Journal Article > ResearchFull Text
Lancet Infect Dis. 1 April 2013; Volume 13 (Issue 4); 303-312.; DOI:10.1016/S1473-3099(13)70007-0
Bonnet MMB, Bhatt NB, Baudin E, Silva C, Michon C, et al.
Lancet Infect Dis. 1 April 2013; Volume 13 (Issue 4); 303-312.; DOI:10.1016/S1473-3099(13)70007-0
BACKGROUND
In countries with a high incidence of HIV and tuberculosis co-infection, nevirapine and efavirenz are widely used as antiretroviral therapy but both interact with antituberculosis drugs. We aimed to compare efficacy and safety of a nevirapine-based antiretroviral therapy (started at full dose) with an efavirenz-based regimen in co-infected patients.
METHODS
We did a multicentre, open-label, randomised, non-inferiority trial at three health centres in Maputo, Mozambique. We enrolled adults (≥18 years) with tuberculosis and previously untreated HIV infection (CD4 cell counts <250 cells per μL) and alanine aminotransferase and total bilirubin concentrations of less than five times the upper limit of normal. 4-6 weeks after the start of tuberculosis treatment, we randomly allocated patients (1:1) with central randomisation, block sizes of two to six, and stratified by site and CD4 cell count to nevirapine (200 mg twice daily) or efavirenz (600 mg once daily), plus lamivudine and stavudine. The primary endpoint was virological suppression at 48 weeks (HIV-1 RNA <50 copies per mL) in all patients who received at least one dose of study drug (intention-to-treat population); death and loss to follow-up were recorded as treatment failure. The non-inferiority margin for the difference of efficacy was 10%. We assessed efficacy in intention-to-treat and per-protocol populations and safety in all patients who received study drug. This study is registered with ClinicalTrials.gov, number NCT00495326.
FINDINGS
Between October, 2007, and March, 2010, we enrolled 285 patients into each group. 242 (85%) patients in the nevirapine group and 233 (82%) patients in the efavirenz group completed follow-up. In the intention-to-treat population, 184 patients (64·6%, 95% CI 58·7-70·1) allocated nevirapine achieved virological suppression at week 48, as did 199 patients (69·8%, 64·1-75·1) allocated efavirenz (one-sided 95% CI of the difference of efficacy 11·7%). In the per-protocol population, 170 (70·0%, 63·8-75·7) of 243 patients allocated nevirapine achieved virological suppression at week 48, as did 194 (78·9%, 73·2-83·8) of 246 patients allocated efavirenz (one-sided 95% CI 15·4%). The median CD4 cell count at randomisation was 89 cells per μL. 15 patients substituted nevirapine with efavirenz and six patients substituted efavirenz with nevirapine. 20 patients allocated nevirapine (7%) had grade 3-4 increase of alanine aminotransferase compared with 17 patients allocated efavirenz (6%). Three patients had severe rash after receipt of nevirapine (1%) but no patients did after receipt of efavirenz. 18 patients in the nevirapine group died, as did 17 patients in the efavirenz group.
INTERPRETATION
Although non-inferiority of the nevirapine-regimen was not shown, nevirapine at full dose could be a safe, acceptable alternative for patients unable to tolerate efavirenz. FUNDING: French Research Agency for HIV/AIDS and hepatitis (ANRS).
In countries with a high incidence of HIV and tuberculosis co-infection, nevirapine and efavirenz are widely used as antiretroviral therapy but both interact with antituberculosis drugs. We aimed to compare efficacy and safety of a nevirapine-based antiretroviral therapy (started at full dose) with an efavirenz-based regimen in co-infected patients.
METHODS
We did a multicentre, open-label, randomised, non-inferiority trial at three health centres in Maputo, Mozambique. We enrolled adults (≥18 years) with tuberculosis and previously untreated HIV infection (CD4 cell counts <250 cells per μL) and alanine aminotransferase and total bilirubin concentrations of less than five times the upper limit of normal. 4-6 weeks after the start of tuberculosis treatment, we randomly allocated patients (1:1) with central randomisation, block sizes of two to six, and stratified by site and CD4 cell count to nevirapine (200 mg twice daily) or efavirenz (600 mg once daily), plus lamivudine and stavudine. The primary endpoint was virological suppression at 48 weeks (HIV-1 RNA <50 copies per mL) in all patients who received at least one dose of study drug (intention-to-treat population); death and loss to follow-up were recorded as treatment failure. The non-inferiority margin for the difference of efficacy was 10%. We assessed efficacy in intention-to-treat and per-protocol populations and safety in all patients who received study drug. This study is registered with ClinicalTrials.gov, number NCT00495326.
FINDINGS
Between October, 2007, and March, 2010, we enrolled 285 patients into each group. 242 (85%) patients in the nevirapine group and 233 (82%) patients in the efavirenz group completed follow-up. In the intention-to-treat population, 184 patients (64·6%, 95% CI 58·7-70·1) allocated nevirapine achieved virological suppression at week 48, as did 199 patients (69·8%, 64·1-75·1) allocated efavirenz (one-sided 95% CI of the difference of efficacy 11·7%). In the per-protocol population, 170 (70·0%, 63·8-75·7) of 243 patients allocated nevirapine achieved virological suppression at week 48, as did 194 (78·9%, 73·2-83·8) of 246 patients allocated efavirenz (one-sided 95% CI 15·4%). The median CD4 cell count at randomisation was 89 cells per μL. 15 patients substituted nevirapine with efavirenz and six patients substituted efavirenz with nevirapine. 20 patients allocated nevirapine (7%) had grade 3-4 increase of alanine aminotransferase compared with 17 patients allocated efavirenz (6%). Three patients had severe rash after receipt of nevirapine (1%) but no patients did after receipt of efavirenz. 18 patients in the nevirapine group died, as did 17 patients in the efavirenz group.
INTERPRETATION
Although non-inferiority of the nevirapine-regimen was not shown, nevirapine at full dose could be a safe, acceptable alternative for patients unable to tolerate efavirenz. FUNDING: French Research Agency for HIV/AIDS and hepatitis (ANRS).
Journal Article > Pre-PrintFull Text
F1000Research. 8 February 2019; Volume 8; 169.; DOI:10.12688/f1000research.17776.1
Baudin E, Bhatt NB, Rouzioux C, Serafini M, Molfino L, et al.
F1000Research. 8 February 2019; Volume 8; 169.; DOI:10.12688/f1000research.17776.1
BACKGROUND
In the CARINEMO ANRS 12146 clinical trial, HIV-tuberculosis co-infected patients in Mozambique were randomized to nevirapine (NVP) or to efavirenz (EFV)-based antiretroviral therapy to compare these two non-nucleoside reverse transcriptase inhibitors (NNRTIs) in treatment naïve patients.
METHODS
In this sub study, we explored the relationship of NNRTI concentrations with virological escape and the possible emergence of resistance mutations at week 48. The virological escape was defined as an HIV-RNA above 400 copies/m at week 48.
RESULTS
Among the 570 randomized patients, 470 (82%) had an HIV-RNA result at week 48; 54 (12.1%) patients had a viral escape and 35 patients had at least one major resistance mutation detected. Low drug concentration at weeks 12 and 24 (below the 10th percentile) were independently associated with virologic escape at week 48 (adjusted odds ratio [aOR]=2.9; 95% CI: 1.1 -7.2; p=0.0312 and aOR=4.2; 95% CI: 1.8-9.8; p=0.0019, respectively), and independently associated with an increased risk of emergence of resistance mutation (aOR=4.5; 95% CI: 1.8-14.6; p=0.009 at week 12; aOR=5.1; 95% CI: 1.8-14.6 at week 24). Receiver operating characteristic curves analyses indicated a better predictability of the mid-dose concentration and of the HIV-1 RNA values on resistance mutations in contrast to virological escape.
CONCLUSIONS
Very low drug plasma concentrations early after treatment initiation (week 12) were predictive factors of virological escape and the emergence of resistance mutations at week 48, and early monitoring of drug intake may prevent the occurrence of late virological escape and the selection of vial resistance mutations.
In the CARINEMO ANRS 12146 clinical trial, HIV-tuberculosis co-infected patients in Mozambique were randomized to nevirapine (NVP) or to efavirenz (EFV)-based antiretroviral therapy to compare these two non-nucleoside reverse transcriptase inhibitors (NNRTIs) in treatment naïve patients.
METHODS
In this sub study, we explored the relationship of NNRTI concentrations with virological escape and the possible emergence of resistance mutations at week 48. The virological escape was defined as an HIV-RNA above 400 copies/m at week 48.
RESULTS
Among the 570 randomized patients, 470 (82%) had an HIV-RNA result at week 48; 54 (12.1%) patients had a viral escape and 35 patients had at least one major resistance mutation detected. Low drug concentration at weeks 12 and 24 (below the 10th percentile) were independently associated with virologic escape at week 48 (adjusted odds ratio [aOR]=2.9; 95% CI: 1.1 -7.2; p=0.0312 and aOR=4.2; 95% CI: 1.8-9.8; p=0.0019, respectively), and independently associated with an increased risk of emergence of resistance mutation (aOR=4.5; 95% CI: 1.8-14.6; p=0.009 at week 12; aOR=5.1; 95% CI: 1.8-14.6 at week 24). Receiver operating characteristic curves analyses indicated a better predictability of the mid-dose concentration and of the HIV-1 RNA values on resistance mutations in contrast to virological escape.
CONCLUSIONS
Very low drug plasma concentrations early after treatment initiation (week 12) were predictive factors of virological escape and the emergence of resistance mutations at week 48, and early monitoring of drug intake may prevent the occurrence of late virological escape and the selection of vial resistance mutations.
Journal Article > ResearchFull Text
BMC Pediatr. 26 July 2011; Volume 11 (Issue 1); DOI:10.1186/1471-2431-11-67
Ahoua L, Guenther G, Rouzioux C, Pinoges LLP, Anguzu P, et al.
BMC Pediatr. 26 July 2011; Volume 11 (Issue 1); DOI:10.1186/1471-2431-11-67
Children living with HIV continue to be in urgent need of combined antiretroviral therapy (ART). Strategies to scale up and improve pediatric HIV care in resource-poor regions, especially in sub-Saharan Africa, require further research from these settings. We describe treatment outcomes in children treated in rural Uganda after 1 and 2 years of ART start.
Journal Article > ResearchFull Text
AIDS. 12 November 2007; Volume 21 (Issue 17); DOI:10.1097/QAD.0b013e32828cc8b7
Ferradini LLF, Laureillard D, Prak N, Ngeth C, Fernandez MAL, et al.
AIDS. 12 November 2007; Volume 21 (Issue 17); DOI:10.1097/QAD.0b013e32828cc8b7
OBJECTIVES: African and Asian cohort studies have demonstrated the feasibility and efficacy of HAART in resource-poor settings. The long-term virological outcome and clinico-immunological criteria of success remain important questions. We report the outcomes at 24 months of antiretroviral therapy (ART) in patients treated in a Médecins Sans Frontières/Ministry of Health programme in Cambodia. METHODS: Adults who started HAART 24 +/- 2 months ago were included. Plasma HIV-RNA levels were assessed by real-time polymerase chain reaction. Factors associated with virological failure were analysed using logistic regression. RESULTS: Of 416 patients, 59.2% were men; the median age was 33.6 years. At baseline, 95.2% were ART naive, 48.9% were at WHO stage IV, and 41.6% had a body mass index less than 18 kg/m. The median CD4 cell count was 11 cells/microl. A stavudine-lamivudine-efavirenz-containing regimen was initiated predominantly (81.0%). At follow-up (median 23.8 months), 350 (84.1%) were still on HAART, 53 (12.7%) had died, six (1.4%) were transferred, and seven (1.7%) were lost to follow-up. Estimates of survival were 85.5% at 24 months. Of 346 tested patients, 259 (74.1%) had CD4 cell counts greater than 200 cells/microl and 306 (88.4%) had viral loads of less than 400 copies/ml. Factors associated with virological failure at 24 months were non-antiretroviral naive, an insufficient CD4 cell gain of less than 350 cells/microl or a low trough plasma ART concentration. In an intention-to-treat analysis, 73.6% of patients were successfully treated. CONCLUSION: Positive results after 2 years of advanced HIV further demonstrate the efficacy of HAART in the medium term in resource-limited settings.