Environmental, dietary and case-control study of Nodding Syndrome in Uganda: A post-measles brain disorder triggered by malnutrition?

AbstractNodding Syndrome (NS) is an epileptic encephalopathy characterized by involuntary vertical head nodding, other types of seizures, and progressive neurological deficits. The etiology of the east African NS epidemic is unknown. In March 2014, we conducted a case-control study of medical, nutritional and other risk factors associated with NS among children (aged 5–18years) of Kitgum District, northern Uganda (Acholiland). Data on food availability, rainfall, and prevalent disease temporally related to the NS epidemic were also analyzed. In NS Cases, the mean age of reported head nodding onset was 7.6years (range 1–17years). The epidemiologic curve of NS incidence spanned 2000–2013, with peaks in 2003 and 2008. Month of onset of head nodding was non-uniform, with all-year-aggregated peaks in April and June when food availability was low. Families with one or more NS Cases had been significantly more dependent on emergency food and, immediately prior to head nodding onset in the child, subsistence on moldy plant materials, specifically moldy maize. Medical history revealed a single significant association with NS, namely prior measles infection. NS is compared with the post-measles disorder subacute sclerosing panencephalitis, with clinical expression triggered by factors associated with poor nutrition

Raltegravir-intensified initial antiretroviral therapy in advanced HIV in Africa: a randomized controlled trial

BACKGROUND: In sub-Saharan Africa, severely immunocompromised HIV-infected individuals have high mortality (10%) shortly after starting antiretroviral therapy (ART). This group also have the greatest risk of morbidity and mortality associated with immune reconstitution inflammatory syndrome (IRIS), a paradoxical response to successful ART. Integrase inhibitors lead to significantly more rapid declines in HIV viral load (VL) than all other ART classes. We hypothesised that intensifying standard triple-drug ART with the integrase inhibitor, raltegravir, would reduce HIV VL faster, and hence reduce early mortality, although this strategy could also risk more IRIS events. METHODS AND FINDINGS: In a 2x2x2 factorial open-label parallel-group trial, treatment-naïve HIV-infected adults, adolescents and children >5 years with CD4 0.7), and despite significantly greater VL suppression with raltegravir-intensified-ART at 4-weeks (343/836 (41.0%) vs 113/841 (13.4%) standard-ART, p<0.001) and 12-weeks (567/789 (71.9%) vs 415/803 (51.7%) standard-ART, p<0.001). Through 48-weeks there was no evidence of differences in mortality (aHR=0.98 (95%CI 0.76-1.28) p=0.91); serious (aHR=0.99 (0.81-1.21) p=0.88), grade-4 (aHR=0.88 (0.71-1.09) p=0.29) or ART-modifying (aHR=0.90 (0.63-1.27) p=0.54) adverse events (the latter occurring in occurring in 59 (6.5%) raltegravir-intensified-ART vs 66 (7.3%) standard-ART); in events judged compatible with IRIS (occurring in 89 (9.9%) raltegravir-intensified-ART vs 86 (9.5%) standard-ART, p=0.79) or hospitalizations (aHR=0.94 (95%CI 0.76-1.17) p=0.59). At 12 weeks, one and two raltegravir-intensified participants had predicted intermediate-level and high-level raltegravir resistance respectively. At 48 weeks, the NRTI mutation K219E/Q (p=0.004), and the NNRTI mutations K101E/P (p=0.03) and P225H (p=0.007), were less common in raltegravir-intensified-ART, with weak evidence of less intermediate or high-level resistance to tenofovir (p=0.06), abacavir (p=0.08) and rilpivirine (p=0.07). Limitations were limited clinical, radiological and/or microbiological information for some participants, reflecting available services at the centres, and lack of baseline genotypes. CONCLUSIONS: Although 12-weeks raltegravir-intensification was well-tolerated and reduced HIV viraemia significantly faster than standard triple-drug ART during the time of greatest risk for early death, this strategy did not reduce mortality or clinical events, and is not warranted. There was no excess of IRIS-compatible events, suggesting integrase inhibitors can be used safely as part of standard triple-drug first-line therapy in severely immuno-compromised individuals

The cost‐effectiveness of prophylaxis strategies for individuals with advanced HIV starting treatment in Africa

Introduction Many HIV‐positive individuals in Africa have advanced disease when initiating antiretroviral therapy (ART) so have high risks of opportunistic infections and death. The REALITY trial found that an enhanced‐prophylaxis package including fluconazole reduced mortality by 27% in individuals starting ART with CD4 <100 cells/mm3. We investigated the cost‐effectiveness of this enhanced‐prophylaxis package versus other strategies, including using cryptococcal antigen (CrAg) testing, in individuals with CD4 <200 cells/mm3 or <100 cells/mm3 at ART initiation and all individuals regardless of CD4 count. Methods The REALITY trial enrolled from June 2013 to April 2015. A decision‐analytic model was developed to estimate the cost‐effectiveness of six management strategies in individuals initiating ART in the REALITY trial countries. Strategies included standard‐prophylaxis, enhanced‐prophylaxis, standard‐prophylaxis with fluconazole; and three CrAg testing strategies, the first stratifying individuals to enhanced‐prophylaxis (CrAg‐positive) or standard‐prophylaxis (CrAg‐negative), the second to enhanced‐prophylaxis (CrAg‐positive) or enhanced‐prophylaxis without fluconazole (CrAg‐negative) and the third to standard‐prophylaxis with fluconazole (CrAg‐positive) or without fluconazole (CrAg‐negative). The model estimated costs, life‐years and quality‐adjusted life‐years (QALY) over 48 weeks using three competing mortality risks: cryptococcal meningitis; tuberculosis, serious bacterial infection or other known cause; and unknown cause. Results Enhanced‐prophylaxis was cost‐effective at cost‐effectiveness thresholds of US$300 and US$500 per QALY with an incremental cost‐effectiveness ratio (ICER) of US$157 per QALY in the CD4 <200 cells/mm3 population providing enhanced‐prophylaxis components are sourced at lowest available prices. The ICER reduced in more severely immunosuppressed individuals (US$113 per QALY in the CD4 <100 cells/mm3 population) and increased in all individuals regardless of CD4 count (US$722 per QALY). Results were sensitive to prices of the enhanced‐prophylaxis components. Enhanced‐prophylaxis was more effective and less costly than all CrAg testing strategies as enhanced‐prophylaxis still conveyed health gains in CrAg‐negative patients and savings from targeting prophylaxis based on CrAg status did not compensate for costs of CrAg testing. CrAg testing strategies did not become cost‐effective unless the price of CrAg testing fell below US$2.30. Conclusions The REALITY enhanced‐prophylaxis package in individuals with advanced HIV starting ART reduces morbidity and mortality, is practical to administer and is cost‐effective. Efforts should continue to ensure that components are accessed at lowest available prices

Measuring fish catch and consumption: Practical methods for small‐scale fisheries based on length as an alternative to weight‐based approaches

Small-scale fisheries are recognised as making important contributions to nutrition and economic development despite a lack of accurate quantitative information on catches and consumption. While direct measurement remains the most appropriate way of collecting such data, it is impractical at large scales. Instead, household surveys based upon informant recall of fish caught and/or consumed are frequently used. However, the accuracy of weight recall by informants (even over short recall periods) has not been established. Using data from household surveys, the accuracy and precision of catch and consumption estimates derived from: (a) asking informants to recall weights of fish caught and (b) asking respondents to recall lengths of fish caught and converting to weight were tested. Length-based methods, using visual aids to assist recall, were more accurate, precise and correctable. These methods could be useful for catch estimation, especially where fish are processed, sold or consumed shortly after capture

Enhanced prophylaxis with antiretroviral therapy for advanced HIV in Africa

Background: In sub-Saharan Africa, severely immunocompromised HIV-infected individuals have high mortality (10%) from infections shortly after starting antiretroviral therapy (ART). Methods: The REALITY factorial open-label trial (ISRCTN43622374) randomized Ugandan/Zimbabwean/Malawian/Kenyan ART-naïve HIV-infected adults and children ≥5 years with CD4&lt;100 cells/mm3 to ART with either enhanced-prophylaxis (continuous co-trimoxazole plus ≥12-weeks isoniazid/pyridoxine (co-formulated scored fixed-dose-combination tablet), 12-weeks fluconazole, 5-days azithromycin, single-dose albendazole), or standard-of-care co-trimoxazole. Two other randomizations investigated 12-week adjunctive raltegravir and supplementary food. The primary endpoint was 24-week mortality. Results: 1733(96.0%) adults and 72(4.0%) children/adolescents (median 36 years; 961(53.2%) male) were randomized to enhanced-prophylaxis (n=906) or standard-prophylaxis (n=899) and followed for 48 weeks (56(3.1%) lost-to-follow-up). Median baseline CD4 count was 37 cells/mm3 (IQR 16-63) but 854(47.3%) were asymptomatic or mildly symptomatic (stage 1/2 using the WHO clinical disease staging). 80(8.9%) individuals on enhanced-prophylaxis versus 108(12.2%) on standard-prophylaxis died before 24 weeks (hazard ratio[HR]=0.73 (95% CI 0.55-0.98) p=0.03), and 98(11.0%) versus 127(14.4%) respectively died before 48 weeks (HR=0.76 (0.58-0.99) p=0.04, number-needed-to-treat=29), with no evidence of interaction with other randomizations (p&gt;0.7). Enhanced-prophylaxis significantly reduced cases of tuberculosis (p=0.02), cryptococcal disease (p=0.01), oral/oesophageal candidiasis (p=0.02), deaths of unknown cause (p=0.03), and new hospitalisations (p=0.03) but not presumed severe bacterial infections (p=0.32). Serious (p=0.08) and grade-4 (p=0.09) adverse events were marginally less common with enhanced-prophylaxis. Viral suppression (p=0.80) and ART adherence (p=0.31) were similar between groups. Conclusions: Enhanced infection prophylaxis at ART initiation reduced mortality among HIV-infected individuals with advanced immunosuppression, without compromising viral suppression or increasing toxicity. </p

Raltegravir-intensified initial antiretroviral therapy in advanced HIV disease in Africa: A randomised controlled trial

Background: In sub-Saharan Africa, individuals infected with HIV who are severely immunocompromised have high mortality (about 10%) shortly after starting antiretroviral therapy (ART). This group also has the greatest risk of morbidity and mortality associated with immune reconstitution inflammatory syndrome (IRIS), a paradoxical response to successful ART. Integrase inhibitors lead to significantly more rapid declines in HIV viral load (VL) than all other ART classes. We hypothesised that intensifying standard triple-drug ART with the integrase inhibitor, raltegravir, would reduce HIV VL faster and hence reduce early mortality, although this strategy could also risk more IRIS events. Methods and findings: In a 2×2×2 factorial open-label parallel-group trial, treatment-naive adults, adolescents, and children &gt;5 years old infected with HIV, with cluster of differentiation 4 (CD4) &lt;100 cells/mm3, from eight urban/peri-urban HIV clinics at regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe were randomised 1:1 to initiate standard triple-drug ART, with or without 12-week raltegravir intensification, and followed for 48 weeks. The primary outcome was 24-week mortality, analysed by intention to treat. Of 2,356 individuals screened for eligibility, 1,805 were randomised between 18 June 2013 and 10 April 2015. Of the 1,805 participants, 961 (53.2%) were male, 72 (4.0%) were children/adolescents, median age was 36 years, CD4 count was 37 cells/mm3, and plasma viraemia was 249,770 copies/mL. Fifty-six participants (3.1%) were lost to follow-up at 48 weeks. By 24 weeks, 97/902 (10.9%) raltegravir-intensified ART versus 91/903 (10.2%) standard ART participants had died (adjusted hazard ratio [aHR] = 1.10 [95% CI 0.82–1.46], p = 0.53), with no evidence of interaction with other randomisations (pheterogeneity &gt; 0.7) and despite significantly greater VL suppression with raltegravir-intensified ART at 4 weeks (343/836 [41.0%] versus 113/841 [13.4%] with standard ART, p &lt; 0.001) and 12 weeks (567/789 [71.9%] versus 415/803 [51.7%] with standard ART, p &lt; 0.001). Through 48 weeks, there was no evidence of differences in mortality (aHR = 0.98 [95% CI 0.76–1.28], p = 0.91); in serious (aHR = 0.99 [0.81–1.21], p = 0.88), grade-4 (aHR = 0.88 [0.71–1.09], p = 0.29), or ART-modifying (aHR = 0.90 [0.63–1.27], p = 0.54) adverse events (the latter occurring in 59 [6.5%] participants with raltegravir-intensified ART versus 66 [7.3%] with standard ART); in events judged compatible with IRIS (occurring in 89 [9.9%] participants with raltegravir-intensified ART versus 86 [9.5%] with standard ART, p = 0.79) or in hospitalisations (aHR = 0.94 [95% CI 0.76–1.17], p = 0.59). At 12 weeks, one and two raltegravir-intensified participants had predicted intermediate-level and high-level raltegravir resistance, respectively. At 48 weeks, the nucleoside reverse transcriptase inhibitor (NRTI) mutation K219E/Q (p = 0.004) and the non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E/P (p = 0.03) and P225H (p = 0.007) were less common in virus from participants with raltegravir-intensified ART, with weak evidence of less intermediate- or high-level resistance to tenofovir (p = 0.06), abacavir (p = 0.08), and rilpivirine (p = 0.07). Limitations of the study include limited clinical, radiological, and/or microbiological information for some participants, reflecting available services at the centres, and lack of baseline genotypes. Conclusions: Although 12 weeks of raltegravir intensification was well tolerated and reduced HIV viraemia significantly faster than standard triple-drug ART during the time of greatest risk for early death, this strategy did not reduce mortality or clinical events in this group and is not warranted. There was no excess of IRIS-compatible events, suggesting that integrase inhibitors can be used safely as part of standard triple-drug first-line therapy in severely immunocompromised individuals