Bonnet M, Bhatt N, Baudin E, Silva C, Michon C, Taburet AM, Ciaffi L, Sobry A, Bastos R, Nunes E, Rouzioux C, Jani I, Calmy A; for the CARINEMO study group. Nevirapine versus efavirenz for patients co-infected with HIV and tuberculosis: a randomised non-inferiority trial. Lancet Infect Dis. 2013 Apr;13(4):303-12.
To compare efficacy and safety of nevirapine- (NVP)-based antiretroviral therapy (ART) with efavirenz- (EFV)-based regimen in HIV-infected patients with tuberculosis (TB).
Three clinics in Maputo, Mozambique.
Randomized non-inferiority trial.
Adults (≥18 years) in TB treatment for less than four weeks and with previously untreated HIV infection. Participant were enrolled if they had CD4 cell counts <250 cells/µL, alanine aminotransferase (ALT) and total bilirubin concentrations of <grade 3, a negative pregnancy test in women, a Karnofsky score of ≥60% in ambulatory patients, and absence of any grade 4 clinical or biological adverse event.
Virologic suppression at week 48, increase in CD4 cell count by ≥20% from baseline to week 48, occurrence of AIDS-defining illness, completion of TB treatment, treatment-emergent adverse events, and paradoxical TB immune reconstitution inflammatory syndrome (IRIS) ≤12 weeks of beginning ART. Deaths or loss to follow-up (LTFU) were categorized as treatment failures.
Participants first received two weeks of psychosocial support and adherence counseling. Investigators randomly allocated participants to EFV- or NVP-based regimens. Participants in the NVP arm received one tablet, taken twice daily, of fixed-dose combination (FDC) NVP 200 mg, lamivudine (3TC) 150 mg and stavudine (d4T) 30 mg. Later in the trial, this FDC was replaced with one containing NVP 200 mg, 3TC 150 mg and zidovudine (AZT) 300 mg. Participants in the EFV arm received one tablet of EFV 600 mg, taken once daily; and an FDC of 3TC 150 mg and d4T 30 mg, taken twice daily. Later in the trial, the latter FDC was replaced with one containing 3TC 150 mg and AZT 300 mg.
For the two-month intensive phase of TB treatment, all participants received once-daily FDC tablets, each containing rifampicin (RMP) 150 mg, isoniazid (INH) 75 mg, pyrazinamide (PZA) 400 mg, and ethambutol (EMB) 275 mg. For the four-month continuation phase, patients received tablets containing RMP 150 mg and INH 75 mg. Dosage schedules for TB drugs were according to patient body weight to ensure that doses remained within therapeutic margins.
For the first eight weeks, investigators performed examinations and ordered laboratory analyses at weekly clinical visits. These visits then were scheduled every four weeks. Patients with pulmonary TB began treatment at external clinics before being referred to one of the trial clinics.
Virologic suppression was defined as an HIV-1 RNA count of <50 copies/mL. Investigators measured plasma HIV-1 RNA at the initial clinical visit and at weeks 12, 24, 36, and 48. CD4 cell count was assessed at the screening visit, week 24, and week 48. ALT and total bilirubin concentrations were assessed at screening visits and at weeks two, four, six, eight, 12, 16, 20, 24, 36, and 48. The intensity of adverse events was graded with the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) table for grading adult adverse events(1) (a gradient of one through four, corresponding to mild, moderate, severe and life-threatening). Serious adverse events were defined as any clinical or biological incident that required hospitalization (or an extension of hospitalization), was life-threatening, or resulted in disability, incapacity, a congenital abnormality or birth defect, or death. Investigators measured plasma NVP and EFV concentrations every 12 weeks.
Investigators defined the non-inferiority margin for the difference in efficacy between NVP and EFV as 10%.
A total of 573 patients were enrolled, three of whom were assigned to EFV without randomization. Investigators randomized 285 patients to EFV and 285 to NVP. Patient characteristics were comparable across treatment arms, though marginally fewer patients had smear-positive pulmonary TB in the nevirapine group than the EFV group (p=0.0584). In the intention-to-treat analysis, virologic suppression at 48 weeks was achieved in 184 (64.6%) of 285 patients on NVP-based regimens and 199 (69.8%) of 285 patients on EFV-based regimens. The one sided 95% confidence interval (CI) of the difference in efficacy between the two regimens was 11.7%, exceeding the pre-specified 10% non-inferiority margin. This difference increased in the intention-to-treat (switch equals failure) analysis (15.0%) and in the per protocol analysis (15.4%).
There were no significant differences between treatment arms in terms of increased CD4 count or incidence of AIDS-defining illness. TB treatment outcomes also did not differ between arms, with ≥90% cured in each group. More patients in the NVP group than the EFV group had paradoxical TB IRIS at ≤12 weeks (n=32, 11% vs. n=21, 7%, p=0.1039). There were no significant differences between groups in the number of treatment-emergent or other serious adverse events. Fourteen (5%) NVP patients discontinued regimens due to toxicity, compared to two (1%) in the EFV arm (p=0.002). Eighteen (6%) patients in the NVP arm died of any cause, compared to 17 (6%) in the EFV arm. Three (17%) deaths in the NVP arm were TB-related, compared to five (29%) in the EFV arm.
The authors concluded that this trial did not show non-inferiority of NVP in HIV-infected patients with TB for the endpoint of virologic failure. Additionally, the switch equals failure analysis also favored EFV (six substitutions vs. 15), but the switches were made for pregnancy or safety reasons, not loss of efficacy. They suggest that NVP-based regimens could be acceptable in cases where EFV is contraindicated or poorly tolerated.
The overall risk of bias in this trial is low. Randomization and allocation concealment procedures were appropriate. The trial was not blinded, but this is unlikely to have affected the outcomes. LTFU are accounted for appropriately. The report compares favorably to the trial's registration documents. (2)
These results differ from those of two other RCTs in patients co-infected with HIV and TB, one trial conducted in Thailand (3) and one in India. (4) The Thai study reported similar efficacy of the two regimens but was not powered to detect inferiority. The Indian trial was terminated early due to much lower (20%) NVP efficacy at week 24. In addition, the Indian patients received once-daily NVP 400 mg, which a Cochrane review (5) found to be associated with worse outcomes than twice-daily NVP 200 mg.
EFV is increasingly preferred to NVP in first-line ART, (6) in patients with and without TB co-infection. The difference in cost between the drugs is decreasing. (6, 7) A recent systematic review found no evidence for an increased risk of birth defects in infants with first trimester EFV exposure. (6, 8) Unlike NVP, EFV is available as a once-daily FDC. (6) NVP is associated with a much higher risk of severe toxicity than EFV. (6, 9) As more patients begin ART at high CD4 levels, EFV becomes a more attractive option, as starting NVP with a high CD4 count increases the risk for NVP hypersensitivity reactions. (6)
The World Health Organization (WHO) recommends (10) that first-line ART in HIV-infected patients with TB should contain either EFV or NVP, with EFV-based regimens preferred. Clinicians treating HIV-TB co-infected patients should continue to follow current WHO guidelines. (10, 11, 12) WHO is expected to release new consolidated ART guidelines (including guidance on TB and other co-infections) in July 2013.
- Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS). ANRS scale to grade the severity of adverse events in adults (2008). [accessed 21 March 2013].
- ClinicalTrials.gov. Comparison of Nevirapine and Efavirenz for the Treatment of HIV-TB Co-infected Patients (ANRS 12146 CARINEMO), registration #NCT00495326. [accessed 22 March 2013]
- Manosuthi W, Sungkanuparph S, Tantanathip P, et al. A randomized trial comparing plasma drug concentrations and efficacies between 2 nonnucleoside reverse-transcriptase inhibitor-based regimens in HIV-infected patients receiving rifampicin: the N2R Study. Clin Infect Dis 2009; 48: 1752-59.
- Swaminathan S, Padmapriyadarsini C, Venkatesan P, et al. Efficacy and safety of once-daily nevirapine- or efavirenz-based antiretroviral therapy in HIV-associated tuberculosis: a randomized clinical trial. Clin Infect Dis 2011; 53: 716-24.
- Mbuagbaw LC, Irlam JH, Spaulding A, Rutherford GW, Siegfried N. Efavirenz or nevirapine in three-drug combination therapy with two nucleoside-reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral-naive individuals. Cochrane Database Syst Rev 2010; 12: CD004246
- Maartens G. ART and tuberculosis: the final nail in nevirapine's coffin? Lancet Infect Dis. 2013 Feb 19. [Epub ahead of print]
- World Health Organization. Use of efavirenz during pregnancy: a public health perspective. [accessed 22 March 2013).
- Ford N, Calmy A, Mofenson L. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS 2011; 25: 2301-04.
- Shubber Z, Calmy A, Andrieux-Meyer I, Vitoria M, Renaud-Thery F, Shaffer N, Hargreaves S, Mills EJ, Ford N. Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis. AIDS. 2013 Jan 22. [Epub ahead of print].
- World Health Organization (2010). Treatment of Tuberculosis: guidelines for national programmes (4th edition).[accessed 22 March 2013]
- World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents: Recommendations for a public health approach (2010). [accessed 22 March 2013]
- World Health Organization. Antiretroviral therapy for HIV infection in infants and children: Towards universal access. Recommendations for a public health approach (2010). [accessed 22 March 2013]