Nevirapine versus Efavirenz for patients co-infected with HIV and Tuberculosis: A Randomised Non-Inferiority Trial

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)

A multi-center, open-label trial to compare the efficacy and pharmacokinetics of Artemether-Lumefantrine in children with severe acute malnutrition versus children without severe acute malnutrition: study protocol for the MAL-NUT study

BACKGROUND:Malnutrition and malaria frequently coexist in sub-Saharan African countries. Studies on efficacy of antimalarial treatments usually follow the WHO standardized protocol in which severely malnourished children are systematically excluded.Few studies have assessed the efficacy of chloroquine, sulfadoxine-pyrimethamine and quinine in severe acute malnourished children. Overall, efficacy of these treatments appeared to be reduced, attributed to lower immunity and for some antimalarials altered pharmacokinetic profiles and lower drug concentrations. However, similar research on the efficacy and pharmacokinetic profiles of artemisinin-combination therapies (ACTs) and especially artemether-lumefantrine in malnourished children is currently lacking.The main objective of this study is to assess whether artemether-lumefantrine is less efficacious in children suffering from severe acute malnutrition (SAM) compared to non-SAM children, and if so, to what extent this can be attributed to a sub-optimal pharmacokinetic profile.METHODS/DESIGN:In two sites, Ouelessebougou, Mali and Maradi, Niger, children with uncomplicated microscopically-confirmed P. falciparum malaria aged between 6 and 59 months will be enrolled. Two non-SAM children will be enrolled after the enrolment of each SAM case. Children with severe manifestations of malaria or complications of acute malnutrition needing intensive treatment will be excluded.Treatment intakes will be supervised and children will be followed-up for 42 days, according to WHO guidance for surveillance of antimalarial drug efficacy. Polymerase Chain Reaction genotyping will be used to distinguish recrudescence from re-infection. SAM children will also benefit from the national nutritional rehabilitation program.Outcomes will be compared between the SAM and non-SAM populations. The primary outcome will be adequate clinical and parasitological response at day 28 after PCR correction, estimated by Kaplan-Meier analysis. To assess the pharmacokinetic profile of lumefantrine, a sparse sampling approach will be used with randomized allocation of sampling times (5 per child). A total of 180 SAM children and 360 non-SAM children will be recruited during the 2013 and 2014 malaria seasons.DISCUSSION:This study will provide important information that is currently lacking on the effect of SAM on therapeutic efficacy and pharmacokinetic profile of artemether-lumefantrine. If it shows lower therapeutic efficacy and decreased lumefantrine concentrations, it would inform dose optimization studies in SAM children.TRIAL REGISTRATION:ClinicalTrials.gov: NCT0195890

Recent sedimentation of organic matter along the SE Atlantic Margin : A key for understanding deep offshore petroleum source rocks.

Classical views for the deposition of organic-rich sediments in deep-sea environments invoke two principal types of oceanographic and sedimentologic settings. The first is confined basins in which stratified oxygen depleted waters lead to anoxic preservation of organic matter in the water column and in underlying sediments (Demaison and Moore, 1980). The second is an open ocean setting where the episodic mass transfers due to slope sediment instability lead to the rapid burial of outer-shelf and upper slope-derived organic matter and its consequent preservation due to limited oxic or anoxic degradation (Stow, 1987). Other studies have shown, however, that organic matter in modern deep-sea sediments may occur in high amounts where oxygen is not significantly depleted (Pedersen and Calvert, 1990). Recent studies have demonstrated that highly biological productive areas, such as the upwelling zones associated to the Benguela Current in S-E Atlantic, may deliver sufficient quantity of organic material to (1) outbalance the degradative capacity of the water column and (2) sustain the formation of organic-rich sediments even in deep and oxygenated conditions (Bertrand et al., 2003). It appears that the S-E Atlantic margins provide a good example for revisiting the sedimentology of organic matter in deep water environments in the frame of the GDR Marges Continentales. This may have important implications for a better understanding of the distribution of ancient source rocks in deep offshore petroleum systems (Huc et al., 2001; Bertrand et al., 2003)

Inhaled Nitric Oxide as an Adjunctive Treatment for Cerebral Malaria in Children: A Phase II Randomized Open-Label Clinical Trial

Background. Children with cerebral malaria (CM) have high rates of mortality and neurologic sequelae. Nitric oxide (NO) metabolite levels in plasma and urine are reduced in CM. Methods. This randomized trial assessed the efficacy of inhaled NO versus nitrogen (N2) as an adjunctive treatment for CM patients receiving intravenous artesunate.We hypothesized that patients treated with NO would have a greater increase of the malaria biomarker, plasma angiopoietin-1 (Ang-1) after 48 hours of treatment. Results. Ninety-two children with CM were randomized to receive either inhaled 80 part per million NO or N2 for 48 or more hours. Plasma Ang-1 levels increased in both treatment groups, but there was no difference between the groups at 48 hours (P = not significant [NS]). Plasma Ang-2 and cytokine levels (tumor necrosis factor-α, interferon- γ, interleukin [IL]-1β, IL-6, IL-10, and monocyte chemoattractant protein-1) decreased between inclusion and 48 hours in both treatment groups, but there was no difference between the groups (P = NS). Nitric oxide metabolite levels—blood methemoglobin and plasma nitrate—increased in patients treated with NO (both P \u3c .05). Seven patients in the N2 group and 4 patients in the NO group died. Five patients in the N2 group and 6 in the NO group had neurological sequelae at hospital discharge. Conclusions. Breathing NO as an adjunctive treatment for CM for a minimum of 48 hours was safe, increased blood methemoglobin and plasma nitrate levels, but did not result in a greater increase of plasma Ang-1 levels at 48 hours

Articles Nevirapine versus efavirenz for patients co-infected with HIV and tuberculosis: a randomised non-inferiority trial

Summary 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 effi cacy and safety of a nevirapine-based antiretroviral therapy (started at full dose) with an efavirenz-based regimen in coinfected patients

High severity of abortion complications in fragile and conflict-affected settings: a cross-sectional study in two referral hospitals in sub-Saharan Africa (AMoCo study)

BACKGROUND: Abortion-related complications are one of the five main causes of maternal mortality. However, research about abortion is very limited in fragile and conflict-affected settings. Our study aims to describe the magnitude and severity of abortion-related complications in two referral hospitals supported by Médecins Sans Frontières and located in such settings in northern Nigeria and Central African Republic (CAR). METHODS: We used a methodology similar to the World Health Organization (WHO) near-miss approach adapted in the WHO multi-country study on abortion (WHO-MCS-A). We conducted a cross-sectional study in the two hospitals providing comprehensive emergency obstetric care. We used prospective medical records' reviews of women presenting with abortion-related complications between November 2019 and July 2021. We used descriptive analysis and categorized complications into four mutually exclusive categories of increasing severity. RESULTS: We analyzed data from 520 and 548 women respectively in Nigerian and CAR hospitals. Abortion complications represented 4.2% (Nigerian hospital) and 19.9% (CAR hospital) of all pregnancy-related admissions. The severity of abortion complications was high: 103 (19.8%) and 34 (6.2%) women were classified as having severe maternal outcomes (near-miss cases and deaths), 245 (47.1%) and 244 (44.5%) potentially life-threatening, 39 (7.5%) and 93 (17.0%) moderate, and 133 (25.6%) and 177 (32.3%) mild complications, respectively in Nigerian and CAR hospitals. Severe bleeding/hemorrhage was the main type of complication in both settings (71.9% in the Nigerian hospital, 57.8% in the CAR hospital), followed by infection (18.7% in the Nigerian hospital, 27.0% in the CAR hospital). Among the 146 women (Nigerian hospital) and 231 women (CAR hospital) who did not report severe bleeding or hemorrhage before or during admission, anemia was more frequent in the Nigerian hospital (66.7%) compared to the CAR hospital (37.6%). CONCLUSION: Our data suggests high severity of abortion-related complications in these two referral facilities of fragile and conflict-affected settings. Factors that could contribute to this high severity in these contexts include greater delays in accessing post-abortion care, decreased access to contraceptive and safe abortion care that result in increased unsafe abortions; as well as increased food insecurity leading to iron-deficiencies and chronic anaemia. The results highlight the need for better access to safe abortion care, contraception, and high quality postabortion care to prevent and manage complications of abortion in fragile and conflict-affected settings