The measurement and estimation of tuberculosis mortality.

Tuberculosis (TB) ranks among the 10 principal causes of death and disability worldwide, largely on the basis of mortality estimates. These estimates have been derived by a variety of methods, from a limited database. Here we review the data and methods used to measure and estimate TB mortality in adults, assess the strengths and weaknesses of each and suggest ways to improve current mortality statistics. In principle, deaths attributable to TB can be obtained directly from national vital registration (VR) systems. However, only 59 of 213 countries in 2005 (including three in the World Health Organization Africa Region and one in the South-East Asia Region) had VR systems that reported TB deaths, corresponding to just 10% of all estimated deaths attributable to TB. Until comprehensive, national VR systems are established, an interim solution is to carry out verbal autopsies within sample VR schemes. The number of TB deaths from VR should ultimately converge with deaths recorded in national TB control programmes. At present, deaths in treatment cohorts cover a small subset of all estimated TB deaths (<13% in 2006), as deaths are missed among patients who are never diagnosed, who default or fail treatment, and among patients with untreated recurrent TB or TB sequelae. In contrast, some deaths recorded during treatment are not due to TB. To ensure convergence between cohort monitoring and VR, definitions of causes of death--including TB as an associate cause in deaths from human immunodeficiency virus/acquired immune-deficiency syndrome--should be standardised, so that both systems adhere to the International Classification of Diseases.

Determinants of the impact of sexually transmitted infection treatment on prevention of HIV infection: a synthesis of evidence from the Mwanza, Rakai, and Masaka intervention trials.

Community-randomized trials in Mwanza, Tanzania, and Rakai and Masaka, Uganda, suggested that population characteristics were an important determinant of the impact of sexually transmitted infection (STI) treatment interventions on incidence of human immunodeficiency virus (HIV) infection. We performed simulation modeling of HIV and STI transmission, which confirmed that the low trial impact in Rakai and Masaka could be explained by low prevalences of curable STI resulting from lower-risk sexual behavior in Uganda. The mature HIV epidemics in Uganda, with most HIV transmission occurring outside core groups with high STI rates, also contributed to the low impact on HIV incidence. Simulated impact on HIV was much greater in Mwanza, although the observed impact was larger than predicted from STI reductions, suggesting that random error also may have played some role. Of proposed alternative explanations, increasing herpetic ulceration due to HIV-related immunosuppression contributed little to the diminishing impact of antibiotic treatment during the Ugandan epidemics. The strategy of STI treatment also was unimportant, since syndromic treatment and annual mass treatment showed similar effectiveness in simulations of each trial population. In conclusion, lower-risk behavior and the mature HIV epidemic explain the limited impact of STI treatment on HIV incidence in Uganda in the 1990s. In populations with high-risk sexual behavior and high STI rates, STIs treatment interventions may contribute substantially to prevention of HIV infection.

Monitoring trends in under-5 mortality rates through national birth history surveys.

BACKGROUND: We assessed whether Demographic and Health Surveys (DHS), a large and high-quality source of under-5 mortality estimates in developing countries, would be able to detect reductions in under-5 mortality as established in global child health goals. METHODS AND RESULTS: Mortality estimates from 41 DHS conducted in African countries between 1986 and 2002, for the interval of 0-4 years preceding each survey (with a mean time lag of 2.5 years), were reviewed. The median relative error on national mortality rates was 4.4%. In multivariate regression, the relative error decreased with increasing sample size, increasing fertility rates, and increasing mortality rates. The error increased with the magnitude of the survey design effect, which resulted from cluster sampling. With levels of precision observed in previous surveys, reductions in all-cause under-5 mortality rates between two subsequent surveys of 15% or more would be detectable. The detection of smaller mortality reductions would require increases in sample size, from a current median of 7060 to over 20,000 women. Across the actual surveys conducted between 1986 and 2002, varying mortality trends were apparent at a national scale, but only around half of these were statistically significant. CONCLUSIONS: The interpretation of changes in under-5 mortality rates between subsequent surveys needs to take into account statistical significance. DHS birth history surveys with their present sampling design would be able to statistically confirm under-5 mortality reductions in African countries if true reductions were 15% or larger, and are highly relevant to tracking progress towards existing international child health targets.

Comparison of STD prevalences in the Mwanza, Rakai, and Masaka trial populations: the role of selection bias and diagnostic errors.

OBJECTIVES: To assess bias in estimates of STD prevalence in population based surveys resulting from diagnostic error and selection bias. To evaluate the effects of such biases on STD prevalence estimates from three community randomised trials of STD treatment for HIV prevention in Masaka and Rakai, Uganda and Mwanza, Tanzania. METHODS: Age and sex stratified prevalences of gonorrhoea, chlamydia, syphilis, HSV-2 infection, and trichomoniasis observed at baseline in the three trials were adjusted for sensitivity and specificity of diagnostic tests and for sample selection criteria. RESULTS: STD prevalences were underestimated in all three populations because of diagnostic errors and selection bias. After adjustment, gonorrhoea prevalence was higher in men and women in Mwanza (2.8% and 2.3%) compared to Rakai (1.1% and 1.9%) and Masaka (0.9% and 1.8%). Chlamydia prevalence was higher in women in Mwanza (13.0%) compared to Rakai (3.2%) and Masaka (1.6%) but similar in men (2.3% in Mwanza, 2.7% in Rakai, and 2.2% in Masaka). Prevalence of trichomoniasis was higher in women in Mwanza compared to women in Rakai (41.9% versus 30.8%). Herpes simplex virus type 2 (HSV-2) seroprevalence and prevalence of serological syphilis (TPHA+/RPR+) were similar in the three populations but the prevalence of high titre syphilis (TPHA+/RPR >/=1:8) in men and women was higher in Mwanza (5.6% and 6.3%) than in Rakai (2.3% and 1.4%) and Masaka (1.2% and 0.7%). CONCLUSIONS: Limited sensitivity of diagnostic and screening tests led to underestimation of STD prevalence in all three trials but especially in Mwanza. Adjusted prevalences of curable STD were higher in Mwanza than in Rakai and Masaka.

The effect of HIV, behavioural change, and STD syndromic management on STD epidemiology in sub-Saharan Africa: simulations of Uganda.

An assessment was made of how the HIV epidemic may have influenced sexually transmitted disease (STD) epidemiology in Uganda, and how HIV would affect the effectiveness of syndromic STD treatment programmes during different stages of the epidemic. The dynamic transmission model STDSIM was used to simulate the spread of HIV and four bacterial and one viral STD. Model parameters were quantified using demographic, behavioural, and epidemiological data from rural Rakai and other Ugandan populations. The findings suggest that severe HIV epidemics can markedly alter STD epidemiology, especially if accompanied by a behavioural response. Likely declines in bacterial causes of genital ulcers should be considered in defining policies on syndromic STD management in severe HIV epidemics.

Estimating the magnitude of STD cofactor effects on HIV transmission: how well can it be done?

BACKGROUND: If sexually transmitted disease (STD) cofactor effects are strong and STDs are highly prevalent, STD control can be a strategy for HIV prevention. OBJECTIVE: To review possibilities for estimating cofactor effects of STDs on HIV transmission based on observational studies. STUDY DESIGN: This study consisted of an analysis of factors influencing associations between HIV and STDs, which can bias STD cofactor studies, from a sexual network perspective. Study designs that reduce distortions and methods to improve estimates in the presence of confounding are discussed. RESULTS: Standard statistical adjustments of cofactor estimates are insufficient because they ignore clustering between HIV and STDs in partners of study subjects, resulting from population heterogeneity in risk factors and assortative mixing. Reverse causation due to HIV-related immunosuppression may further inflate cofactor estimates. Misclassification of STDs and clustering between STDs can bias estimates in either direction. This study demonstrates quantitatively that ignorance of sexual network effects may result in considerable overestimation of cofactor magnitudes. CONCLUSION: The limitations of observational studies complicate quantitative inferences on the role of STDs in HIV transmission.

Focusing strategies of condom use against HIV in different behavioural settings: an evaluation based on a simulation model.

Using a sexually transmitted diseases simulation model (STDSIM), we made projections of HIV spread for four profiles of sexual behaviour reflecting patterns encountered across the developing world: 1) much commercial sex, no short relationships; 2) commercial sex, concurrent short relationships; 3) concurrent relationships, no commercial sex; 4) serial short relationships, some commercial sex. We studied the effects of increasing condom use in three target groups: commercial sex workers (CSWs); men engaging in commercial contacts and short relationships; and females in steady relationships. The projections indicated that the CSW and male strategies were more effective in reducing HIV incidence than the strategy focusing on females in steady relationships. In the long run, even the group of men and women with one recent partner were better protected against HIV infection by condom use in high-risk contacts than by condom use in steady relationships. Furthermore, the numbers of HIV cases prevented per condom used were 7 to 500 times higher for condoms used by CSWs or men engaging in short relationships and commercial sex than for ones used by females in steady relationships. The results indicated the merit of focusing on high-risk groups irrespective of the pattern of sexual behaviour, even in epidemics that had already spread throughout populations.

Model-based evaluation of single-round mass treatment of sexually transmitted diseases for HIV control in a rural African population.

OBJECTIVES: To compare the impact of single-round mass treatment of sexually transmitted diseases (STD), sustained syndromic treatment and their combination on the incidence of HIV in rural Africa. METHODS: We studied the effects of STD interventions by stochastic simulation using the model STDSIM. Parameters were fitted using data from a trial of improved STD treatment services in Mwanza, Tanzania. Effectiveness was assessed by comparing the prevalences of gonorrhoea, chlamydia, syphilis and chancroid, and the incidence of HIV, in the general adult population in simulations with and without intervention. RESULTS: Single-round mass treatment was projected to achieve an immediate, substantial reduction in STD prevalences, which would return to baseline levels over 5-10 years. The effect on syphilis was somewhat larger if participants cured of latent syphilis were not immediately susceptible to re-infection. At 80% coverage, the model projected a reduction in cumulative HIV incidence over 2 years of 36%. A similar impact was achieved if treatment of syphilis was excluded from the intervention or confined to those in the infectious stages. In comparison with sustained syndromic treatment, single-round mass treatment had a greater short-term impact on HIV (36 versus 30% over 2 years), but a smaller long-term impact (24 versus 62% over 10 years). Mass treatment combined with improved treatment services led to a rapid and sustained fall in HIV incidence (57% over 2 years; 70% over 10 years). CONCLUSIONS: In populations in which STD control can reduce HIV incidence, mass treatment may, in the short run, have an impact comparable to sustained syndromic treatment. Mass treatment combined with sustained syndromic treatment may be particularly effective.

Relative risks and population attributable fraction of incident HIV associated with symptoms of sexually transmitted diseases and treatable symptomatic sexually transmitted diseases in Rakai District, Uganda. Rakai Project Team.

OBJECTIVES: To assess the linkage of sexually transmitted disease (STD) symptoms and treatable STD to HIV incidence. DESIGN: Analysis of a randomized trial of STD control for HIV prevention, Rakai, Uganda. METHODS: Consenting adults 15-59 years of age were seen at 10-monthly home visits, interviewed regarding STD symptoms, and asked to provide samples for HIV and STD diagnoses. HIV incidence was determined in 8089 HIV-negative subjects over 10 457 person years. Adjusted rate ratios (RR) and 95% confidence intervals (CI) of HIV acquisition associated with genital ulcer disease (GUD) and discharge/dysuria were used to estimate the population attributable fraction (PAF) of HIV acquisition. HIV transmission risks associated with STD symptoms in HIV-positive partners of 167 HIV discordant couples and the numbers of sexual partners reported by HIV-positive subjects were used to estimate the PAF of HIV transmission attributable to STD. RESULTS: HIV prevalence was 16%. The risk of HIV acquisition was increased with GUD (RR 3.14; CI 1.98-4.98) and in males with discharge/dysuria (RR 2.44; CI 1.17-5.12), but not in females with discharge/dysuria. The PAF of HIV acquisition was 9.5% (CI 2.8-15.8%) with any of the three STD symptoms. The PAF for GUD was 8.8% (CI 3.7-13.8), but only 8.2% of reported GUD was caused by treatable syphilis or chancroid . The PAF for discharge/dysuria in males was 6.7% (CI 1.1-13.8), but only 25% of symptomatic males had concurrent gonorrhea or chlamydial infection. No significant differences were seen in PAF between study treatment arms. The PAF of HIV transmission associated with STD symptoms in HIV-positive persons was indirectly estimated to be 10.4%. CONCLUSION: In this mature, generalized HIV epidemic setting, most HIV seroconversion occurs without recognized STD symptoms or curable STD detected by screening. Therefore, syndromic management or other strategies of STD treatment are unlikely to substantially reduce HIV incidence in this population. However, STD is associated with significant HIV risk at the individual level, and STD management is needed to protect individuals.

Natural killer cell activity during UVR-induced skin tumor formation in the Skh hairless mouse.

We analyzed natural killer (NK) cell activity in the hairless albino Skh/HR1 mouse, to study whether the NK cell activity plays a role during UV radiation (UVR)-induced carcinogenesis. In 4 h 51Cr-release assays, spleen lymphocytes of specific pathogen-free (spf) Skh/HR1 mice displayed 5-10% spontaneous NK cell activity. This was comparable to NK cell activity in C57B1/6, C3H and athymic NMRI nu/nu mice, which were also kept under spf conditions. In all strains investigated, the low spontaneous NK cell activity could be increased up to 20-30% by intraperitoneal administration of polyinosinic:polycytidylic acid (polyI:C), a standardized in vivo NK cell induction method. The polyI:C potentiation of NK cells in Skh/HR1 mice was similar to that in C57B1/6 and NMRI, but significantly less than in C3H mice. Chronic daily UV irradiation according to a protocol that was also used for induction of carcinogenesis (11-12 weeks, 95 mJ/cm2 of UV exposure from FS40 sunlamps) did not decrease NK cell activity on a cell for cell basis. Neither was the inducibility of NK spleen cell activity with polyI:C in Skh/HR1 mice during UV exposure reduced. Based on total organ basis, the pooled lymph node cells (axillary, mandibulary and inguinal lymph node) showed a doubling of NK cell activity (P < 0.001), mainly due to an almost 100% increase in the number of lymph node cells. In conclusion, UVR does not suppress the normal or inducible NK cell activity at the time of clinical appearance of skin tumors. This suggests that such suppression of NK cell activity is not likely to contribute to UVR-induced carcinogenesis in the Skh/HR1 strain.