of NVP-based ART initiated in HIV-infected patients receiving RFP. By on-treatment analysis, >85% of patients in the TB group achieved undetectable plasma HIV RNA levels of <50 copies/mL, and this percentage was not different from that in the control group. Although some baseline factors (i.e., sex, age, history of previous opportunistic infections, and plasma HIV RNA level) were significantly different between the TB group and the control group, the logistic regression analysis showed that these factors were not associated with undetectable HIV RNA levels at week 60 of ART.

Among 17 patients in the TB group who had trough plasma NVP levels of <3.4 mg/L after 8 weeks of ART, 14 patients continued through follow-up and were assessed for virological response at 60 weeks of ART. Twelve (86.0%) of 14 patients achieved undetectable plasma HIV RNA levels at 60 weeks. Therefore, the virological response among patients in the TB group with NVP levels <3.4 mg/L was comparable to that for patients with NVP levels ⩾ 3.4 mg/L (85.7%). In addition, demographic characteristics for patients who had NVP levels <3.4 mg/L after 8 weeks of ART were not different with those for patients who had NVP levels ⩾ 3.4 mg/L (data not shown). This may be explained by the fact that NVP has a high therapeutic index. In HIV-infected patients receiving the standard dose of NVP, the mean minimum plasma level (±;SD) in the steady state is 6.56 ±; 3.11 mg/L, which is much greater than the usual IC₅₀ of this drug (0.0025–0.025 mg/L) [15].

A limitation of the present study is that the incidence of adverse events should be interpreted with caution because of the sample size and the small number of women in the present study. The sample size may not be large enough to detect differences regarding the relatively low incidence of clinical hepatitis. However, our sample size is adequate to determine differences with respect to NVP levels and treatment outcomes. Another caution is that our patients had a mean body weight of 55 kg. The results may not be applicable to patients with higher body weight.

In conclusion, NVP-associated adverse events do not occur after RFP discontinuation in patients coinfected HIV and TB who have previously received NVP-based ART and RFP-based antituberculosis regimens, despite increases in NVP level and CD4⁺ cell count. Long-term efficacy of NVP-based ART is comparable for HIV-infected patients who do and HIV-infected patients who do not receive RFP. NVP-based ART should be an appropriate option for patients with HIV and TB coinfection, particularly in resource-limited countries.

• Received July 21, 2006.
• Accepted September 1, 2006.

• © 2007 by the Infectious Diseases Society of America