Multi-Cause Calibration of Verbal Autopsy-Based Cause-Specific Mortality Estimates of Children and Neonates in Mozambique.

The Countrywide Mortality Surveillance for Action platform is collecting verbal autopsy (VA) records from a nationally representative sample in Mozambique. These records are used to estimate the national and subnational cause-specific mortality fractions (CSMFs) for children (1-59 months) and neonates (1-28 days). Cross-tabulation of VA-based cause-of-death (COD) determination against that from the minimally invasive tissue sampling (MITS) from the Child Health and Mortality Prevention project revealed important misclassification errors for all the VA algorithms, which if not accounted for will lead to bias in the estimates of CSMF from VA. A recently proposed Bayesian VA-calibration method is used that accounts for this misclassification bias and produces calibrated estimates of CSMF. Both the VA-COD and the MITS-COD can be multi-cause (i.e., suggest more than one probable COD for some of the records). To fully use this probabilistic COD data, we use the multi-cause VA calibration. Two different computer-coded VA algorithms are considered-InSilicoVA and EAVA-and the final CSMF estimates are obtained using an ensemble calibration that uses data from both the algorithms. The calibrated estimates consistently offer a better fit to the data and reveal important changes in the CSMF for both children and neonates in Mozambique after accounting for VA misclassification bias.

Completeness and Factors Affecting Community Workers' Reporting of Births and Deaths in the Countrywide Mortality Surveillance for Action in Mozambique.

Since March 2018, the Countrywide Mortality Surveillance for Action project, implemented as a national sample registration system by the Mozambique Instituto Nacional de Saude and the Instituto Nacional de Estatistica in 700 geographic clusters randomly distributed across the 11 provinces, has trained and deployed community surveillance agents (CSAs) to report births and deaths in each cluster prospectively. An independent, retrospective data collection was conducted to assess the completeness of surveillance data. Record linkage procedures were used to match households and vital events reported in the two data sources. We calculated birth and death reporting rates and used a regression model to determine factors associated with the likelihood of vital events being reported by the CSAs. Between March 2018 and December 2019, CSAs reported 54% of births (8,787/16,421) and 45% of deaths (1,726/3,867). Births of smaller cluster sizes (< 1,000 people) were more likely to be reported (adjusted odds ratio [aOR] = 1.45; 95% CI = 1.15-1.83) compared with those of larger cluster sizes (> 1,500 people). Deaths of rural clusters were more likely to be reported (aOR = 1.41; 95% CI = 1.07-1.85) than those of urban clusters. Adult deaths were more likely to be reported (aOR = 1.49; 95% CI = 1.10-2.02) than child deaths. Our findings suggest that a fully functioning sample vital registration system must adopt a dual system with high-quality surveys or other ways to estimate underregistration periodically, consider a smaller cluster size manageable by a community worker, and pay special attention to urban clusters as underreporting is larger.

Correcting for Verbal Autopsy Misclassification Bias in Cause-Specific Mortality Estimates.

Verbal autopsies (VAs) are extensively used to determine cause of death (COD) in many low- and middle-income countries. However, COD determination from VA can be inaccurate. Computer coded verbal autopsy (CCVA) algorithms used for this task are imperfect and misclassify COD for a large proportion of deaths. If not accounted for, this misclassification leads to biased estimates of cause-specific mortality fractions (CSMFs), a critical piece in health-policy making. Recent work has demonstrated that the knowledge of the CCVA misclassification rates can be used to calibrate raw VA-based CSMF estimates to account for the misclassification bias. In this manuscript, we review the current practices and issues with raw COD predictions from CCVA algorithms and provide a complete primer on how to use the VA calibration approach with the calibratedVA software to correct for verbal autopsy misclassification bias in cause-specific mortality estimates. We use calibratedVA to obtain CSMFs for child (1-59 months) and neonatal deaths using VA data from the Countrywide Mortality Surveillance for Action project in Mozambique.

Long-term protection against HBV chronic carriage of Gambian adolescents vaccinated in infancy and immune response in HBV booster trial in adolescence.

BACKGROUND: Chronic infection with hepatitis B virus (HBV) arising in childhood is associated with hepatocellular carcinoma in adult life. Between 1986 and 1990, approximately 120,000 Gambian newborns were enrolled in a randomised controlled trial to assess the effectiveness of infant HBV vaccination on the prevention of hepatocellular carcinoma in adulthood. These children are now in adolescence and approaching adulthood, when the onset of sexual activity may challenge their hepatitis B immunity. Thus a booster dose in adolescence could be important to maintain long-term protection. METHODS: Fifteen years after the start of the HBV infant vaccination study, 492 vaccinated and 424 unvaccinated children were identified to determine vaccine efficacy against infection and carriage in adolescence. At the same time, 297 of the 492 infant-vaccinated subjects were randomly offered a booster dose of HBV vaccine. Anti-HBs was measured before the booster, and two weeks and 1 year afterwards (ISRCTN71271385). RESULTS: Vaccine efficacy 15 years after vaccination was 67.0% against infection as manifest by anti-HBc positivity (95% CI 58.2-74.6%), and 96.6% against HBsAg carriage (95% CI 91.5-100%). 31.2% of participants had detectable anti-HBs with a GMC of 32 IU/l. For 168 boosted participants GMC anti-HBs responses were 38 IU/l prior to vaccination, 524 IU/l two weeks after boosting, and 101 IU/l after 1 year. CONCLUSIONS: HBV vaccination in infants confers very good protection against carriage up to 15 years of age, although a large proportion of vaccinated subjects did not have detectable anti-HBs at this age. The response to boosting persisted for at least a year. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN71271385.

Is HIV-2- induced AIDS different from HIV-1-associated AIDS? Data from a West African clinic.

BACKGROUND: Although AIDS is less frequent following HIV-2 than HIV-1 infection, it is unclear whether the clinical picture and clinical course of AIDS are similar in the two infections. OBJECTIVES: To compare the pattern of AIDS-defining events, CD4 cell count at the time of AIDS diagnosis, survival from time of AIDS, and CD4 cell count near time of death in HIV-1 and HIV-2-infected patients. METHODS: Adult patients with AIDS who attended the clinics of the MRC in The Gambia were enrolled. AIDS was diagnosed according to the expanded World Health Organization case definition for AIDS surveillance (1994). RESULTS: Three hundred and forty-one AIDS patients with HIV-1 and 87 with HIV-2 infection were enrolled. The most common AIDS-defining events in both infections were the wasting syndrome and pulmonary tuberculosis. The median CD4 cell count at AIDS was 109 cells/microl in HIV-1 and 176 in HIV-2 (P = 0.01) and remained significantly higher in HIV-2 after adjustment for age and sex (P = 0.03). The median time to death was 6.3 months in HIV-1 and 12.6 months in HIV-2-infected patients (P = 0.03). In a multivariable analysis adjusting for age, sex and CD4 cell count, the mortality rates of HIV-1 and HIV-2-infected patients were similar (P = 0.25). The median CD4 cell count near time of death was 62 and 120 cells/microl in HIV-1 and HIV-2-infected patients, respectively (P = 0.02). CONCLUSIONS: HIV-2 patients have a higher CD4 cell count at the time of AIDS, and a longer survival after AIDS. The mortality after an AIDS diagnosis is more influenced by CD4 cell count than HIV type.

Sixteen years of HIV surveillance in a West African research clinic reveals divergent epidemic trends of HIV-1 and HIV-2.

BACKGROUND: The HIV-1 epidemic in West Africa is characterized by a slower rise than that in Eastern and Southern Africa. The HIV-2 epidemic in West Africa may be declining, but few long-term data exist. METHODS: In a research clinic in The Gambia, HIV-1 and HIV-2 prevalence trends among all new patients being tested for HIV were examined over a 16 year period (1988 till 2003). In newly diagnosed patients a baseline CD4 count was done. RESULTS: An HIV test was done in 23 363 patients aged 15 years or older. The prevalence of HIV-1 was 4.2% in 1988-91 and rose to 17.5% in 2001-03 (P < 0.0001, chi(2)-test for trend). The prevalence of HIV-2 was 7.0% in 1988-91 and declined to 4.0% in 2001-03 (P < 0.0001). HIV-1 prevalence increased and HIV-2 prevalence decreased with time in logistic regression models adjusting for age, sex, and indication for test (P < 0.0001). Baseline CD4 counts were available for 65% of patients. The median CD4 count was 215 cells/mm3 [interquartile range (IQR) 72-424] for HIV-1, and 274 (IQR 100-549) for HIV-2 infected patients. There was no marked trend of rise or decline in baseline CD4 count in either HIV-1 or HIV-2 infected patients over the study period. Forty-five per cent of newly diagnosed HIV patients had a CD4 count <200 cells/mm3. CONCLUSIONS: These data suggest that HIV-1 prevalence is rising in The Gambia, and that HIV-2 is declining. HIV patients in The Gambia present late and almost half of patients would qualify for anti-retroviral treatment at their first visit.

Baseline plasma viral load and CD4 cell percentage predict survival in HIV-1- and HIV-2-infected women in a community-based cohort in The Gambia.

OBJECTIVES: To estimate and compare the all-cause mortality rates among HIV-1-infected, HIV-2-infected, and uninfected women and to assess the predictive value of baseline plasma viral load (PVL) and CD4 cell percentage (CD4%) for mortality. DESIGN: Cohort study. METHODS: At presentation to antenatal clinics in The Gambia in 1993-1995, pregnant women were screened for antibodies to HIV-1 and HIV-2. Seropositive subjects and a similar number of seronegative controls were enrolled, and baseline PVL and CD4% were measured. Participants were visited regularly by field-workers until 18 months after delivery and again 4-7 years later. RESULTS: Thirty-two of 101 women infected with HIV-1, 23 of 243 infected with HIV-2, and 9 of 468 seronegative women died during a median follow-up of 6.9 years. The mortality rate was 56 deaths per 1000 person years of observation (pyo) for HIV-1-infected, 16 deaths per 1000 pyo for HIV-2-infected, and 3.1 deaths per 1000 pyo for HIV-uninfected women. After 8 years of follow-up, >50% of HIV-1-infected women were still alive. In multivariate analysis, a 1-log increase of HIV-1 PVL was associated with a 1.8-fold higher rate of mortality (95% confidence interval [CI], 0.9-3.4). In HIV-2 infection, women with a high PVL (>10,000 copies/mL) had an 8.7-fold (95% CI, 2.8-28) higher rate of mortality than did those with a low PVL (<1000 copies/mL). A 10% decrease in CD4% was associated with higher mortality rates among HIV-1-infected (1.6-fold; 95% CI, 1.1-2.3) and HIV-2-infected (1.5-fold; 95% CI, 1.0-2.3) subjects. DISCUSSION: Survival of HIV-1-infected women in The Gambia is similar to that in industrialized countries before the introduction of antiretroviral treatment. Survival of HIV-2-infected women is much better. However, women with high PVLs die as quickly as their HIV-1-infected counterparts.

Survival of HIV-1 and HIV-2 perinatally infected children in The Gambia.

BACKGROUND: The risk of mother-to-child transmission (MTCT) of HIV-2 is much lower than that of HIV-1, but the long-term prognosis of perinatally infected HIV-2 children is unknown. We re-visited children who were part of a large MTCT study in The Gambia (conducted during 1993-1997), in order to compare the long-term survival of children perinatally infected with HIV-2 with that of seronegative and of HIV-1 infected children. METHODS: Five to eight years' follow-up of a cohort of children born to HIV-negative, HIV-1 positive, and HIV-2 positive mothers. RESULTS: Seven hundred and seventy-four children were followed up for a median of 6.6 years. Of 17 perinatally HIV-1 infected children, three were still alive on 1 July 2001, two had been lost to follow-up, and 12 had died. The median survival was 2.5 years. Of eight HIV-2 infected children five were still alive, none were lost to follow-up and three had died. The mortality hazards ratio of both HIV-1 [9.9; 95% confidence interval (CI), 5.2-19], and of HIV-2 infected children (3.9; CI, 1.2-12) was significantly increased compared with children of seronegative mothers. The mortality hazards ratio of HIV uninfected children of HIV-1 or HIV-2 infected mothers was not significantly increased compared to that of children of seronegative mothers (P = 0.17 and P = 0.5 respectively). CONCLUSIONS: Children with perinatally acquired HIV-2 infection have a higher mortality than children of seronegative mothers. Guidelines for treatment of HIV-1 infected children should be used for treatment of HIV-2 infected children.

Regional differences in HIV trends in The Gambia: results from sentinel surveillance among pregnant women.

OBJECTIVE: To monitor HIV-1 and HIV-2 trends in The Gambia, West Africa. METHODS: In 1993-1995 a nationwide survey among 29 670 pregnant women attending eight antenatal clinics estimated the seroprevalence of HIV-1 at 0.6%, and of HIV-2 at 1.1%. Five years later, sentinel surveillance in pregnant women was established, using unlinked anonymous testing in four clinics. A dried blood spot on filter paper was obtained and tested for HIV antibodies. RESULTS: Between May 2000 and August 2001, 8054 analysable samples were collected at four sites. The prevalence of HIV-1 rose sharply in one rural area from 0.6 to 3.0% (P < 0.0001), but the increase was small and non-significant in two other rural sites and in the urban site. The prevalence of HIV-2 did not change significantly at any of the sites. The overall prevalence of HIV-1 was 1.0% [95% confidence interval (CI) 0.8-1.3%], and of HIV-2 0.8% (CI 0.6-1.0%). Site, nationality and higher age were significantly associated with HIV-1 infection, and higher parity and site were significantly associated with HIV-2 infection. CONCLUSION: Fifteen years after the first case of HIV-1 was described in The Gambia, the epidemic is still at a low level. There is heterogeneity within the country, with one rural area experiencing a fivefold increase in 6 years. The prevalence of HIV-2 in The Gambia is stable.

Evaluation of a new rapid diagnostic kit (FemExam) for bacterial vaginosis in patients with vaginal discharge syndrome in The Gambia.

BACKGROUND: Diagnosis of bacterial vaginosis (BV) in resource-poor primary health care settings is often overlooked; there is a need for a cheap, rapid, objective point-of-care diagnostic test. GOAL: The goal was to determine the prevalence of BV and to evaluate the performance of a new commercial diagnostic test kit in a developing country environment. STUDY DESIGN: Vaginal and cervical swabs were collected from 230 consecutive women attending a genitourinary medicine clinic with reported symptoms of vaginal discharge and/or itching. Etiological testing was carried out. BV was diagnosed on the basis of the Nugent score, the Amsel clinical criteria, and results of FemExam card tests. Card 1 is for pH and amines, and card 2 measures proline iminopeptidase (PIP) activity. RESULTS: BV prevalence was 47.9% according to the Nugent score. When compared with the Nugent score, the Amsel clinical criteria had a sensitivity of 77.9% and specificity of 58.4%, FemExam card 1 had a sensitivity of 71.4% and specificity of 72.8%, FemExam card 2 had a sensitivity of 70% and specificity of 81.0%, and FemExam cards 1 and 2 combined had a sensitivity of 91.0% and specificity of 61.5%. Cost per patient and cost per true case detected ranged from US $0.74 and US $1.54, respectively, for Gram stain diagnosis, to US $8.32 and US $18.49 for the FemExam two-card method. CONCLUSIONS: In a setting where BV was frequently associated with vaginal discharge, the FemExam test compared favorably with conventional clinical diagnosis, and it has the advantage of being rapid, less subjective, and easily performed. Cutting its cost would provide wider accessibility in developing countries.

Plasma viral load, CD4 cell percentage, HLA and survival of HIV-1, HIV-2, and dually infected Gambian patients.

OBJECTIVE: To examine baseline plasma viral loads according to the CD4 cell percentage (CD4%) in HIV-1, HIV-2 and dually infected patients (HIV-D), and to relate these measurements to survival. PATIENTS AND METHODS: A total of 119 HIV-1, 137 HIV-2 and 81 HIV-D-infected patients attending the Medical Research Council clinic in The Gambia were recruited from 1991 according to baseline CD4%, and followed until death or the end of December 2000. HIV-1 and HIV-2 RNA levels were measured by in-house reverse transcriptase polymerase chain reaction assays. RESULTS: The plasma viral load, which varied inversely with CD4%, was similar in HIV-1 singly and dually infected patients, but was significantly higher in HIV-1 than in HIV-2 singly infected patients, except in those with a CD4% less than 14%. HIV-2 plasma viral load in dually infected patients did not vary significantly with CD4%, but was significantly lower than in HIV-2 singly infected patients with CD4% less than 14%. Multivariate analysis showed that only CD4% was independently associated with survival in HIV-1 and HIV-D infections; whereas both CD4% and plasma viral load were independently associated with survival in HIV-2 infections. The mortality rate of HIV-D-infected patients was not significantly different from that of HIV-1-infected patients, but was significantly higher in the absence of HLA B58. CONCLUSION: HIV-2 infection does not alter HIV-1 replication or prolong survival in dually infected patients. In a clinical setting in Africa, where many patients present with advanced disease, CD4% may be a more important predictor of prognosis than plasma viral load.