Tuberculosis among HIV-infected population: incidence and risk factors in rural Tanzania.

BACKGROUND: The incidence of tuberculosis among HIV-infected populations with high CD4 count in high burden countries has not been well studied. OBJECTIVE: To assess the TB incidence in HIV-infected adults and its associated risk factors. METHOD: A cohort study with retrospective review of medical records and prospective follow-up of HIV-infected adult participants attending CTC who were 18-55 years old, had CD4 count more than 250 cells/mm3 in the period of 2008-2010 and were not on ART at enrolment. Cox proportional hazard regression was used to explore the predictors of incident TB. RESULTS: Overall 777 (24%) of 3,279 CTC enrolled HIV-infected adults fulfilled the inclusion criteria of the study. The incidence of TB in the study population ranged from 0.8/100 per person years (PY) at risk (95% CI 0.5-1.3) in the main analysis to 1.7/100 PY at risk (95% CI 1.0-2.6) in sensitivity analyses. Only prior history of TB disease was found to have a significant association with an increased risk of TB, hazard ratio 5.7 (95% CI 2.0-16.4, p value 0.001). CONCLUSION: Tuberculosis incidence among HIV-infected adults with medium/high CD4 count in Bagamoyo is lower than in other high TB burden countries. Previously TB treated patients have a much higher risk of getting TB again than those who never had TB before.

Validation of indirect tuberculosis treatment adherence measures in a resource-constrained setting.

SETTING: Arusha, Mwanza, Mufindi and Kilosa in Tanzania. OBJECTIVE: To assess the test characteristics of three indirect adherence measures against a gold standard of direct measurements of drug intake for use in a resource-constrained setting. METHODS: We assessed sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), and the diagnostic odds ratio (dORs) of three indirect adherence measurement tools against direct measurement in urine using the IsoScreen assay. RESULTS: The single adherence question of missed doses in the last 2 days had the highest dOR (40.3) compared to the Morisky medication adherence scale (MMAS, 2.5) and pill counts (3.4). The sensitivities of these measures were respectively 97.9%, 92% and 89.6%. Specificity ranged from 46.4% (adherence question) to 17.9% (MMAS). The PPVs of adherence question, pill counts and MMAS were respectively 97.6%, 96.5% and 94.2%, while the NPVs ranged from 50% (adherence question) to 3.1% (MMAS). CONCLUSION: Among several instruments for indirect adherence measure in the routine setting of the Tanzanian National Tuberculosis and Leprosy Programme, a single adherence question was found to have the best discriminatory power. However, the single adherence question might not adequately identify patients who are non-adherent. Confirmatory studies are needed, especially in settings with low adherence rates.

Surveillance for MDR-TB: is there an obligation to ensure treatment for individuals identified with MDR-TB?

This article raises ethical issues that result if individuals, during the course of research to measure the prevalence of drug-resistant tuberculosis, are identified with the disease but are not provided with or referred for appropriate treatment. It draws attention to and applauds recently published World Health Organization guidelines on the subject. Questions posed are: 1) Should treatment be provided for individuals identified through surveillance projects for MDR-TB, whatever their purpose (specific research or 'routine' national prevalence studies)? 2) If treatment availability is a problem, who is responsible for assuring this?

National anti-tuberculosis drug resistance study in Tanzania.

OBJECTIVE: To assess the prevalence of anti-tuberculosis drug resistance in a national representative sample of tuberculosis (TB) patients in Tanzania according to recommended methodology. DESIGN: Cluster survey, with 40 clusters sampled proportional to size, of notified TB patients from all diagnostic centres in the country. RESULTS: The survey enrolled 1019 new and 148 retreatment patients. The adjusted prevalence of Mycobacterium tuberculosis strains resistant to any of the four first-line drugs in new patients was 8.3%, while the prevalence of multidrug-resistant TB (MDR-TB) was 1.1%. In retreatment patients, the crude prevalence for any resistance and for MDR-TB was respectively 20.6% and 3.9%. The prevalence of drug resistance did not differ in relapse patients compared to failure patients. These estimates are among the lowest in those African countries with an estimated level of drug resistance in the last 5 years. CONCLUSION: The low levels of drug resistance in Tanzania are likely due to a well performing TB control programme and the absence of noticeable involvement of the private sector in TB treatment.

African pouched rats for the detection of pulmonary tuberculosis in sputum samples.

SETTING: Resource-limited settings in sub-Saharan African countries. OBJECTIVE: To utilise African giant pouched rats (Cricetomys gambianus) for the diagnosis of tuberculosis (TB) in human sputum. DESIGN: A specially designed cage with 10 sniffing holes and cassette-carrier was used. The sputum samples were put in the sample cassette, containing 10 samples in line, placed under matching sniffing holes. Rats were trained to sniff each consecutive sample, and indicate TB positives by fixing their nose for 5 seconds at the sniffing hole. This behaviour was maintained by food reinforcement upon correct indications. A total of 3416 samples were used. RESULTS: Of the 20 trained rats, 18 were able to discriminate positive from negative sputum samples, with average daily sensitivities ranging from 72% to 100%, and average daily false-positives ranging from 0.7% to 8.1%. The use of multiple rats significantly increased sensitivity and negative predictive value. CONCLUSION: Utilising trained sniffer rats for TB detection is a potentially faster screening method and is at least as sensitive as smear microscopy. This method could therefore be suitable for active case finding, especially where large numbers of samples are to be analysed in resource-limited settings, to complement existing diagnostic techniques.

Cholera outbreak in southern Tanzania: risk factors and patterns of transmission.

To identify risk factors and describe the pattern of spread of the 1997 cholera epidemic in a rural area (Ifakara) in southern Tanzania, we conducted a prospective hospital-based, matched case- control study, with analysis based on the first 180 cases and 360 matched controls. Bathing in the river, long distance to water source, and eating dried fish were significantly associated with risk for cholera. Toxigenic Vibrio cholerae O1, biotype El Tor, serotype Ogawa, was isolated in samples from Ifakara's main water source and patients' stools. DNA molecular analyses showed identical patterns for all isolates.

Diagnostic accuracy and case management of clinical malaria in the primary health services of a rural area in south-eastern Tanzania.

Malaria control continues to rely on the diagnosis and prompt treatment of both suspected and confirmed cases through the health care structures. In south-eastern Tanzania malaria is one of the leading causes of morbidity and mortality. The absence of microscopic examination in most of the health facilities implies that health workers must rely on clinical suspicion to identify the need of treatment for malaria. Of 1558 randomly selected paediatric consultations at peripheral health facilities throughout Kilombero District, 41.1% were diagnosed by the attending health worker as clinical malaria cases and 42.5% prescribed an antimalarial. According to our malaria case definition of fever or history of fever with asexual falciparum parasitaemia of any density, 25.5% of all children attending the health services had malaria. This yielded a sensitivity of 70.4% (IC95% = 65.9-74.8%) and a specificity of 68.9% (IC95% = 66.2-71.5%). Accordingly, 30.4% of confirmed cases left with no antimalarial treatment. Among malaria-diagnosed patients, 10% were underdosed and 10.5% were overdosed. In this area, as in many African rural areas, the low diagnostic accuracy may imply that the burden of malaria cases may be overestimated. Greater emphasis on the functioning and quality of basic health services in rural endemic areas is required if improved case management of malaria is to help roll back this scourge.

Humoral immune responses during a malaria vaccine trial in Tanzanian infants.

The development of a malaria vaccine is a priority for improved and sustained malaria control. Optimal use of a vaccine in Africa will only be achieved if it can be delivered through the Expanded Programme of Immunization (EPI). We have completed a trial of the peptide vaccine SPf66 in Tanzanian infants, given alongside the EPI vaccines. This paper describes the humoral responses to SPf66 and the EPI vaccines. A total of 1207 infants were recruited into a two-arm, double-blind, individually randomized placebo-controlled trial of SPf66. The objectives of the trial were to determine the safety, immunogenicity and efficacy of SPf66 and to assess interactions with EPI vaccines when three doses of SPf66 were delivered alongside the EPI vaccines. Cross-sectional surveys were carried out to asses seroconversion rates to the EPI vaccines and the antibody response to SPf66 (NANP)50 and Plasmodium falciparum lysates. Seroconversion rates to EPI vaccines were high and no statistically significant differences in prevalence or titres were found between SPf66 and placebo recipients. IgG antibodies against SPf66 (NANP)50 and whole P. falciparum lysate were present in high titres in mothers of recruited children at the time of birth. Vaccination with SPf66 stimulated a good anti-SPf66 IgG response which declined to preimmunization levels by 2 years of age and which was not associated with protection against clinical malaria. The vaccine induced no IgG antibodies against (NANP)50 or P. falciparum lysates. SPf66 stimulated a humoral immune response when given to very young infants and did not interfere with seroconversion to EPI vaccines. The response to SPf66 was qualitatively different from that seen in older children, in whom SPf66 has been shown to be moderately efficacious. This difference raises concerns about the difficulties of immunizing very young infants who need to be targeted by antimalarial vaccination programs.

Maternal mortality in a rural district of southeastern Tanzania: an application of the sisterhood method.

BACKGROUND: Deaths from maternal causes represent the leading cause of death among women of reproductive age in most developing countries. It is estimated that the highest risk occurs in Africa, with 20% of world births but 40% of the world maternal deaths. The level of maternal mortality is difficult to assess especially in countries without an adequate vital registration system. Indirect techniques are an attractive cost-effective tool to provide estimates of orders of magnitude for maternal mortality. METHOD: The level of maternal mortality estimated by the sisterhood method is presented for a rural district in the Morogoro Region of Southeastern Tanzania and the main causes of maternal death are studied. Information from region-specific data using the sisterhood method is compared to data from other sources. RESULTS: The maternal mortality ratio (MMR) was 448 maternal deaths per 100,000 live births (95%CI : 363-534 deaths per 100,000 live births). Maternal causes accounted for 19% of total mortality in this age group. One in 39 women who survive until reproductive age will die before age 50 due to maternal causes. The main cause of death provided by hospital data was puerperal sepsis (35%) and postpartum haemorrhage (17%); this is compatible with the main causes reported for maternal death in settings with high levels of maternal mortality, and similar to data for other regions in Tanzania. The sisterhood method provides data comparable with others, together with a cost-effective and reliable estimate for the determination of the magnitude of maternal mortality in the rural Kilombero District.

Evaluation of the SPf66 vaccine for malaria control when delivered through the EPI scheme in Tanzania.

BACKGROUND: Malaria control programmes need to protect young children, who bear the brunt of malaria disease and death in Africa. The development of a vaccine is a priority if improved and sustained malaria control is to be achieved. The best use of a vaccine in Africa will be achieved if it can be delivered through the expanded programme of immunization (EPI). We conducted a trial designed to evaluate the efficacy of SPf66 vaccine for malaria control when delivered through the EPI scheme in Tanzania. METHODS: The study was a two-arm, double blind, individually randomized placebo controlled trial involving 1207 infants. The primary objective of the trial was to estimate the efficacy of three doses of SPf66 given at 1, 2 and 7 months of age in preventing clinical episodes of malaria. These were documented through a health facility-based passive case detection system. RESULTS: Among 1207 randomized children, overall compliance for third dose was 91%. SPf66 was safe, immunogenic and did not interfere with the humoral immune responses to EPI vaccines. There were 294 children among SPf66 recipients and 288 among placebo recipients with at least one malaria episode, yielding a vaccine efficacy estimate of 2% (95% CI: -16, 16; P = 0.84). CONCLUSION: This has been the first trial of a malaria vaccine among very young infants. It provides information on the safety of peptide vaccines administered at this early age as well as their capacity to induce immune responses without negatively interacting with EPI vaccines. Given the modest protection previously documented in older age groups and the lack of efficacy in younger infants, this vaccine in its current alum-based formulation does not appear to have a role in malaria control in sub-Saharan Africa. The lack of efficacy found in this trial also raises concerns about potential difficulties of inducing protective immune responses against malaria through immunization in infants.

Safety in infants of SPf66, a synthetic malaria vaccine, delivered alongside the EPI.

The most likely mechanism to deliver a malaria vaccine in African countries is through the Expanded Program of Immunization (EPI). So far only SPf66, a multistage synthetic peptide, has shown any evidence of protection in Phase III field trials. In Tanzania, SPf66 reduced the risk of clinical malaria by 31% in children aged 1-5 years. In order to progress in the critical path of vaccine development and testing towards the implementation of a new vaccine in malaria control programs, we carried out a randomized double-blind placebo controlled efficacy trial of SPf66 when given alongside the EPI scheme. Monitoring of safety and reactogenicity during this trial included detailed clinical and laboratory assessments on 98 infants and assessment of adverse effects within 1 h of vaccination for all 1207 children vaccinated. Surveillance systems monitored attendances as outpatients, admissions to hospital and fatal events in the community. No serious adverse effects were detected more frequently amongst SPf66 recipients compared to placebo. This first assessment in very young infants of a synthetic vaccine provides evidence of a good safety profile.