Short communication: Aging not gender is associated with high atazanavir plasma concentrations in Asian HIV-infected patients.

Physiological effects of aging make the older population more susceptible to adverse drug events and drug-drug interactions. We evaluated the impact of aging and gender on the pharmacokinetics (PK) of atazanavir/ritonavir (ATV/r) 300/100 mg once daily (qd) in 22 well-suppressed HIV-infected patients. This was a 24-h intensive PK study. Subjects were HIV-1-infected adults aged ≥18 years with HIV RNA <50 copies/ml and treated with ATV/r 300/100 mg once daily plus two nucleoside reverse transcriptase inhibitors (NRTIs) for at least 2 weeks. Atazanavir and ritonavir plasma concentrations were measured by validated high-performance liquid chromatography (HPLC). Plasma PK parameters were calculated using noncompartmental methods. Since 50% of the patients were older than 42 years, age 42 was selected as the cut-off point for the older (>42 years) group. Gender, weight, duration of ATV/r therapy, and proportion treated with tenofovir disoproxil fumarate (TDF)-containing regimens did not differ between both groups. Patients from the aging group had a reduced creatinine clearance (91 versus 76 ml/min). The older group had a higher atazanavir exposure with median AUC(0-24) 71.2 vs. 53.1 mg·h/liter, C(max) 8.5 vs. 5.5 mg/liter, and C(trough) 1.17 vs. 0.78 mg/liter, and slower apparent clearance (3.5 vs. 4.8 liter/h). Ten patients (91%) from the older group and 36% from the younger group had ATV C(trough) levels higher than the proposed upper limit for toxicity of 0.85 mg/liter. Females had a lower body weight (BW) (46 versus 63 kg) than the males, but atazanavir concentrations in females were greater. However, in multivariate analysis, older age was the only significant predictor for higher atazanavir concentrations. Parameter estimate for age and atazanavir AUC after adjusting for gender and BW was 2.17 (95% CI 1.01-3.33). That is, for every year increase in age, AUC increases by approximately 2 mg·h/liter. Age seems to be an important factor influencing atazanavir pharmacokinetics. Patients from the aging group appeared to have higher atazanavir exposure compared to the younger group. Further PK explorations of ATV in the extremely aged population are warranted.

Efavirenz, in contrast to nevirapine, is associated with unfavorable progesterone and antiretroviral levels when coadministered with combined oral contraceptives.

BACKGROUND: Effective contraception has been widely promoted for HIV-positive women. However, there are limited data on the interactions between combined hormonal contraceptives and nonnucleoside reverse transcriptase inhibitors . METHODS: This study assessed the steady-state contraceptive effectiveness and safety of combined oral contraceptive (COC) containing 0.150 mg desogestrel /0.030 mg ethinyl estradiol with either nevirapine (NVP) or efavirenz (EFV) in 34 HIV-positive women. The targeted level for contraceptive effectiveness was endogenous progesterone level < 3.0 ng/mL. We measured NVP/EFV plasma concentrations 12 hours after administration (C12) with and without COC. The desired therapeutic levels were >3.1 mg/L for NVP and 1.0-4.0 mg/L for EFV, respectively. RESULTS: All 18 subjects in the NVP group had serum progesterone <1.0 ng/mL. Four of 16 subjects (25%) in the EFV group had serum progesterone >1.0 ng/mL, including 3 subjects with >3.0 ng/mL (might indicate ovulation). The difference in progesterone levels between the 2 groups was statistically significant (P = 0.04). The median C12 of NVP increased insignificantly by 17% with COC; the median C12 of EFV decreased significantly (P = 0.02) by 22%. In 3 of 16 subjects (19%) in the EFV group, C12 of EFV dropped below 1.0 mg/L. CONCLUSIONS: In contrast to NVP, coadministrating desogestrel/ethinyl estradiol containing COC with EFV was associated with unfavorable progesterone and antiretroviral levels. Our results suggest that NVP may be superior to EFV when used with COC in HIV-positive women.

Pharmacokinetics and 48-week safety and efficacy of generic lopinavir/ritonavir in Thai HIV-infected patients.

BACKGROUND: Generic products reduce the costs of HIV treatment. Few generic second-line antiretroviral products are available. We assessed pharmacokinetics, safety and efficacy of generic lopinavir/ritonavir (LPV/r) produced by the Government Pharmaceutical Organization (GPO) of Thailand in Thai HIV-infected adults. METHODS: This was a single-arm prospective study. Patients with plasma HIV-1 RNA<50 copies/ml for ≥24 weeks, who were protease inhibitor (PI)-naive or experienced, were eligible. Patients started generic LPV/r tablets, 400/100 mg twice daily. At week 4, therapeutic drug monitoring was performed and analysed by validated HPLC. In patients using Kaletra(®) (Abbott Laboratories, North Chicago, IL, USA) soft gel capsules (SGC) or generic LPV/r tablets produced by Mylan (Canonsburg, PA, USA; formerly Matrix, Hyderabad, India) prior to study entry, we compared the plasma minimum concentrations (Cmin) of the different formulations. Plasma HIV-1 RNA and safety were assessed until week 48. RESULTS: A total of 70 patients (32 males) were enrolled. Mean (sd) age was 40.7 (7.9) years and mean (sd) body weight was 60.3 (9.0) kg. Before study entry, all patients were virologically suppressed using a PI-based regimen; 62 (88.6%) were using LPV/r (Kaletra(®) SGC n=22 and Mylan generic tablets n=40). Mean (sd) Cmin of GPO lopinavir and GPO ritonavir at week 4 were 7.1 (2.9) mg/l and 0.39 (0.21) mg/l, respectively, and not significantly different from the Cmin when taking Kaletra(®) SGC or Mylan generic tablets. After 48 weeks, 95.6% of patients maintained plasma HIV-1 RNA<50 copies/ml. Four grade 3 and no grade 4 adverse events were reported. CONCLUSIONS: Generic LPV/r showed adequate levels, good tolerability and excellent 48-week efficacy.

Pharmacokinetics of darunavir/ritonavir in Asian HIV-1-infected children aged ≥7 years.

BACKGROUND: The Asian population, in general, has higher antiretroviral concentrations than those who are not Asian, but there are limited pharmacokinetic data for darunavir/ritonavir in Asian children. METHODS: Thai children aged ≥7 years and with body weight (BW)≥20 kg who were on darunavir/ritonavir for ≥2 weeks underwent 12-h pharmacokinetics with blood sampling before and at 1, 2, 4, 6, 8, 10 and 12 h post-dosing. Darunavir/ritonavir doses were 375/100 mg twice daily (BW 20 to <30 kg, n=12), 450/100 mg twice daily (BW 30 to <40 kg, n=2) or 600/100 mg twice daily (BW ≥40 kg, n=5). Ritonavir 100 mg soft gel capsules were used instead of solution. RESULTS: Of the 19 children, 8 were female, median age was 13 years (range 7-16) and median BW was 29.4 kg. The median duration of darunavir/ritonavir treatment was 11 months. The geometric mean values for darunavir were 60.3 h×mg/l for the area under the concentration-time curve at 0-12 h (AUC(0-12)), 8.3 mg/l for the maximum concentration (C(max)) and 3.1 for the concentration prior to the next dose (C(12)) with no differences between dosing groups. All had C(12) above the protein binding adjusted 50% effective concentration (EC(50)) of protease inhibitor-resistant virus (0.55 mg/l). The darunavir pharmacokinetic parameters were similar to those in non-Asian individuals from the DELPHI study, in which 13 of 20 with BW<40 kg used 50 or 60 mg ritonavir boosting. CONCLUSIONS: Thai children aged ≥7 years who were on standard darunavir dosing with 100 mg ritonavir boosting had adequate and comparable darunavir AUC(0-12), C(max) and C(12) to non-Asian children who mainly used lower doses of ritonavir boosting. A ritonavir boosting dose of 100 mg can be used for children weighing ≥20 kg, particularly when lower dose formulations are unavailable or if intolerant to the solution.

Low dose lopinavir/ritonavir tablet achieves adequate pharmacokinetic parameters in HIV-infected Thai adolescents.

BACKGROUND: Lopinavir/ritonavir (LPV/r) is an effective and commonly used protease inhibitor in HIV-infected adolescents. Previous data showed high plasma concentrations of LPV in Thai patients. This study determined the pharmacokinetic (PK) parameters of a low-dose LPV/r tablet (70% of standard dose) in HIV-infected Thai adolescents. METHODS: A total of 24 adolescents on LPV/r-containing HAART regimens with HIV RNA<50 copies/ml were included. Standard and low doses for two different weight bands using LPV/r 100/25 mg tablet formulation twice daily were prescribed as follows: 3 and 2 tablets for adolescents weighing 25-35 kg, and 4 and 3 tablets for those weighing >35 kg, respectively. On the fourth week of treatment, PK was performed for all doses at 0 (pre-dose), 2, 4, 6, 8, 10 and 12 h. LPV and ritonavir concentrations were measured using the HPLC method. RESULTS: The median (IQR) age was 13.5 (12-15) years. The median LPV doses of standard and low doses were 290 and 208 mg/m(2). The mean (sd) area under the concentration-time curve at 0-12 h, maximum concentration and plasma concentration at 12 h for the standard dose were 97.6 (25.7) mg•h/l, 11.1 (2.6) mg/l and 4.1 (2.0) mg/l, and for the low dose were 87.4 (29.0) mg•h/l, 11.0 (3.1) mg/l and 3.2 (1.9) mg/l, respectively. No significant differences were detected between the groups. One child had plasma concentration at 12 h <1.0 mg/l while on low-dose LPV/r but HIV RNA was undetectable. CONCLUSIONS: The low-dose LPV/r tablet provides adequate PK parameters in HIV-infected Thai adolescents. A randomized study to assess the efficacy of low and standard doses of LPV/r among Thai HIV-infected adolescents should be explored.

Pharmacokinetics and 48 week efficacy of adjusted dose indinavir/ritonavir in rifampicin-treated HIV/tuberculosis-coinfected patients: a pilot study.

HIV/tuberculosis (HIV/TB)-coinfected patients intolerant/resistant to nonnucleoside reverse transcriptase inhibitors (NNRTIs) have limited treatment options. We evaluated the pharmacokinetics (PK)/safety/efficacy of an adjusted dose of indinavir/ritonavir (IDV/r) 600/100 mg plus two NRTIs in HIV/TB-coinfected Thais receiving rifampicin-based anti-TB treatment. This was a prospective, open-label study. Eighteen Thai, HIV/TB-coinfected patients between 18 and 60 years were recruited. IDV/r 600 mg/100 mg plus lamivudine and stavudine were administered every 12 h (bid). When rifampicin was stopped, IDV/r was reduced to 400/100 mg BID. Clinical outcomes, adverse events, and concomitant drugs were intensively collected. Intensive 12-h PK was performed after 2 weeks of IDV/r while on rifampicin. Samples were collected: predosing and 1, 2, 3, 4, 6, 8, 10, and 12 h after drug intake. The median body weight was 55 kg. The median CD4 was 26 cells/µl. The median HIV RNA was 5.05 log(10) copies/ml. Then 15/18 underwent intensive PK at week 2. The median time between initiating rifampicin and IDV/r was 4.5 months. The median duration of rifampicin during study (rifampicin/IDV/r together) was 15.6 weeks. All received a total of 9 months of antituberculous drugs. The geometric means (GM) of indinavir AUC(0-12) and C(12) were 8.11 mg*h/liter and 0.03 mg/liter, respectively. After stopping rifampicin and reducing IDV/r to 400/100 bid, the GM indinavir C(12) increased to 0.68 mg/liter (p=0.004). In all, 8/18 (44%) had asymptomatic ALT elevation and 2/18 (11%) had symptomatic hepatotoxicity requiring IDV/r discontinuation. All 13 patients who remained on IDV/r treatment had HIV RNA <50 copies/ml at 48 weeks. Concomitant use of rifampicin and IDV/r resulted in subtherapeutic indinavir concentrations. Although 44% of them developed asymptomatic Grade 3/4 transaminitis, the rate of study drug discontinuation due to hepatotoxicity was low. Despite good virological outcome in our cohort, prolonged exposure to subtherapeutic indinavir concentrations may lead to treatment failure.

Pharmacokinetics of and short-term virologic response to low-dose 400-milligram once-daily raltegravir maintenance therapy.

Because studies showed similar viral suppression with lower raltegravir doses and because Asians usually have high antiretroviral concentrations, we explored low-dose raltegravir therapy in Thais. Nineteen adults on raltegravir at 400 mg twice daily (BID) with HIV RNA loads of <50 copies/ml were randomized to receive 400 mg once daily (QD) or 800 mg QD for 2 weeks, followed by the other dosing for 2 weeks. Intensive pharmacokinetic analyses were performed, and HIV RNA was monitored. Two patients were excluded from the 400-mg QD analysis due to inevaluable pharmacokinetic data. The mean patient weight was 58 kg. Mean pharmacokinetic values were as follows: for raltegravir given at 400 mg BID, the area under the concentration-time curve from 0 to 12 h (AUC0₋12) was 15.6 mg/liter-h and the minimum plasma drug concentration (C(trough)) was 0.22 mg/liter; for raltegravir given at 800 mg QD, the AUC0₋24 was 33.6 mg/liter-h and the C(trough) was 0.06 mg/liter; and for raltegravir given at 400 mg QD, the AUC0₋24 was 18.6 mg/liter-h and the C(trough) was 0.08 mg/liter. The HIV RNA load was <50 copies/ml at each dose level. Compared to the adjusted AUC0₋24 for Westerners on raltegravir at 400 mg BID, Thais on the same dose had double the AUC0₋24 and those on raltegravir at 400 mg QD had a similar AUC0₋24. More patients had a C(trough) of <0.021 mg/liter on raltegravir at 400 mg QD (9/17 patients) than on raltegravir at 800 mg QD (1/19 patients) or 400 mg BID (0/19 patients). Seventeen patients used raltegravir at 400 mg QD for a median of 35 weeks; two had confirmed HIV RNA loads between 50 and 200 copies/ml, and both had low C(trough) values. Low-dose raltegravir could be a cost-saving option for maintenance therapy in Asians or persons with low body weight. However, raltegravir at 400 mg QD was associated with a low C(trough) and with a risk for HIV viremia. Raltegravir at 200 or 300 mg BID should be studied, but new raltegravir formulations will be needed.

Neither branded nor generic lopinavir/ritonavir produces adequate lopinavir concentrations at a reduced dose of 200/50 mg twice daily.

We assessed pharmacokinetic (PK) parameters of reduced dose lopinavir/ritonavir (LPV/r) and compared generic and branded tablets. Twenty HIV-infected patients using protease inhibitors with HIV RNA <50 copies per milliliter were randomized to generic or branded LPV/r 200/50mg twice daily (BID). At week 2, PK-sampling was performed. Patients crossed over to the other arm until week 12, with another PK-sampling at week 4. Subtherapeutic lopinavir concentrations were observed in 10/40 samples. PK parameters were comparable between branded and generic tablets. All patients remained virologically suppressed at week 12. In conclusion, LPV/r 200/50mg BID does not lead to adequate lopinavir plasma concentrations. Generic and branded LPV/r have comparable PK-parameters.

Thai HIV-1-infected women do not require a dose increase of lopinavir/ritonavir during the third trimester of pregnancy.

OBJECTIVES: To investigate whether Thai HIV-1-infected pregnant women require a dose increase of lopinavir/ritonavir (LPV/r) and to assess the safety and efficacy of the generic tablets during pregnancy. DESIGN: Prospective, single-center pharmacokinetic study. METHODS: HIV-infected pregnant, antiretroviral therapy-naive or experienced women started HAART containing generic LPV/r 400/100 mg tablets twice daily. The 12-h pharmacokinetic curves were recorded at gestational age 20 weeks (GA20, optional), 33 weeks (GA33) and 12 weeks postpartum (12PP, optional). RESULTS: Twenty women were included. Median [interquartile range (IQR)] age was 28 (25-33) years and mean (SD) weight at GA33 was 59.9 (4.2) kg. Mean (SD) values for LPV area under the curve(0-12 h), C(max), C(min), and T(half) were 72.9 (19.2) mg/l h, 9.3 (2.2) mg/l, 3.2 (1.3) mg/l and 4.8 (2.4) h, respectively, on GA33 and 98.0 (24.1) mg/l h, 11.7 (2.2) mg/l, 4.7 (2.2) mg/l and 5.9 (2.7) h, respectively on 12PP. Twelve women recorded both GA33 and 12PP curves; mean LPV AUC(0-12) was significantly lower at GA33 [-24.1 (95% confidence interval -44.4 to -3.7) mg/l h]. At GA33, 19 of 20 women had sufficient LPV trough concentrations (>1.0 mg/l) and at 12PP, all had sufficient LPV trough concentrations. None of the women stopped LPV/r before planned discontinuation due to side-effects. At delivery, 19 of 20 women had a viral load below 50 copies/ml. One woman had a viral load of 60 copies/ml, but was undetectable at 12PP. CONCLUSION: Standard dose generic LPV/r (400/100 mg twice daily) in Thai HIV-1-infected pregnant women leads to adequate plasma concentrations during the third trimester. The generic LPV/r tablet is well tolerated and effective for use during pregnancy.

Pharmacokinetics of low-dose protease inhibitors and efavirenz in low- and middle-income countries.

PURPOSE OF REVIEW: The costs associated with antiretroviral therapy are becoming a major concern for the treatment of HIV-infected patients in resource-limited countries. Potential risk for the increase in toxicity due to higher drug exposure among Asians is also a concern. In this article, we discuss the studies performed using low-dose antiretroviral therapy as an effective and well tolerated strategy. RECENT FINDINGS: The studies reviewed demonstrate that dose reduction of antiretroviral therapy provides adequate plasma concentrations and effective immunological and virological responses in, mainly, a Thai population compared with whites. The differences in these pharmacokinetic parameters could possibly be due to differences in body weight and composition, drug-food interactions, metabolism, environmental factors and genetic background. Moreover, dose reduction can possibly decrease toxicity and save costs for patients in low- and middle-income countries. SUMMARY: Although the use of low-dose antiretroviral drugs showed adequate plasma levels in an Asian population, in particular, careful attention has to be given to pharmacokinetic, safety and efficacy data to avoid problems of subtherapeutic levels and drug resistance. Large, phase III studies are warranted.

Therapeutic drug monitoring of lopinavir in human immunodeficiency virus-infected children receiving adult tablets.

Because of the lack of a lopinavir/ritonavir (LPV/r) pediatric formulation, 54 HIV-infected children were given generic LPV/r adult tablets. Of 54 children, 21 took cut pills to get the appropriate dose. The median (interquartile range) LPV trough serum concentration (C trough) was 6.7 (5.0-9.9) mg/L. All the children had C trough >1.0 mg/L and 96% had values >4.0 mg/L. LPV/r adult tablets can be used in children when it is necessary.

Plasma concentrations of generic lopinavir/ritonavir in HIV type-1-infected individuals.

BACKGROUND: Generic drugs can contribute to access to treatment for HIV-infected patients. However quality and safety remains an issue of concern. Therefore, we evaluated minimal plasma concentrations and short-term safety of a generic lopinavir/ritonavir 200/50 mg tablet formulation. METHODS: In a single-centre prospective pilot study, patients receiving protease-inhibitor-based antiretroviral treatment were switched to a generic lopinavir/ritonavir tablet at the standard dose (400/100 mg twice daily). Minimum drug concentrations (C(min)) of lopinavir and ritonavir were performed before switching (in 16 patients who were on Kaletra((R)) soft-gel capsules) and after 4 weeks (in all patients). Plasma levels of lopinavir and ritonavir were determined by a validated HPLC method. Either the Wilcoxon signed-rank or Mann-Whitney U test was used to compare the groups. RESULTS: A total of 37 patients (18 females) were included in the study. Two stopped their study medications prematurely because of intolerance. The median (interquartile range) lopinavir C(min) was 7.2 mg/l (5.8-8.3) and no patients had subtherapeutic levels <1.0 mg/l. No significant difference of lopinavir C(min) levels was found between Kaletra((R)), and the generic product (P=0.224). By contrast, the C(min) of generic ritonavir was higher (P=0.012). Food did not affect the drug levels. Mild gastrointestinal complaints were reported in 12 patients. CONCLUSIONS: The generic lopinavir/ritonavir tablet showed C(min) plasma concentrations similar to what is described for the branded product, with good stability, independent of food intake. These data support the efforts in scaling up access to generic second-line treatment in middle- and low-income countries.

Pharmacokinetics and 48 week efficacy of low-dose lopinavir/ritonavir in HIV-infected children.

BACKGROUND: Lopinavir/ritonavir is a common protease inhibitor (PI) used for second-line regimens in children. Several studies have shown higher plasma concentrations of antiretroviral agents in Thai adults than in Caucasians, suggesting that lower doses may be used. METHODS: An open label study in 24 HIV-infected children between the age of 2 and 18 years, naive to PIs, randomized to receive either the WHO-recommended dose of lopinavir/ritonavir or a low dose (70% of the standard dose) twice daily in combination with zidovudine and lamivudine. A 12 h pharmacokinetic study was done at 4-6 weeks after starting treatment. Treatment outcomes were evaluated at week 48. The clinical trial number of the study is NCT00887120. RESULTS: The medians [interquartile ranges (IQRs)] of age, body surface area, percentage CD4 and plasma HIV RNA were 9.5 years (7.0-12.3), 0.9 m(2) (0.8-1.1), 17% (11%-24%) and 4.6 log(10) copies/mL (4.1-4.9), respectively. The median (IQR) lopinavir dose was 279 mg/m(2)/dose (263-294) and 194 mg/m(2)/dose (176-206) in the standard and low-dose arms, respectively. Median (IQR) AUC(0-12) and C(trough) of lopinavir were 117.6 mg.h/L (74.0-128.5) and 4.9 mg/L (2.7-8.0) for the standard arm and 83.8 mg.h/L (56.0-112.9) and 3.4 mg/L (2.7-5.4) for the low-dose arm. One child in the low-dose arm had a lopinavir pre-dose level of <1.0 mg/L. At week 48, the median percentage CD4 was 22% (15%-28%) and 27% (21%-31%) in the standard and low-dose arms, respectively, while 50% and 83% of children had HIV RNA <50 copies/mL, respectively (P = 0.19). CONCLUSIONS: Low-dose lopinavir displayed adequate pharmacokinetic parameters and good efficacy as compared with standard-dose lopinavir in Thai children. A larger study to investigate the efficacy of low-dose lopinavir is warranted.

Reducing the boosting dose of ritonavir does not affect saquinavir plasma concentrations in HIV-1-infected individuals.

Currently, the optimal boosting dose for saquinavir is unknown. Therefore, we evaluated the pharmacokinetics profiles in a cross over setting comparing saquinavir/ritonavir 1500/50 mg (plus NRTI backbone) to saquinavir/ritonavir 1500/100 mg in the same HIV-infected, Thai individuals. The 50% reduction of ritonavir boosting did not result in a change in the pharmacokinetics of saquinavir, whereas the ritonavir exposure was significantly lower when a dose of 50 mg was administered.

Pharmacokinetics and 48-week efficacy of nevirapine: 400 mg versus 600 mg per day in HIV-tuberculosis coinfection receiving rifampicin.

BACKGROUND: We aim here to determine the appropriate dose of nevirapine (NVP) in Thai HIV-tuberculosis (TB)-coinfected patients receiving rifampicin. METHODS: Thirty-two HIV-infected adults with CD4+ T-cell counts <200 cells/mm3 and active TB, receiving rifampicin for 2-6 weeks were randomized to receive either NVP 400 mg (NVP400) or 600 mg (NVP600) per day plus two nucleoside reverse transcriptase inhibitors; a 2-week NVP lead-in was performed at 200 mg once daily (OD) and 200 mg twice daily, respectively. Plasma NVP levels were determined at weeks 2, 4 and 12. Twelve-hour pharmacokinetics (PK) were obtained (n=20) at week 4. RESULTS: Baseline body weight was comparable. There were more patients with NVP plasma concentration at 12 h (C12) <3.1 mg/l at week 2 in NVP400 than in NVP600 (79% versus 19%, respectively; P=0.002). However, the proportions were comparable at weeks 4 and 12. From week 4, 12 h PK studies showed that NVP400 had lower median NVP area under the plasma concentration-0-12 h (AUC0-12 h, maximum concentration in plasma (Cmax) and C12 than NVP600 (P<0.05). Four patients in NVP600 developed NVP hypersensitivity. At week 48, the median CD4+ T-cell count rise and proportion with viral load <50 copies/ml (intention-to-treat analysis 56% versus 50% and as-treated analysis 75% versus 89%) were comparable. CONCLUSIONS: In rifampicin-treated patients, 200 mg NVP OD lead-in led to a significant short-term suboptimal NVP C12 level, while NVP 400 mg lead-in then 600 mg/day was associated with a high rate of NVP hypersensitivity. Forty-eight week efficacy was comparable. Thus, NVP 600 mg/day in rifampicin-treated patients is not recommended.