Sensitivity, Specificity, and Public-Health Utility of Clinical Case Definitions Based on the Signs and Symptoms of Cholera in Africa.

During 2014, Africa reported more than half of the global suspected cholera cases. Based on the data collected from seven countries in the African Cholera Surveillance Network (Africhol), we assessed the sensitivity, specificity, and positive and negative predictive values of clinical cholera case definitions, including that recommended by the World Health Organization (WHO) using culture confirmation as the gold standard. The study was designed to assess results in real-world field situations in settings with recent cholera outbreaks or endemicity. From June 2011 to July 2015, a total of 5,084 persons with suspected cholera were tested for Vibrio cholerae in seven different countries of which 35.7% had culture confirmation. For all countries combined, the WHO case definition had a sensitivity = 92.7%, specificity = 8.1%, positive predictive value = 36.1%, and negative predictive value = 66.6%. Adding dehydration, vomiting, or rice water stools to the case definition could increase the specificity without a substantial decrease in sensitivity. Future studies could further refine our findings primarily by using more sensitive methods for cholera confirmation.

Temporo-spatial dynamics and behavioural patterns of 2012 cholera epidemic in the African mega-city of Conakry, Guinea.

BACKGROUND: Cholera is endemic in Guinea, having suffered consecutive outbreaks from 2004 to 2008 followed by a lull until the 2012 epidemic. Here we describe the temporal-spatial and behavioural characteristics of cholera cases in Conakry during a three-year period, including the large-scale 2012 epidemic. METHODS: We used the national and African Cholera Surveillance Network (Africhol) surveillance data collected from every cholera treatment centre in Conakry city from August 2011 to December 2013. The prevalence of suspect and confirmed cholera cases, the case fatality ratio (CFR), and the factors associated with suspected cholera were described according to three periods: pre-epidemic (A), epidemic 2012 (B) and post epidemic (C). Weekly attack rates and temporal-spatial clustering were calculated at municipality level for period B. Cholera was confirmed by culture at the cholera national reference laboratory. RESULTS: A total of 4559 suspect cases were reported: 66, 4437, and 66 suspect cases in periods A, B and C, respectively. Among the 204 suspect cases with culture results available, 6%, 60%, and 70% were confirmed in periods A, B, and C, respectively. With 0.3%, the CFR was significantly lower in period B than in periods A (7.6%) and C (7.1%). The overall attack rate was 0.28% in period B, ranging from 0.17% to 0.31% across municipalities. Concomitantly, a cluster of cases was identified in two districts in the northern part of Conakry. At 14%, rice water stools were less frequent in period A than in period B and C (78% and 84%). Dehydration (31% vs 94% and 89%) and coma (0.4% vs 3.1% and 2.9%) were lower during period B than in periods A and C. The treatment of drinking water was less frequent in period A, while there were more reports of recent travel in period C. CONCLUSIONS: The epidemic dynamic and the sociological description of suspect cases before, during, and after the large-scale epidemic revealed that the Vibrio cholerae was already present before the epidemic. However, it appeared that infected individuals reacted differently in terms of disease severity as well as their access to treated water and travel habits. Such an in-depth description of cholera epidemics should be systematically carried out in cholera endemic settings in order to prioritize higher risk areas, identify transmission factors, and optimize preventive interventions.

The African cholera surveillance network (Africhol) consortium meeting, 10-11 June 2015, Lomé, Togo.

The fifth annual meeting of the African cholera surveillance network (Africhol) took place on 10-11 June 2015 in Lomé, Togo. Together with international partners, representatives from the 11 member countries -Cameroon, Côte d'Ivoire, Democratic Republic of Congo, Guinea, Kenya, Mozambique, Nigeria, Tanzania, Togo, Uganda, Zimbabwe- and an invited country (Malawi) shared their experience. The meeting featured three sessions: i) cholera surveillance, prevention and control in participating countries, ii) cholera surveillance methodology, such as cholera mapping, cost-effectiveness studies and the issue of overlapping epidemics from different diseases, iii) cholera laboratory diagnostics tools and capacity building. The meeting has greatly benefitted from the input of technical expertise from participating institutions and the observations emerging from the meeting should enable national teams to make recommendations to their respective governments on the most appropriate and effective measures to be taken for the prevention and control of cholera. Recommendations for future activities included collecting precise burden estimates in surveillance sites; modeling cholera burden for Africa; setting up cross-border collaborations; strengthening laboratory capacity for the confirmation of suspected cholera cases and for vaccine impact assessment in settings where oral cholera vaccine would be used; adapting cholera surveillance to concurrent issues (e.g., Ebola); and developing national cholera control plans including rationale vaccination strategies together with other preventive and control measures such as improvements in water, sanitation and hygiene (WASH).

Oral cholera vaccine coverage in hard-to-reach fishermen communities after two mass Campaigns, Malawi, 2016.

CONTEXT: From December 2015 to August 2016, a large epidemic of cholera affected the fishermen of Lake Chilwa in Malawi. A first reactive Oral Cholera Vaccines (OCV) campaign was organized, in February, in a 2km radius of the lake followed by a preemptive one, conducted in November, in a 25km radius. We present the vaccine coverage reached in hard-to-reach population using simplified delivery strategies. METHOD: We conducted two-stage random-sampling cross-sectional surveys among individuals living in a 2km and 25km radius of Lake Chilwa (islands and floating homes included). Individuals aged 12months and older from Machinga and Zomba districts were sampled: 43 clusters of 14 households were surveyed. Simplified strategies were used for those living in islands and floating homes: self- delivery and community-supervised delivery of the second dose. Vaccine coverage (VC) for at-least-two-doses was estimated taking into account sampling weights and design effects. RESULTS: A total of 1176 households were surveyed (2.7% of non-response). Among the 2833 individuals living in the 2km radius of Lake and the 2915 in the 25km radius: 457 (16.1%) and 239 (8.2%) lived in floating homes or on islands at some point in the year, respectively. For the overall population, VC was 75.6% and 54.2%, respectively. In the 2km radius, VC was 92.2% for those living on the lake at some point of the year: 271 (64.8%) used the simplified strategies. The main reasons for non-vaccination were absence during the campaign and vaccine shortage. Few adverse events occurring in the 24h following vaccination was reported. CONCLUSIONS: We reached a high two-dose coverage of the most at-risk population using simplified delivery strategies. Because of the high fishermen mobility, regular catch-up campaigns or another strategy specifically targeting fishermen need to be assessed for more efficient vaccines use.

Cholera Incidence and Mortality in Sub-Saharan African Sites during Multi-country Surveillance.

BACKGROUND: Cholera burden in Africa remains unknown, often because of weak national surveillance systems. We analyzed data from the African Cholera Surveillance Network (www.africhol.org). METHODS/ PRINCIPAL FINDINGS: During June 2011-December 2013, we conducted enhanced surveillance in seven zones and four outbreak sites in Togo, the Democratic Republic of Congo (DRC), Guinea, Uganda, Mozambique and Cote d'Ivoire. All health facilities treating cholera cases were included. Cholera incidences were calculated using culture-confirmed cholera cases and culture-confirmed cholera cases corrected for lack of culture testing usually due to overwhelmed health systems and imperfect test sensitivity. Of 13,377 reported suspected cases, 34% occurred in Conakry, Guinea, 47% in Goma, DRC, and 19% in the remaining sites. From 0-40% of suspected cases were aged under five years and from 0.3-86% had rice water stools. Within surveillance zones, 0-37% of suspected cases had confirmed cholera compared to 27-38% during outbreaks. Annual confirmed incidence per 10,000 population was <0.5 in surveillance zones, except Goma where it was 4.6. Goma and Conakry had corrected incidences of 20.2 and 5.8 respectively, while the other zones a median of 0.3. During outbreaks, corrected incidence varied from 2.6 to 13.0. Case fatality ratios ranged from 0-10% (median, 1%) by country. CONCLUSIONS/SIGNIFICANCE: Across different African epidemiological contexts, substantial variation occurred in cholera incidence, age distribution, clinical presentation, culture confirmation, and testing frequency. These results can help guide preventive activities, including vaccine use.

Comparative Characterization of Vibrio cholerae O1 from Five Sub-Saharan African Countries Using Various Phenotypic and Genotypic Techniques.

We used standardized methodologies to characterize Vibrio cholerae O1 isolates from Guinea, Democratic Republic of the Congo (DRC), Togo, Côte d'Ivoire and Mozambique. We investigated 257 human isolates collected in 2010 to 2013. DRC isolates serotyped O1 Inaba, while isolates from other countries serotyped O1 Ogawa. All isolates were biotype El Tor and positive for cholera toxin. All isolates showed multidrug resistance but lacked ciprofloxacin resistance. Antimicrobial susceptibility profiles of isolates varied between countries. In particular, the susceptibility profile of isolates from Mozambique (East-Africa) included resistance to ceftriaxone and was distinctly different to the susceptibility profiles of isolates from countries located in West- and Central-Africa. Molecular subtyping of isolates using pulsed-field gel electrophoresis (PFGE) analysis showed a complex relationship among isolates. Some PFGE patterns were unique to particular countries and clustered by country; while other PFGE patterns were shared by isolates from multiple countries, indicating that the same genetic lineage is present in multiple countries. Our data add to a better understanding of cholera epidemiology in Africa.

Antiretroviral therapy outcomes in resource-limited settings for HIV-infected children <5 years of age.

OBJECTIVE: We describe medium-term outcomes for young children receiving antiretroviral therapy (ART) in resource-limited countries. METHODS: Analyses were conducted on surveillance data for children <5 years of age receiving ART (initiated April 2002 to January 2008) in 48 HIV/AIDS treatment programs in Africa and Asia. Primary outcome measures were probability of remaining in care, probability of developing World Health Organization stage 4 clinical events, rate of switching to second-line ART, and drug toxicity, compared at 6, 12, 24, and 36 months of ART. RESULTS: Of 3936 children (90% in Africa) initiating ART, 9% were <12 months, 50% were 12 to 35 months, and 41% were 36 to 59 months of age. The median time of ART was 10.5 months. Probabilities of remaining in care after 12, 24, and 36 months of ART were 0.85, 0.80, and 0.75, respectively. Compared with children 36 to 59 months of age at ART initiation, probabilities of remaining in care were significantly lower for children <12 months of age. Overall, 55% and 69% of deaths and losses to follow-up occurred in the first 3 and 6 months of ART, respectively. Probabilities of developing stage 4 clinical events after 12, 24, and 36 months of ART were 0.03, 0.06, and 0.09, respectively. Only 33 subjects (0.8%) switched to second-line regimens, and 151 (3.8%) experienced severe drug toxicities. CONCLUSIONS: Large-scale ART for children <5 years of age in resource-limited settings is feasible, with encouraging clinical outcomes, but efforts should be increased to improve early HIV diagnosis and treatment.

Treatment outcomes stratified by baseline immunological status among young children receiving nonnucleoside reverse-transcriptase inhibitor-based antiretroviral therapy in resource-limited settings.

A study of 568 children aged <5 years who commenced nonnucleoside reverse-transcriptase inhibitor-based antiretroviral therapy in resource-limited settings revealed good early outcomes. After 12 months of antiretroviral therapy, survival probability was 0.89 (95% confidence interval, 0.86-0.92), with no significant difference among children stratified on the basis of baseline immunological levels; 62% attained a CD4 cell percentage >25%, and 7% continued to have a CD4 cell percentage <15%.

In resource-limited settings good early outcomes can be achieved in children using adult fixed-dose combination antiretroviral therapy.

OBJECTIVES: To (a) determine early treatment outcomes and (b) assess safety in children treated with adult fixed-dose combination (FDC) antiretroviral tablets. SETTING: Sixteen Medecins Sans Frontieres (MSF) HIV programs in eight countries in resource-limited settings (RLS). METHODS: Analysis of routine program data gathered June 2001 to March 2005. RESULTS: A total of 1184 children [median age, 7 years; inter-quartile range (IQR), 4.6-9.3] were treated with antiretroviral therapy (ART) of whom 616(52%) were male. At ART initiation, Centres for Disease Control stages N, A, B and C were 9, 14, 38 and 39%, respectively. Children were followed up for a median period of 6 months (IQR, 2-12 months). At 12 months the median CD4 percentage gain in children aged 18-59 months was 15% (IQR, 6-18%), and the percentage with CD4 gain < 15% was reduced from 85% at baseline to 11%. In those aged 60-156 months, median CD4 cell count gain was 275 cells/microl (IQR, 84-518 cells/microl), and the percentage with CD4 < 200 cells/mul reduced from 51% at baseline to 11%. Treatment outcomes included; 1012 (85%) alive and on ART, 36 (3%) deaths, 15 (1%) stopped ART, 89 (8%) lost to follow-up, and 31 (3%) with unknown outcomes. Overall probability of survival at 12 months was 0.87 (0.84-0.89). Side effects caused a change to alternative antiretroviral drugs in 26 (2%) but no deaths. CONCLUSIONS: Very satisfactory early outcomes can be achieved in children in RLS using generic adult FDC antiretroviral tablets. These findings strongly favour their use as an "interim solution" for scaling-up ART in children; however, more appropriate pediatric antiretroviral drugs remain urgently needed.

CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial.

BACKGROUND: Structured treatment interruptions of highly-active antiretroviral therapy (HAART) might be particularly relevant for sub-Saharan Africa, where cost-saving strategies could help to increase the number of patients on HAART. We did a randomised trial of structured treatment interruption in Abidjan, Côte d'Ivoire. METHODS: HIV-infected adults were randomised to receive continuous HAART (CT), CD4-guided HAART (CD4GT) with interruption and reintroduction thresholds at 350 and 250 cells per mm3, respectively, or 2-months-off, 4-months-on HAART. Primary endpoints were death and severe morbidity (any WHO stage 3 or 4 events and any events leading to death) at month 24. We report data from the CT and CD4GT groups until Oct 31, 2005, when the data safety monitoring board recommended to prematurely stop the CD4GT arm. Analyses were intention-to-treat. This study is registered at ClinicalTrials.gov, number NCT00158405. RESULTS: 326 adults (median CD4 count nadir 272 per mm3) were randomised to the CT or CD4GT groups and followed up for median of 20 months. Incidence of mortality (per 100 person-years) was not different between groups (CT 0.6, CD4GT 1.2; p=0.57). Incidence of severe morbidity (per 100 person-years) was higher in the CDG4T group (17.6) than in the CT group (6.7; p=0.001). The most frequent severe events were invasive bacterial diseases. 79% of severe morbidity episodes occurred in patients with CD4 count 200-500 per mm3. CONCLUSION: Patients on CD4GT had severe morbidity rates 2.5-fold higher than those on CT. This difference was mainly due to high rates of common diseases in patients with CD4 count 200-500 per mm3. This CD4-guided structured treatment interruption strategy should not be recommended in Abidjan.

Haematological changes in adults receiving a zidovudine-containing HAART regimen in combination with cotrimoxazole in Côte d'Ivoire.

OBJECTIVE: Neutropenia is the most frequent side effect of cotrimoxazole in sub-Saharan Africa. We estimated the incidence of haematological disorders during the first 6 months of a zidovudine-containing highly active antiretroviral therapy (HAART) regimen in sub-Saharan African adults receiving cotrimoxazole. METHODS: Prospective cohort study in Abidjan, with blood cell count measurement at baseline (HAART initiation), month 1, month 3 and month 6. RESULTS: A total of 498 adults [baseline: 80% currently on cotrimoxazole prophylaxis; median CD4 count 237/mm3 [interquartile range (IQR) 181;316]; median neutrophil count 1647/mm3 (IQR 1221;2256); median haemoglobin 113 g/l (IQR 102;122)] started zidovudine (AZT)/lamivudine/efavirenz. During follow-up, 118 patients had a grade 3-4 neutropenia [(56.3/100 person-years (PY)], 23 had a grade 3-4 anaemia (9.6/100 PY) and no cases of grade 3-4 thrombocytopenia. Of the 118 patients with grade 3-4 neutropenia, 86 (73%) had to stop cotrimoxazole because neutropenia persisted, and one (<1%) had to stop AZT because of persistent neutropenia after cotrimoxazole was stopped (neutropenia-related HAART modification: 0.4/100 PY). Of the 23 patients with grade 3-4 anaemia, 11 had to stop AZT (anaemia-related HAART modification: 4.4/100 PY). In patients who stopped cotrimoxazole but not AZT, the median gain in neutrophils at 1 month was +540/mm3 (IQR +150;+896). CONCLUSIONS: At baseline, most patients had a normal neutrophil count and 80% of them were already receiving cotrimoxazole. An unexpectedly high rate of grade 3-4 neutropenia occurred shortly after introduction of AZT. Almost all of the persistent severe neutropenia disappeared after cotrimoxazole was stopped. This suggests an accentuated drug interaction between the two drugs in these sub-Saharan African individuals. Grade 3-4 anaemia was much less frequent, but remained the first cause of AZT discontinuation.

Efficacy and safety of two dosages of cotrimoxazole as preventive treatment for HIV-infected Malawian adults with new smear-positive tuberculosis.

OBJECTIVE: To assess the efficacy and safety of two different dosages of cotrimoxazole (CTX) in prophylaxis in HIV-positive new smear-positive pulmonary tuberculosis (TB) patients in Blantyre, Malawi. METHOD: Randomized, double-blind trial using 480 and 960 mg of CTX given to new TB patients, who were followed up until the end of the tuberculosis treatment. The primary outcome was survival. The outcome in the two groups was also compared with an unselected cohort of similar patients registered in Zomba, Malawi in 1995 and new smear-positive patients registered in the National Tuberculosis Programme in 1999. The secondary outcome was the occurrence of (opportunistic) events, especially bacterial pneumonia. RESULTS: There were no statistically significant differences in mortality and bacterial pneumonia between the groups receiving the two different dosages. The case fatality rate at the end of the tuberculosis treatment was 15.4% in the 480 mg group and 14.0% in the 960 mg group. This was lower than the case fatality rate in the Zomba cohort (19.2%, P = 0.10) and lower than the case fatality rate in the national programme (21.0%, P < 0.001). CTX was well tolerated. Compliance was fair. CONCLUSIONS: CTX prophylaxis may have a beneficial effect on mortality and morbidity in HIV-infected smear-positive tuberculosis patients in Malawi. The efficacy of both dosages is not significantly different. The intervention is cheap and easy to implement. These results would support implementation of CTX in this patient group until better strategies are available or evidence is convincingly presented to suggest that its benefit is marginal.