The control of tuberculosis in the HIV era : improved tuberculosis diagnosis and development of vaccines for HIV prevention

Abstract

The HIV pandemic has reversed the gains in TB control and has thus contributed to an increase in TB morbidity and mortality, especially in low and middle-income countries. Improved TB diagnosis, active case finding as well as interventions towards the control of HIV will therefore conceivably result in better control of TB. Availability of a safe, affordable and efficacious vaccine is the best control measure for HIV. Participation of developing countries in these efforts is crucial. The overall aim of this thesis is to improve tuberculosis control in the era of HIV.

In study I, a cross-sectional study was performed in two urban HIV VCT centers so as to determine the magnitude of TB among clients attending these centers. TB was diagnosed by symptoms screen, sputum and lymph nodes smears and culture of TB. We recruited 1,318 participants, of these 347 (26%) were HIV infected and TB was diagnosed in 63 (4.7%). Pulmonary TB, the most infectious form of TB was the most prevalent form detected in 52 participants.

In study II, we compared manual Isolator lysis centrifugation to automated MB BacT broth systems for the detection of disseminated TB, and also compared 20mLs to 40mLs of blood for detecting disseminated TB. We recruited 258 hospitalized HIV-infected patients suspected to have TB. TB was culture confirmed in 83 (32%) patients. There was no difference between 20mLs or 40mLs of blood for the detection TB [20(15%) vs 21(16%)] p=0.83]. The MB BacT system had a significantly greater yield in detecting disseminated TB compared to the Isolator system [31(76%) vs 20(49%) p=0.001]. 21(51%) of the patients died prior to blood culture detection, the median survival was 6 days range 0-58 days.

In study III, the test performance of a simple rapid urine lipoarabinomannan (LAM) antigen ELISA was compared to sputum and blood culture for the detection of HIV associated TB. Urine LAM sensitivity and specificity was 65% and 86% respectively in culture confirmed TB while the sensitivity and specificity of sputum smear, the conventional TB diagnostic method was 36% and 98% respectively. Urine LAM sensitivity improved with a decrease in CD+4 T-cell counts.

In study IV, we prospectively enrolled and followed up a cohort of police officers so as to determine their suitability for HIV vaccine studies through determination of the current HIV prevalence and incidence. The HIV prevalence and incidence was 5.2% and 8.4 per 1000 PYAR among the 1,240 recruited police. In study V, a randomized multisite phase IIa clinical trial compared the safety and immunogenicity of priming with HIV-DNA at a dose 1000 µg in five injections “standard regimen” to a dose of 600 µg in two injections as separate or combined plasmid pools “simplified regimen” followed by boosting with HIV-MVA. The proportion of IFN-γ ELISpot responders did not differ between 2 injections of 600 µg combined (87%), 2 injections of 600 µg separate (97%) and the 5 injections of 1000 µg separate (97%).

Conclusion: TB screening in VCT centers is feasible and should be offered for early detection and treatment to prevent transmission. Automated liquid blood culture is optimal for diagnosing disseminated TB, however deaths occur prior to detection. Therefore urine LAM ELISA could be used as an adjuvant to sputum smear for rapid identification of TB in advanced HIV infection. The HIV incidence in the police cohort has declined and hence this cohort is now only suitable for phase I/II HIV vaccine trials. Therefore there is a need to prepare other cohorts for efficacy studies. The last study demonstrated a simpler way to administer HIV-DNA vaccines, suitable for efficacy trials.