JAC Advance Access originally published online on September 6, 2006
Journal of Antimicrobial Chemotherapy 2006 58(5):1017-1023; doi:10.1093/jac/dkl357
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Efavirenz trough levels are not associated with virological failure throughout therapy with 800 mg daily and a rifampicin-containing antituberculosis regimen
1 Infectious Diseases Service, Hospitales Universitarios Virgen del Rocío Seville, Spain 2 Infectious Diseases Unit, Hospital Universitario Virgen de la Victoria Malaga, Spain 3 Infectious Diseases Unit, Hospital Universitario de Valme Seville, Spain 4 Infectious Diseases Unit, Hospital Universitario Puerto Real Cádiz, Spain 5 Haematology Service, Hospitales Universitarios Virgen del Rocío Seville, Spain
*Correspondence address. Servicio de Enfermedades Infecciosas, Centro de Diagnóstico y Tratamiento, Hospital Universitario Virgen del Rocío, Avda Manuel Siurot, s/n 41013, Seville, Spain. Tel: +34-955013096; Fax: +34-955234823; E-mail: lflopez{at}telefonica.net
Received 22 April 2006; returned 2 July 2006; revised 21 July 2006; accepted 4 August 2006
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Abstract |
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Objectives: To assess the safety and efficacy of efavirenz 800 mg daily in HIV-infected patients with tuberculosis receiving a rifampicin-containing regimen and to analyse whether a relationship exists between efavirenz Cmin and its virological efficacy.
Methods: Prospective, open-labelled study including HIV-infected patients on rifampicin and efavirenz 800 mg daily. Treatment adherence, adverse events (AEs), HIV-RNA levels, CD4 cell counts and efavirenz Cmin during and after finishing rifampicin treatment were evaluated.
Results: Eighty patients met the inclusion criteria. A permanent drug withdrawal due to AEs occurred in 10 patients, 5 attributable to efavirenz, and 10 patients were lost to follow-up before the third month. Efavirenz Cmin levels with 800 mg plus rifampicin were similar to those with 600 mg after withdrawing rifampicin. Sixty patients were included in the efficacy analysis, eight experiencing virological failure. No relation was observed between the rate of virological failure and efavirenz Cmin, previous antiretroviral treatment or not, baseline CD4 counts or RNA-HIV. The only variable related to virological failure was irregular adherence [odds ratio, 81 (95% CI: 5–1280); P = 0.002].
Conclusions: Given the lack of a demonstrated relationship between efavirenz Cmin and its efficacy in our study, a firm recommendation cannot be made to always increase the dose to 800 mg/day when concomitantly given with rifampicin, but it seems a cautious approach to maintain the same efavirenz plasma levels as with 600 mg daily without rifampicin. Patients weighing <55 kg and also black, Asian and Hispanic subjects in whom genetic-based increased efavirenz plasma levels and rates of AEs have been observed may benefit from a dose of 600 mg.
Keywords: tuberculosis , pharmacokinetics , HIV infection
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Introduction |
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The incidence of tuberculosis in HIV-infected patients is much higher in those severely immunodepressed not receiving highly active antiretroviral treatment (ART).1–4 In this setting, the delay in starting ART can lead to the occurrence of new opportunistic infections and even death.
Current guidelines for the treatment of drug-susceptible tuberculosis recommend rifampicin-based regimens, the use of preparations with fixed-dose combinations of rifampicin, isoniazid and pyrazinamide being desirable.5–7 However, the use of rifampicin in HIV-infected patients needing ART is of particular concern, since it induces the activity of the cytochrome P450 system in the intestinal wall and liver, significantly decreasing plasma levels of both protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). So, the available therapeutic options of ART in HIV patients with tuberculosis taking rifampicin are limited.7–10
We have previously reported that rifampicin decreases mean efavirenz plasma levels by 
25% in HIV-infected patients with tuberculosis, and increasing the efavirenz dose to 800 mg daily provides plasma concentrations similar to those observed in patients receiving efavirenz at 600 mg daily without rifampicin.11 Nevertheless, the available clinical experience and pharmacokinetic data with this combination are still limited.12–15
The objectives of the present study were to evaluate the safety and virological efficacy of efavirenz 800 mg daily as part of ART in HIV-infected patients receiving a rifampicin-containing antituberculosis regimen and to analyse whether a relationship exists between efavirenz Cmin levels and its virological efficacy.
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Patients and methods |
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Patients and setting
A total of 97 patients from different Infectious Diseases Units in Spain were included in this single-arm, prospective, open-labelled study from July 2000 to June 2004. Patients were consecutively included if they were older than 18 years, had a confirmed HIV infection, a diagnosis of active tuberculosis and positive acid-fast stains and/or culture for Mycobacterium tuberculosis complex, had started a rifampicin-containing antituberculosis regimen, were prescribed a daily efavirenz 800 mg based ART, and agreed to participate. There were no exclusion criteria based on illegal drug or methadone use, CD4 cell counts or plasma RNA-HIV-1.
Tuberculosis patients requiring a regimen without rifampicin were not included. Other excluding criteria were an initial mycobacterial isolate resistant to rifampicin, concomitant use of drugs with potential pharmacokinetic interactions with efavirenz or rifampicin, proved or highly probable resistance to NNRTIs on the basis of genotypic resistance testing and/or previous ARTs, and pregnancy. Patients on rifampicin for more than 8 weeks at the moment of starting ART were also excluded from the analysis in order to have enough time for follow-up with both drugs. The study protocol was approved by the ethics committees at each participating centre and written informed consent was given by every participant.
The dose of rifampicin was weight-based (450 mg for body weight 
55 kg, and 600 mg daily for body weight >55 kg). Nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) prescribed as part of ART were selected by the responsible physicians on the basis of genotypic resistance testing and/or previous ARTs. In those patients taking methadone, the doses were increased as clinically needed after the beginning of the treatment with rifampicin and efavirenz.
Patients were assessed at baseline, after 4 weeks and every 2 months thereafter until a year was completed after starting efavirenz therapy. The CD4 counts were assessed by flow cytometry, and plasma HIV-1 RNA (VL) was measured by PCR (lower limit of detection, 50 copies/mL; Amplicor HIV Monitor, Roche Diagnostic Systems, Basel, Switzerland) at each visit.
Safety and efficacy assessment
The safety and tolerability of the study medications was evaluated on the basis of clinical adverse events (AEs), physical examinations and laboratory results. Abnormal laboratory findings or other abnormal assessments judged by the investigator to be clinically significant were recorded as AEs. Drug-related events were reported as related to each of the antiretroviral or antituberculosis drugs.
Virological failure was defined as failure to decrease the VL 
1 log10 by week 12, a VL > 50 copies/mL by week 24 or a confirmed VL > 500 copies/mL after an initial suppression to <50 copies/mL. Only the patients with a follow-up 12 weeks were considered for the efficacy analysis. The level of ART compliance was assessed at each visit by patient questioning, attendance to the programmed visits and number of packages prescribed and withdrawn from the hospital's pharmacy. Irregular compliance was considered when 7 days/month had passed without treatment.16 Loss to follow-up was considered when a patient interrupted his programmed visits and, from that moment on, no further data were available.
Determination of efavirenz concentrations
Efavirenz was administered right after breakfast in all the patients throughout the whole follow-up in order to obtain true efavirenz Cmin (24 ± 0.5 h) since efavirenz trough levels cannot be estimated accurately enough from plasma concentrations at C8, C12 or C16 or from combinations of these points.17 Blood samples for efavirenz levels were planned to be obtained after 1 month on efavirenz treatment and, thereafter, at 3–5, 6–9 months and 1 month after finishing rifampicin treatment.
Plasma efavirenz levels were determined by reverse-phase high-performance liquid chromatography (HPLC-UV) according to a validated method.18 The assay was found to be linear and was validated over a concentration range of 0.2–30 mg/mL. The lower limit of quantification was 0.1 µg/mL. Recovery of efavirenz from human plasma was 100.1%. The mean intra- and inter-assay coefficients of variation were 3.2% (range: 1.5–5%) and 4.7% (range: 2–8%), respectively. Our laboratory participates in an external quality assurance programme (KKGT, The Netherlands).
Statistical analysis
Descriptive statistics were used for demographic, epidemiological and clinical variables. The relationship between efavirenz plasma levels and factors such as gender and weight were analysed by Mann–Whitney U-test, and Spearman rank correlation coefficients and linear regression, respectively. Efavirenz plasma concentrations between different groups were compared by the Mann–Whitney U-test. The paired t-test and binomial logistic regression were used when indicated. Baseline CD4 counts (100 and >100 cells/mm3) and log transformed RNA-HIV, mean efavirenz Cmin during the follow-up and compliance with ART were included in a multivariate logistic regression model to determine the respective contribution of each variable to predicting virological success or failure. A P value <0.05 was considered statistically significant. Statistical calculations were performed with the Statistical Product and Service Solutions (SPSS) for Windows (version 12.0; SPSS, Chicago, IL, USA).
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Results |
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A total of 97 Caucasian patients were sequentially enrolled. Seventeen of them were excluded from the analysis due to the following reasons: six patients did not start ART, tuberculosis was not confirmed in four patients, incomplete data in four patients, baseline genotypic resistance testing with K101E and K103N mutations in one patient, initial mycobacterial isolate resistant to rifampicin in one patient, and starting efavirenz after 5 months on antituberculosis treatment in one patient.
Baseline characteristics of the 80 analysed patients are summarized in Table 1. Most of them had previously been injection-drug-users and 50 of them were taking methadone when included. As for tuberculosis, it was the first episode in 56 patients, and relapses in 24, most of them after previous premature treatment discontinuation. The antituberculosis regimen prescribed consisted of 2 months of daily rifampicin, isoniazid, pyrazinamide±ethambutol followed by daily rifampicin and isoniazid for 4 or 7 months (6 and 66 patients, respectively). The remaining eight patients received other rifampicin-containing regimens.
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Regarding ART, 35 patients (43.8%) were naive and 45 were ART-experienced. These 45 patients had been on treatment for a median of 15 months (range, 1–70). Twenty-five of them had previous virological failures while on NRTIs and 15 patients on PIs. Fifteen patients had previously received NNRTIs without virological failure. In addition to efavirenz 800 mg daily, the ART consisted of thymidine analogues (zidovudine or stavudine) plus lamivudine (20 patients) or didanosine (8 patients), and didanosine plus lamivudine (7 patients) in naive patients. In the 45 ART-experienced patients, it consisted of thymidine analogues plus lamivudine (18 patients) or didanosine (13 patients), and didanosine plus lamivudine (8 patients) or tenofovir (5 patients) or abacavir (1 patient).
A total of 37 (46.2%) patients initiated ART during the first 2 weeks after starting antituberculosis treatment, 23 (28.7%) patients after 1 month and 20 (25%) patients right after finishing the second month of tuberculosis treatment. Out of the 80 patients, 62 (77.5%) were considered to have a good adherence to treatment during their follow-up.
AEs are shown in Table 2. They occurred in 22 out of 74 patients (29.7%) with at least one evaluation after starting ART, causing a permanent drug withdrawal in 10 (13.5%) of them (4 cases attributed to rifampicin as patients continued taking efavirenz and improved after ceasing rifampicin, 5 to efavirenz, 1 unknown). The AEs attributable to efavirenz appeared early and either vanished during the first weeks or caused the permanent drug withdrawal. The only exception was one patient who suffered light-headedness and hangover after 8 months on efavirenz. Among the four most severe episodes attributable to efavirenz, three occurred within the first days on treatment (male patients weighing 45, 52 and 55 kg, respectively) and the fourth episode occurred after 5 months on treatment (a woman of 45 kg who interrupted antituberculosis treatment without modifying efavirenz dose). The symptoms disappeared in all patients after withdrawing efavirenz. In two of them (one of them suffering a confusional syndrome and visual hallucinations) efavirenz was reintroduced at progressively increasing doses up to 800 mg daily with no recurring symptoms.
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Twenty-one (26.2%), all of them illicit drug users, were lost during the follow-up with no further data available. The losses to follow-up occurred before ending the first month on ART in six cases, after 1 month on ART in three cases (VL with a median reduction of 1.3 log10 copies/mL), after 2 months on ART in one case (VL: 60 copies/mL), after 3 months in five cases (VL: 113, 60 and <50 copies/mL in the other three patients, with a median CD4 increase of 142 cells/mm3; range, 108–232), after 5 months in five cases (VL: 147 and <50 copies/mL in the other four patients; median CD4 increase: 86 cells/mm3; range, 38–115) and after 7 months on ART in one case (VL: <50 copies/mL; CD4 increase: 35 cells/mm3). One patient died after 3 months of follow-up due to non-Hodgkin's lymphoma.
Among the 48 patients accomplishing the whole follow-up, 40 completed 1 year on ART with undetectable VL. Therefore, the efficacy was 50% (95% CI: 0.13–0.87) in the intention-to-treat analysis and 83.3% (95% CI: 55–100) in the on-treatment analysis (Figure 1). The median increase in CD4 was 178 cells/mm3 (range, –146 to 592). A decrease in the CD4 count while on ART was observed in two patients, one of them was receiving didanosine (400 mg/day) plus tenofovir and the other zidovudine plus lamivudine. The remaining eight patients experienced virological failure after 3–5 months on ART, all but one with a confirmed poor adherence to treatment. Genotypic resistance testing was available after treatment failure in seven of these eight patients, demonstrating a single K103N mutation in four cases, K101E + K103N mutations in two cases, and K101E + Y181C + G190A + M184V mutations in one patient. Tuberculosis was cured in the 49 patients who completed the antituberculosis treatment.
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A total of 185 efavirenz Cmin determinations were performed in 67 patients while on treatment with rifampicin (1 determination in 10 patients, 2 in 20 patients and
3 in 37 patients) and 24 additional determinations after finishing tuberculosis treatment for at least 1 month (Figure 2). Seven determinations during the follow-up in four patients showed efavirenz levels <0.1 µg/mL while on concomitant treatment with rifampicin, all of them completing the follow-up with VL <50 copies/mL. The median of efavirenz while on rifampicin was 1.39 µg/mL (range, <0.1–24.7). In those patients with 2 efavirenz determinations the median intra- and inter-patient variation coefficients were 41.2% (range, 3–140%) and 90% (95% CI: 82–98), respectively. Efavirenz plasma concentrations were slightly greater in patients weighing 55 kg (n = 24) compared with those in patients weighing >55 kg (n = 41) (median, 1.50 versus 1.19 µg/mL; range, 0.23–5.92 versus 0.1–9.96), but the differences were not statistically significant (P = 0.18). Efavirenz levels were also somewhat higher in women than in men, but again the difference was not statistically significant, probably due to the small number of women included in the study. Additional determinations of efavirenz were available in 24 patients after finishing rifampicin and decreasing efavirenz dose to 600 mg daily; in these patients efavirenz levels were similar to those observed with efavirenz 800 mg daily when given together with rifampicin (median efavirenz levels 1.28 versus 1.39 µg/mL; range, 0.0–2.65 versus 0.17–4).
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Trough levels of efavirenz after 1 month on treatment were similar in patients with and without mild or moderate neurological AEs (dizziness, light-headedness, drowsiness, hangover and/or insomnia), although most of these AEs were transient and had disappeared when the first samples were obtained. Efavirenz levels were only available in one out of four patients with severe neuropsychiatric disorders coinciding with the events. The patient with catatonia had a level >100 µg/mL 3 h after efavirenz intake and 24.7 µg/mL 24 h later.
Sixty patients with a follow-up 12 weeks were included in a multivariate analysis in which the relationship between efficacy and baseline CD4 counts, log transformed RNA-HIV, mean efavirenz Cmin during the follow-up, being naive or ART-experienced, and compliance with ART was assessed. No relation was observed between efavirenz Cmin and the rate of virological failure throughout the follow-up period. Median efavirenz Cmin in those patients with a successful ART was 1.35 µg/mL (range, 0.23–9.96) versus 1.67 µg/mL (range, 0.26–3.36) in those with virological failure. The only variable related to virological failure was the lack of adherence to ART [odds ratio, 81 (95% CI: 5–1280); P= 0.002]. The results did not change when only the 48 patients with a complete follow-up were analysed.
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Discussion |
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After verifying that rifampicin decreases efavirenz plasma concentrations by
25%,11 we initiated this prospective study to evaluate the safety and virological efficacy of efavirenz 800 mg daily in HIV-infected patients receiving a rifampicin-containing antituberculosis regimen in the usual clinical setting, without the bias of patients' selection a clinical trial may have. We also aimed to analyse whether a relationship exists between efavirenz Cmin levels and its virological efficacy. As this drug is usually taken at bedtime in order to minimize its central nervous system AEs, obtaining efavirenz trough plasma levels carries many difficulties. So the published reports studying the relationship between plasma concentrations and efficacy have been based on blood samples taken at 12 h, between 8 and 20 h post-dosing or on a population pharmacokinetic approach,15,19–25 finding a very weak correlation or even no clear association between efavirenz levels and efficacy.21,22,25 Moreover, we have shown that estimations of efavirenz Cmin from samples taken between 8 to 16 h are not precise enough.17 As for previous reports, several aspects are confirmed in our study again: (i) efavirenz levels with a dose of 800 mg daily during the concomitant treatment with rifampicin were similar to those observed after suspending rifampicin and readjusting efavirenz dose to 600 mg daily; (ii) efavirenz plasma concentrations exhibit a large inter- and intra-patient variability; and (iii) an upward trend is observed in efavirenz Cmin in patients with lower weight.11,24,25
Other issues in our results deserve careful consideration. The first of them is the high rate of missing patients. Previous injection-drug-users represent more than 80% of the cases in our series, 30% of them being tuberculosis relapses after prematurely interrupting antituberculosis treatment. The poor adherence to antituberculosis and ART medications in this population and the fact that our patients were not selected for inclusion—as they usually are in clinical trials—probably explain the high incidence of loss to follow-up.4,26–28 Taking efavirenz in the morning could have also influenced the high rate of drop-outs due to neurological AEs, but otherwise obtaining true Cmin would not have been possible. It is unknown whether the six losses to follow-up before ending the first month on ART could have been influenced or not by the occurrence of AEs.
Second, the lack of relationship between efavirenz trough levels and the incidence and/or severity of the CNS AEs may be explained because no efavirenz levels were available during the acute episodes in 3 of the 4 most severely affected cases. In the other patients the first samples were obtained after 1 month on treatment and the symptoms, occurring during the first days or weeks on treatment, had already ceased at the moment of sampling. Similar results have been recently reported.25,29 Worth mentioning is the low weight (45–55 kg) of the four patients with severe neuropsychiatric AEs. Given that the AEs are more severe within the first hours right after drug intake and their incidence is higher during the first days or weeks on treatment, and that efavirenz autoinduces its own metabolism after repeated doses, the most probable hypothesis is that these AEs may be more related to the maximum levels rather than to trough levels or levels after 8–20 h after drug intake, as analysed in ours and other studies.20–22,25,29
The third point is the lack of relationship between efavirenz Cmin and its long-term efficacy, despite the wide range of concentrations observed. Although the minimum required efavirenz plasma concentrations for long-term efficacy have not been clearly established yet, especially in the presence of other drugs with activity against HIV, this fact suggests either that Cmin is not the parameter related to efavirenz efficacy or that antiviral response is independent of Cmin. Namely, the levels observed were in the plateau portion of the dose–response curve.
In the studies by Manosuthi et al.15,30 no differences in efficacy were found between patients treated with efavirenz 600 mg/daily and those treated with 800 mg/daily and concomitant rifampicin therapy, although the patients mean weight was 50 kg and efavirenz plasma samples were obtained at a mean time of 12.5 h after drug administration. Therefore, although increasing efavirenz dose to 800 mg/daily whenever administered concomitantly with rifampicin cannot be firmly recommended, it seems a cautious approach to maintain the same efavirenz plasma levels as with 600 mg daily without rifampicin. However, patients weighing <55 kg as well as black, Asian and Hispanic subjects, in whom increased efavirenz plasma levels and a high rate of AEs have been observed due to genetic-based factors, would mostly benefit from a dose of 600 mg.14,25,31–34
Finally, it is worth highlighting that irregular adherence has been the only variable related to virological failure in our study. So, multidisciplinary interventions to achieve a proper adherence are a critical factor to avoid virological failures and resistance when administering antiretroviral drugs with a low genetic resistance barrier such as efavirenz.
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Transparency declarations |
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L. F. L.-C. has received funds for speaking at symposia organized on behalf of Bristol-Myers Squibb, GlaxoSmithKline, Abbott Laboratories, Gilead Sciences and Roche Pharma SA, and has also received funds for research from Boehringer Ingelheim España S.A, DuPont Pharma and Roche Pharma SA. Other authors: none to declare.
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Acknowledgements |
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This work was partially supported with unrestricted research funds by DuPont Pharma.
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References |
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