Articles tagged as "Botswana"

Better virological outcomes with efavirenz compared to nevirapine

Outcomes for efavirenz versus nevirapine-containing regimens for treatment of HIV-1 infection: a systematic review and meta-analysis.

Pillay P, Ford N, Shubber Z, Ferrand RA., PLoS One. 2013 Jul 22;8(7):e68995. doi: 10.1371/journal.pone.0068995. Print 2013

Introduction: There is conflicting evidence and practice regarding the use of the non-nucleoside reverse transcriptase inhibitors (NNRTI) efavirenz (EFV) and nevirapine (NVP) in first-line antiretroviral therapy (ART).

Methods: We systematically reviewed virological outcomes in HIV-1 infected, treatment-naive patients on regimens containing EFV versus NVP from randomised trials and observational cohort studies. Data sources include PubMed, Embase, the Cochrane Central Register of Controlled Trials and conference proceedings of the International AIDS Society, Conference on Retroviruses and Opportunistic Infections, between 1996 to May 2013. Relative risks (RR) and 95% confidence intervals were synthesized using random-effects meta-analysis. Heterogeneity was assessed using the I(2) statistic, and subgroup analyses performed to assess the potential influence of study design, duration of follow up, location, and tuberculosis treatment. Sensitivity analyses explored the potential influence of different dosages of NVP and different viral load thresholds.

Results: Of 5011 citations retrieved, 38 reports of studies comprising 114 391 patients were included for review. EFV was significantly less likely than NVP to lead to virologic failure in both trials (RR 0.85 [0.73-0.99] I(2) = 0%) and observational studies (RR 0.65 [0.59-0.71] I(2) = 54%). EFV was more likely to achieve virologic success than NVP, though marginally significant, in both randomised controlled trials (RR 1.04 [1.00-1.08] I(2) = 0%) and observational studies (RR 1.06 [1.00-1.12] I(2) = 68%).

Conclusion: EFV-based first line ART is significantly less likely to lead to virologic failure compared to NVP-based ART. This finding supports the use of EFV as the preferred NNRTI in first-line treatment regimen for HIV treatment, particularly in resource limited settings.

Abstract  Full-text [free] access

Editor’s notes: Efavirenz and nevirapine are key antiretroviral agents, particularly in resource-limited settings. Nevirapine has been widely used, for reasons including safety during pregnancy and lower cost, despite lower potency and a higher risk of hepatotoxicity and severe allergic reactions, than with efavirenz. This article summarizes data on virological outcomes from clinical trials and observational cohort studies comparing efavirenz and nevirapine. The finding that efavirenz is associated with slightly better virological outcomes is not surprising but it is valuable to have the available data summarised. The result, along with recent recommendations allowing efavirenz to be taken throughout pregnancy, and price reductions, supports the move towards efavirenz-based fixed drug combinations as first-line antiretroviral treatment in resource-limited settings.

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Children: higher rates of virological failure on nevirapine-, as compared to efavirenz-based ART

Association between efavirenz-based compared with nevirapine-based antiretroviral regimens and virological failure in HIV-infected children.

Lowenthal ED, Ellenberg JH, Machine E, Sagdeo A, Boiditswe S, Steenhoff AP, Rutstein R, Anabwani G, Gross R. JAMA. 2013 May 1;309(17):1803-9.

Worldwide, the non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine are commonly used in first-line antiretroviral regimens in both adults and children with human immunodeficiency virus (HIV) infection. Data on the comparative effectiveness of these medications in children are limited.

Objective: To investigate whether virological failure is more likely among children who initiated 1 or the other NNRTI-based HIV treatment.

Design, setting, and participants: Retrospective cohort study of children (aged 3-16 years) who initiated efavirenz-based (n = 421) or nevirapine-based (n = 383) treatment between April 2002 and January 2011 at a large pediatric HIV care setting in Botswana.

Main outcomes and measures: The primary outcome was time from initiation of therapy to virological failure. Virological failure was defined as lack of plasma HIV RNA suppression to less than 400 copies/mL by 6 months or confirmed HIV RNA of 400 copies/mL or greater after suppression. Cox proportional hazards regression analysis compared time to virological failure by regimen. Multivariable Cox regression controlled for age, sex, baseline immunologic category, baseline clinical category, baseline viral load, nutritional status, NRTIs used, receipt of single-dose nevirapine, and treatment for tuberculosis.

Results: With a median follow-up time of 69 months (range, 6-112 months; interquartile range, 23-87 months), 57/421 children (13.5%; 95% CI, 10.4%-17.2%) initiating treatment with efavirenz and 101/383 children (26.4%; 95% CI, 22.0%-31.1%) initiating treatment with nevirapine had virological failure. There were 11 children (2.6%; 95% CI, 1.3%-4.6%) receiving efavirenz and 20 children (5.2%; 95% CI, 3.2%-7.9%) receiving nevirapine who never achieved virological suppression. The Cox proportional hazard ratio for the combined virological failure end point was 2.0 (95% CI, 1.4-2.7; log rank P < .001, favoring efavirenz). None of the measured covariates affected the estimated hazard ratio in the multivariable analyses.

Conclusions and relevance: Among children aged 3 to 16 years infected with HIV and treated at a clinic in Botswana, the use of efavirenz compared with nevirapine as initial antiretroviral treatment was associated with less virological failure. These findings may warrant additional research evaluating the use of efavirenz and nevirapine for pediatric patients.

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Editor’s notes: Out of 3.4 million children infected with HIV world-wide, 90% live in sub-Saharan Africa. The majority of children initiating ART receive nevirapine-based regimens, a regimen in-line with WHO recommendations (children > 3 years old should receive nevirapine or efavirenz together with two drugs from the NRTI class). However, data regarding the relative effectiveness of nevirapine and efavirenz in children are limited. In this large retrospective clinic-based cohort study in Botswana rates of virological failure were found to be higher in patients initiating nevirapine as compared to those initiating efavIrenz (HR 2.0 [95% CI: 1.4-2.7; p<0.001). Whilst differences in effectiveness may be one explanation, the authors also discuss alternative explanations: drug interactions and resistance were thought to be unlikely as few patients were on anti-tuberculosis therapy, and only 2.2% of the cohort was known to have been exposed to single-dose nevirapine at birth. The role of sub-optimal adherence could not be assessed as, in common with many programme cohorts, data on adherence were limited. As highlighted by the authors, treatment decisions are rarely made randomly and are often influenced by the characteristics of the patients. Recognizing this limitation the authors explored whether female adolescents were more likely to be prescribed nevirapine (due to concerns about efavirenz in women of child-bearing age), with the underlying assumption that adolescents were more likely to exhibit sub-optimal adherence; however this did not explain the differences in virological outcomes. In summary, this study highlights the need for further research regarding the optimal first-line regimens in children.

Africa
Botswana
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Efavirenz dose adjustments are probably not required in patients taking concurrent rifampicin

Relationship between weight, efavirenz exposure and virologic suppression in HIV-infected patients on rifampin-based TB treatment in the ACTG A5221 STRIDE study

Luetkemeyer AF, Rosenkranz SL, Lu D, Marzan F, Ive P, Hogg E, et al. Adult AIDS Clinical Trials Group A5221 Study Team. Clinical Infectious Diseases Advance Access published April 19, 2013.

Background: Rifampin (RIF) upregulates CYP 450 isoenzymes potentially lowering efavirenz (EFV) exposure. The US EFV package insert recommends EFV dose increase for patients on RIF weighing ≥50 kg. We conducted a pharmacokinetic study to evaluate EFV trough concentrations (Cmin) and HIV virologic suppression in patients on EFV (600 mg) and RIFbased TB treatment as part of a multicenter randomized trial (ACTG A5221)

Methods: EFV Cmin was measured using HPLC 20‐28 hours post‐EFV dose at weeks 4,8,16,24 on‐RIF and weeks 4,8 off‐RIF. Results evaluated with two‐sided Wilcoxon rank‐sum, chi‐square and Fisher's Exact tests and logistic regression (5% Type I error rate).

Results: 780 patients from 11 countries received EFV, 543 provided ≥ 1 EFV Cmin. Median (IQR) weight was 52.8 kg (48.0,59.5), BMI 19.4 kg/m2 (17.5,21.6), age 34 (29,41), 63% male, race Black (74%), Hispanic (20%), non‐Hispanic White (5%), Asian (1%). Median Cmin was 1.96μg/mL onRIF vs. 1.80 offRIF (p=0.067). EFV concentrations were significantly higher onRIF vs. offRIF in Blacks (2.08 vs. 1.75, p=0.005). Weight ≥60 kg onRIF, compared to <60 kg, was associated with lower EFV Cmin (1.68 vs. 2.02, p=0.021). However, weight ≥60 kg was associated with more frequent HIV RNA<400 copies/mL at week 48, compared to weight <60 kg (81.9% vs. 73.8%, p=0.023).

Conclusions: Coadministration of EFV and RIFbased TB therapy was associated with a trend toward higher, not lower, EFV Cmin compared to EFV alone, which was statistically significant in Black patients. Patients weighing ≥60 kg had lower median EFV Cmin vs. those <60 kg, but there was no association of higher weight with reduced virologic suppression. These data do not support weightbased dosing of EFV with RIF co-administration.

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Editor’s notes: Effective treatment of HIV-TB co-infection is complicated by drug-drug interactions. Rifampicin, the key component of effective anti-TB therapy, is a potent inducer of the cytochrome P450 enzymes which metabolize many antiretrovirals including efavirenz. Appropriate dosing of efavirenz in patients taking concomitant TB treatment has been debated, with both US and British national treatment guidelines recommending efavirenz dose increases. The WHO does not recommend adjusting dosing. This study, an analysis of efavirenz levels from 543 participants in the STRIDE study of ART timing in TB co-infected patients, suggests that efavirenz dose adjustments are not required in patients taking concurrent rifampicin based TB treatment. Efavirenz levels were not reduced in patients who were taking TB treatment. In fact trough efavirenz levels were slightly increased in patients during TB treatment. This increase in efavirenz levels was most marked in black patients. Virological outcomes with efavirenz based ART in this cohort of patients on TB treatment were good, with 76% fully suppressed at 48 weeks.  Perhaps unsurprisingly, efavirenz levels were slightly lower in patients weighing over 60 kg compared to those below 60 kg, but this did not translate into worse virological outcomes. Given the racial differences seen in efavirenz metabolism in this study there is a question about the generalisability of the study to certain populations, notably Caucasians who only made up 5% of the study population. However the demographics were representative of the vast majority of HIV-TB co-infected patients worldwide. These results strongly suggest that efavirenz at standard doses can be safely used in patients receiving rifampicin based TB treatment, avoiding the need to complicate ART treatment regimens in the large number of individuals receiving TB treatment in resource-limited public health programmes.

Avoid TB deaths
Comorbidity, HIV Treatment
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Comparing adverse effects of nevirapine and efavirenz

Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis.

Shubber Z, Calmy A, Andrieux-Meyer I, Vitoria M, Renaud-Thery F, Shaffer N, Hargreaves S, Mills EJ, Ford N. AIDS. 2013 Jan 22. [Epub ahead of print]

Since 2002, the World Health Organization has recommended either nevirapine (NVP) or efavirenz (EFV) as part of first-line antiretroviral therapy. These two drugs are known to have differing toxicity profiles, but the clinical importance of these toxicities overall is not well established. The authors systematically reviewed adverse events among treatment-naïve HIV-positive adults and children receiving either NVP or EFV as part of first-line antiretroviral therapy. The primary outcome was drug discontinuation as a result of any adverse event; specific toxicities were evaluated as secondary outcomes. Point estimates and 95% confidence intervals (95% CI) were calculated and proportions and odds ratios (OR) pooled using fixed-effects meta-analysis. Data was reviewed on 26446 adult and 3975 children from 8 randomized trials and 26 prospective cohorts. Overall, adults on NVP were more than two times more likely to discontinue treatment due to any adverse event compared to patients on EFV (OR 2.2, 95%CI 1.9-2.6). Severe hepatotoxicity (OR 3.3, 95%CI 2.5-4.2), severe skin toxicity (OR 3.9, 95%CI 2.5-5.4), and severe hypersensitivity reactions (OR 2.4, 95%CI 1.9-2.9) were more likely to occur among patients on NVP. Patients receiving EFV were more likely to experience severe CNS-events (OR 3.4, 95%CI 2.1-5.4). Similar associations were seen in children. Compared to NVP, EFV is associated with a lower frequency of severe adverse events, in particular treatment discontinuations. This finding supports a move towards efavirenz-based therapy as the preferred first-line treatment regimen for HIV treatment within a public health approach.

Abstract access 

Editor’s notes: As increased progress is being made towards universal access to treatment, increased attention is being addressed towards retention in care and on treatment. Simpler, less toxic regimens have been a cornerstone of the Treatment 2.0 initiative of UNAIDS and WHO. Nevirapine has been widely utilized as an essential component of three drug antiretroviral therapy, in part due to low cost and safety at a population level. While efavirenz does have a greater incidence of central nervous system side effects (many of them manageable with supportive treatment), the overall discontinuation rate is significantly lower than with nevirapine. This data in combination with the continued reduction in efavirenz price, and incorporation into combination pill form, supports the move towards increased use of efavirenz for first line antiretroviral therapy.

HIV Treatment
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