The impact of long-term azithromycin on antibiotic resistance in HIV-associated chronic lung disease

Selection for resistance to azithromycin (AZM) and other antibiotics such as tetracyclines and lincosamides remains a concern with long-term AZM use for treatment of chronic lung diseases (CLD). We investigated the impact of 48 weeks of AZM on the carriage and antibiotic resistance of common respiratory bacteria among children with HIV-associated CLD. Nasopharyngeal (NP) swabs and sputa were collected at baseline, 48 and 72 weeks from participants with HIV-associated CLD randomised to receive weekly AZM or placebo for 48 weeks and followed postintervention until 72 weeks. The primary outcomes were prevalence and antibiotic resistance of Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Haemophilus influenzae (HI) and Moraxella catarrhalis (MC) at these timepoints. Mixed-effects logistic regression and Fisher’s exact test were used to compare carriage and resistance, respectively. Of 347 (174 AZM, 173 placebo) participants (median age 15 years (IQR 13–18), female 49%), NP carriage was significantly lower in the AZM (n=159) compared to placebo (n=153) arm for SP (18% versus 41%, p<0.001), HI (7% versus 16%, p=0.01) and MC (4% versus 11%, p=0.02); SP resistance to AZM (62% (18 out of 29) versus 13% (8 out of 63), p<0.0001) or tetracycline (60% (18 out of 29) versus 21% (13 out of 63), p<0.0001) was higher in the AZM arm. Carriage of SA resistant to AZM (91% (31 out of 34) versus 3% (1 out of 31), p<0.0001), tetracycline (35% (12 out of 34) versus 13% (4 out of 31), p=0.05) and clindamycin (79% (27 out of 34) versus 3% (1 out of 31), p<0.0001) was also significantly higher in the AZM arm and persisted at 72 weeks. Similar findings were observed for sputa. The persistence of antibiotic resistance and its clinical relevance for future infectious episodes requiring treatment needs further investigation

Population-Level Reduction in Adult Mortality after Extension of Free Anti-Retroviral Therapy Provision into Rural Areas in Northern Malawi

BACKGROUND: Four studies from sub-Saharan Africa have found a substantial population-level effect of ART provision on adult mortality. It is important to see if the impact changes with time since the start of treatment scale-up, and as treatment moves to smaller clinics. METHODS AND FINDINGS: During 2002-4 a demographic surveillance site (DSS) was established in Karonga district, northern Malawi. Information on births and deaths is collected monthly, with verbal autopsies conducted for all deaths; migrations are updated annually. We analysed mortality trends by comparing three time periods: pre-ART roll-out in the district (August 2002-June 2005), ART period 1 (July 2005-September 2006) when ART was available only in a town 70 km away, and ART period 2 (October 2006-September 2008), when ART was available at a clinic within the DSS area. HIV prevalence and ART uptake were estimated from a sero-survey conducted in 2007/2008. The all-cause mortality rate among 15-59 year olds was 10.2 per 1000 person-years in the pre-ART period (288 deaths/28285 person-years). It fell by 16% in ART period 1 and by 32% in ART period 2 (95% CI 18%-43%), compared with the pre-ART period. The AIDS mortality rate fell from 6.4 to 4.6 to 2.7 per 1000 person-years in the pre-ART period, period 1 and period 2 respectively (rate ratio for period 2 = 0.43, 95% CI 0.33-0.56). There was little change in non-AIDS mortality. Treatment coverage among individuals eligible to start ART was around 70% in 2008. CONCLUSIONS: ART can have a dramatic effect on mortality in a resource-constrained setting in Africa, at least in the early years of treatment provision. Our findings support the decentralised delivery of ART from peripheral health centres with unsophisticated facilities. Continued funding to maintain and further scale-up treatment provision will bring large benefits in terms of saving lives

Predicting the Current and Future Potential Distributions of Lymphatic Filariasis in Africa Using Maximum Entropy Ecological Niche Modelling

Modelling the spatial distributions of human parasite species is crucial to understanding the environmental determinants of infection as well as for guiding the planning of control programmes. Here, we use ecological niche modelling to map the current potential distribution of the macroparasitic disease, lymphatic filariasis (LF), in Africa, and to estimate how future changes in climate and population could affect its spread and burden across the continent. We used 508 community-specific infection presence data collated from the published literature in conjunction with five predictive environmental/climatic and demographic variables, and a maximum entropy niche modelling method to construct the first ecological niche maps describing potential distribution and burden of LF in Africa. We also ran the best-fit model against climate projections made by the HADCM3 and CCCMA models for 2050 under A2a and B2a scenarios to simulate the likely distribution of LF under future climate and population changes. We predict a broad geographic distribution of LF in Africa extending from the west to the east across the middle region of the continent, with high probabilities of occurrence in the Western Africa compared to large areas of medium probability interspersed with smaller areas of high probability in Central and Eastern Africa and in Madagascar. We uncovered complex relationships between predictor ecological niche variables and the probability of LF occurrence. We show for the first time that predicted climate change and population growth will expand both the range and risk of LF infection (and ultimately disease) in an endemic region. We estimate that populations at risk to LF may range from 543 and 804 million currently, and that this could rise to between 1.65 to 1.86 billion in the future depending on the climate scenario used and thresholds applied to signify infection presence

Enhanced infection prophylaxis reduces mortality in severely immunosuppressed HIV-infected adults and older children initiating antiretroviral therapy in Kenya, Malawi, Uganda and Zimbabwe: the REALITY trial

Meeting abstract FRAB0101LB from 21st International AIDS Conference 18–22 July 2016, Durban, South Africa. Introduction: Mortality from infections is high in the first 6 months of antiretroviral therapy (ART) among HIV‐infected adults and children with advanced disease in sub‐Saharan Africa. Whether an enhanced package of infection prophylaxis at ART initiation would reduce mortality is unknown. Methods: The REALITY 2×2×2 factorial open‐label trial (ISRCTN43622374) randomized ART‐naïve HIV‐infected adults and children >5 years with CD4 <100 cells/mm3. This randomization compared initiating ART with enhanced prophylaxis (continuous cotrimoxazole plus 12 weeks isoniazid/pyridoxine (anti‐tuberculosis) and fluconazole (anti‐cryptococcal/candida), 5 days azithromycin (anti‐bacterial/protozoal) and single‐dose albendazole (anti‐helminth)), versus standard‐of‐care cotrimoxazole. Isoniazid/pyridoxine/cotrimoxazole was formulated as a scored fixed‐dose combination. Two other randomizations investigated 12‐week adjunctive raltegravir or supplementary food. The primary endpoint was 24‐week mortality. Results: 1805 eligible adults (n = 1733; 96.0%) and children/adolescents (n = 72; 4.0%) (median 36 years; 53.2% male) were randomized to enhanced (n = 906) or standard prophylaxis (n = 899) and followed for 48 weeks (3.8% loss‐to‐follow‐up). Median baseline CD4 was 36 cells/mm3 (IQR: 16–62) but 47.3% were WHO Stage 1/2. 80 (8.9%) enhanced versus 108(12.2%) standard prophylaxis died before 24 weeks (adjusted hazard ratio (aHR) = 0.73 (95% CI: 0.54–0.97) p = 0.03; Figure 1) and 98(11.0%) versus 127(14.4%) respectively died before 48 weeks (aHR = 0.75 (0.58–0.98) p = 0.04), with no evidence of interaction with the two other randomizations (p > 0.8). Enhanced prophylaxis significantly reduced incidence of tuberculosis (p = 0.02), cryptococcal disease (p = 0.01), oral/oesophageal candidiasis (p = 0.02), deaths of unknown cause (p = 0.02) and (marginally) hospitalisations (p = 0.06) but not presumed severe bacterial infections (p = 0.38). Serious and grade 4 adverse events were marginally less common with enhanced prophylaxis (p = 0.06). CD4 increases and VL suppression were similar between groups (p > 0.2). Conclusions: Enhanced infection prophylaxis at ART initiation reduces early mortality by 25% among HIV‐infected adults and children with advanced disease. The pill burden did not adversely affect VL suppression. Policy makers should consider adopting and implementing this low‐cost broad infection prevention package which could save 3.3 lives for every 100 individuals treated