A phase IIA randomized clinical trial of a multiclade HIV-1 DNA prime followed by a multiclade rAd5 HIV-1 vaccine boost in healthy adults (HVTN204)

BACKGROUND: The safety and immunogenicity of a vaccine regimen consisting of a 6-plasmid HIV-1 DNA prime (envA, envB, envC, gagB, polB, nefB) boosted by a recombinant adenovirus serotype-5 (rAd5) HIV-1 with matching inserts was evaluated in HIV-seronegative participants from South Africa, United States, Latin America and the Caribbean. METHODS: 480 participants were evenly randomized to receive either: DNA (4 mg IM by Biojector) at 0, 1 and 2 months, followed by rAd5 (10 10 PU IM by needle/syringe) at 6 months; or placebo. Participants were monitored for reactogenicity and adverse events throughout the 12-month study. Peak and duration of HIV-specific humoral and cellular immune responses were evaluated after the prime and boost. RESULTS: The vaccine was well tolerated and safe. T-cell responses, detected by interferon-γ (IFN-γ) ELISpot to global potential T-cell epitopes (PTEs) were observed in 70.8% (136/192) of vaccine recipients overall, most frequently to Gag (54.7%) and to Env (54.2%). In U.S. vaccine recipients T-cell responses were less frequent in Ad5 sero-positive versus sero-negative vaccine recipients (62.5% versus 85.7% respectively, p = 0.035). The frequency of HIV-specific CD4+ and CD8+ T-cell responses detected by intracellular cytokine staining were similar (41.8% and 47.2% respectively) and most secreted ≥2 cytokines. The vaccine induced a high frequency (83.7%-94.6%) of binding antibody responses to consensus Group M, and Clades A, B and C gp140 Env oligomers. Antibody responses to Gag were elicited in 46% of vaccine recipients. CONCLUSION: The vaccine regimen was well-tolerated and induced polyfunctional CD4+ and CD8+ T-cells and multi-clade anti-Env binding antibodies. Trial Registration: ClinicalTrials.gov NCT0012597

Efficacy of secondary isoniazid preventive therapy among HIVinfected Southern Africans: time to change policy?

Objective. To determine the efficacy of secondary preventive therapy against tuberculosis (TB) among goldminers working in South Africa. Design. An observational study. Methods. The incidence of recurrent TB was compared between two cohorts of HIV-infected miners: one cohort had received secondary preventive therapy with isoniazid and the other had not. Setting. Health service providing comprehensive care for goldminers. Participants. 338 men received secondary preventive therapy and 221 did not. Main outcome measure. Incidence of recurrent TB. Results. The overall incidence of recurrent TB was reduced by 55% among men who received isoniazid preventive therapy (IPT) compared to those who did not (incidence rates 8.6 and 19.1 per 100 person-years respectively, incidence rate ratio 0.45; 95% CI 0.26 – 0.78). The efficacy of isoniazid preventive therapy was unchanged after controlling for CD4 count and age. The number of person-years of isoniazid preventive therapy required to prevent one case of recurrent TB among individuals with a CD4 count < 200/µl and &#8805;&#61472;200/µl was 5 and 19, respectively. Conclusion. Secondary preventive therapy reduces TB recurrence: the absolute impact appears to be greatest among individuals with low CD4 counts. International TB preventive therapy guidelines for HIV-infected individuals need to be expanded to include recommendations for secondary preventive therapy in settings where TB prevalence is high. Southern African Journal of HIV Medicine Vol. 5(3) 2004: 8-1

Cytomegalovirus Viremia as a Risk Factor for Mortality Prior to Antiretroviral Therapy among HIV-Infected Gold Miners in South Africa

BACKGROUND: Cytomegalovirus (CMV) viremia has been shown to be an independent risk factor for increased mortality among HIV-infected individuals in the developing world. While CMV infection is nearly ubiquitous in resource-poor settings, few data are available on the role of subclinical CMV reactivation on HIV. METHODS: Using a cohort of mineworkers with stored plasma samples, we investigated the association between CMV DNA concentration and mortality prior to antiretroviral therapy availability. RESULTS: Among 1341 individuals (median CD4 count 345 cells/µl, 70% WHO stage 1 or 2, median follow-up 0.9 years), 70 (5.2%) had CMV viremia at baseline; 71 deaths occurred. In univariable analysis CMV viremia at baseline was associated with a three-fold increase in mortality (hazard ratio [HR] 3.37; 95% confidence intervals [CI] 1.60, 7.10). After adjustment for CD4 count, WHO stage and HIV viral load (N = 429 with complete data), the association was attenuated (HR 2.27; 95%CI 0.88, 5.83). Mortality increased with higher CMV viremia (≥1,000 copies/ml vs. no viremia, adjusted HR 3.65, 95%CI: 1.29, 10.41). Results were similar using time-updated CMV viremia. CONCLUSIONS: High copy number, subclinical CMV viremia was an independent risk factor for mortality among male HIV-infected adults in South Africa with relatively early HIV disease. Studies to determine whether anti-CMV therapy to mitigate high copy number viremia would increase lifespan are warranted

Effect of Xpert MTB/RIF on clinical outcomes in routine care settings: individual patient data meta-analysis.

BACKGROUND: Xpert MTB/RIF, the most widely used automated nucleic acid amplification test for tuberculosis, is available in more than 130 countries. Although diagnostic accuracy is well documented, anticipated improvements in patient outcomes have not been clearly identified. We performed an individual patient data meta-analysis to examine improvements in patient outcomes associated with Xpert MTB/RIF. METHODS: We searched PubMed, Embase, ClinicalTrials.gov, and the Pan African Clinical Trials Registry from inception to Feb 1, 2018, for randomised controlled trials (RCTs) comparing the use of Xpert MTB/RIF with sputum smear microscopy as tests for tuberculosis diagnosis in adults (aged 18 years or older). We excluded studies of patients with extrapulmonary tuberculosis, and studies in which mortality was not assessed. We used a two-stage approach for our primary analysis and a one-stage approach for the sensitivity analysis. To assess the primary outcome of cumulative 6-month all-cause mortality, we first performed logistic regression models (random effects for cluster randomised trials, with robust SEs for multicentre studies) for each trial, and then pooled the odds ratio (OR) estimates by a fixed-effects (inverse variance) or random-effects (Der Simonian Laird) meta-analysis. We adjusted for age and gender, and stratified by HIV status and previous tuberculosis-treatment history. The study protocol has been registered with PROSPERO, number CRD42014013394. FINDINGS: Our search identified 387 studies, of which five RCTs were eligible for analysis. 8567 adult clinic attendees (4490 [63·5%] of 7074 participants for whom data were available were HIV-positive) were tested for tuberculosis with Xpert MTB/RIF (Xpert group) versus sputum smear microscopy (sputum smear group), across five low-income and middle-income countries (South Africa, Brazil, Zimbabwe, Zambia, and Tanzania). The primary outcome (reported in three studies) occurred in 182 (4·5%) of 4050 patients in the Xpert group and 217 (5·3%) of 4093 patients in the smear group (pooled adjusted OR 0·88, 95% CI 0·68-1·14 [p=0·34]; for HIV-positive individuals OR 0·83, 0·65-1·05 [p=0·12]). Kaplan-Meier estimates showed a lower rate of death (12·73 per 100 person-years in the Xpert group vs 16·38 per 100 person-years in the sputum smear group) for HIV-positive patients (hazard ratio 0·76, 95% CI 0·60-0·97; p=0·03). The risk of bias was assessed as reasonable and the statistical heterogeneity across studies was low (I2<20% for the primary outcome). INTERPRETATION: Despite individual patient data analysis from five RCTs, we were unable to confidently rule in nor rule out an Xpert MTB/RIF-associated reduction in mortality among outpatients tested for tuberculosis. Reduction in mortality among HIV-positive patients in a secondary analysis suggests the possibility of population-level impact. FUNDING: US National Institutes of Health

WHO global research priorities for antimicrobial resistance in human health

The WHO research agenda for antimicrobial resistance (AMR) in human health has identified 40 research priorities to be addressed by the year 2030. These priorities focus on bacterial and fungal pathogens of crucial importance in addressing AMR, including drug-resistant pathogens causing tuberculosis. These research priorities encompass the entire people-centred journey, covering prevention, diagnosis, and treatment of antimicrobial-resistant infections, in addition to addressing the overarching knowledge gaps in AMR epidemiology, burden and drivers, policies and regulations, and awareness and education. The research priorities were identified through a multistage process, starting with a comprehensive scoping review of knowledge gaps, with expert inputs gathered through a survey and open call. The priority setting involved a rigorous modified Child Health and Nutrition Research Initiative approach, ensuring global representation and applicability of the findings. The ultimate goal of this research agenda is to encourage research and investment in the generation of evidence to better understand AMR dynamics and facilitate policy translation for reducing the burden and consequences of AMR

The relationship between changes in critically ill septic and non septic patients and circulating thyroxine levels

A dissertation submitted to the Faculty of Medicine, University of the Witwatersrand, Johannesburg, in part fulfilment of the requirements for the degree Master of Medicine in Internal Medicine. 1993.Normal thyroid physiology and pathophysiOlogy with reference to non-thyroidal illness is reviwed, including infections, specific disease states and drugs and their effects on thyroid function tests. A review of the literature reveals that following almost any infection the serum T4 and T3 decrease as a result of diminished secretion of TSH and thyroxine, accelerated T4 disappearance, inhibition of hormone binding to transport proteins and decreased peripheral T4 to T3 conversion. [Abbreviated Abstract. Open document to view full version]AC201

The relationship between changes in critically ill septic and non septic patients and circulating thyroxine levels

A dissertation submitted to the Faculty of Medicine, University of the Witwatersrand, Johannesburg, in part fulfilment of the requirements for the degree Master of Medicine in Internal Medicine. 1993.Normal thyroid physiology and pathophysiOlogy with reference to non-thyroidal illness is reviwed, including infections, specific disease states and drugs and their effects on thyroid function tests. A review of the literature reveals that following almost any infection the serum T4 and T3 decrease as a result of diminished secretion of TSH and thyroxine, accelerated T4 disappearance, inhibition of hormone binding to transport proteins and decreased peripheral T4 to T3 conversion. [Abbreviated Abstract. Open document to view full version]AC201

HIV infection and chronic chest disease as risk factors for bacterial pneumonia: a case-control study.

OBJECTIVES: To investigate risk factors for severe acute pneumonia in South African gold miners. DESIGN AND METHODS: An inclusive case-control study drawn from a predefined cohort of 4762 miners of known HIV status. Cases were defined by hospital admission meeting the clinical and radiological case definitions for pneumonia during 1998. Controls were randomly selected from the starting cohort. Considered risk factors were: HIV infection, smoking, age, occupation, previous tuberculosis, and chronic premorbid chest disease caused by post-tuberculous lung disease or silicosis (International Labour Office grades 1/0 and above) defined from routine screening radiographs taken before the start of the study. RESULTS: There were 109 cases and 400 controls. HIV infection [odds ratio (OR) 31.6], previous tuberculosis (OR 2.4), and an abnormal premorbid radiograph (OR 2.8) were each significantly more prevalent in cases than controls, whereas other variables were not. On multivariate analysis, HIV infection [OR 30.7, 95% confidence interval (CI) 12.1-78.1] and an abnormal premorbid radiograph (OR 2.3, 95% CI 1.1-4.8) remained significant risk factors. Median CD4 cell counts in HIV-positive cases with and without abnormal premorbid radiographs were 185 and 162 x 106/l, making confounding between chronic chest disease and the extent of immunocompromise an unlikely explanation for this association. CONCLUSION: HIV infection and an abnormal premorbid chest radiograph are both strong risk factors for pneumonia in miners. Pre-existing chronic chest disease may be an important risk factor for HIV-associated pneumonia in other populations, and if so, is an additional indication for considering antibiotic prophylaxis in HIV-positive individuals

Efficacy of secondary isoniazid preventive therapy among HIV-infected Southern Africans: time to change policy?

OBJECTIVE: To determine the efficacy of secondary preventive therapy against tuberculosis (TB) among gold miners working in South Africa. DESIGN: An observational study. SETTING: Health service providing comprehensive care for gold miners. METHODS: The incidence of recurrent TB was compared between two cohorts of HIV-infected miners: one cohort (n = 338) had received secondary preventive therapy with isoniazid (IPT) and the other had not (n = 221). RESULTS: The overall incidence of recurrent TB was reduced by 55% among men who received IPT compared with those who did not (incidence rates 8.6 and 19.1 per 100 person-years, respectively; incidence rate ratio, 0.45; 95% confidence interval 0.26-0.78). The efficacy of isoniazid preventive therapy was unchanged after controlling for CD4 cell count and age. The number of person-years of IPT required to prevent one case of recurrent TB among individuals with a CD4 cell count or = 200 x 106 cells/l was 5 and 19, respectively. CONCLUSION: Secondary preventive therapy reduces TB recurrence: the absolute impact appears to be greatest among individuals with low CD4 cell counts. International TB preventive therapy guidelines for HIV-infected individuals need to be expanded to include recommendations for secondary preventive therapy in settings where TB prevalence is high

Effect of routine isoniazid preventive therapy on tuberculosis incidence among HIV-infected men in South Africa: a novel randomized incremental recruitment study.

CONTEXT: Tuberculosis preventive therapy reduces tuberculosis incidence among human immunodeficiency virus (HIV)-infected individuals in clinical trials, but implementation has been limited and there are no data on effectiveness under routine conditions. OBJECTIVE: To determine the effect on tuberculosis incidence of a clinic providing isoniazid preventive therapy to HIV-infected adults under routine conditions. DESIGN, SETTING, AND PARTICIPANTS: Randomized intervention study with a novel incremental recruitment design. Between 1999 and 2001 (before antiretroviral therapy was available), 1655 HIV-infected male employees of a South African gold-mining company (median age, 37 years) were enrolled in the study. Median follow-up was 22.1 months. INTERVENTION: Employees were invited in random sequence to attend a workplace HIV clinic. Isoniazid, 300 mg/d, was self-administered for 6 months among attendees with no evidence of active tuberculosis. MAIN OUTCOME MEASURE: Incidence of tuberculosis (including both first and recurrent episodes) during the periods before and after clinic enrollment. RESULTS: A total of 1016 of 1655 men included in the analysis attended the clinic at least once. Six hundred seventy-nine (97%) of 702 men eligible to start primary isoniazid preventive therapy did so. The tuberculosis incidence rate before vs after clinic enrollment was 11.9 vs 9.0 per 100 person-years, respectively (incidence rate ratio [IRR] after adjustment for calendar period, 0.68; 95% confidence interval [CI], 0.48-0.96). In a multivariable analysis adjusting for calendar period, age, and silicosis grade, the tuberculosis IRR for clinic enrollment was 0.62 (95% CI, 0.43-0.89). In a further analysis excluding individuals with a history of tuberculosis (and, hence, ineligible for isoniazid preventive therapy), the adjusted IRR for clinic enrollment was 0.54 (95% CI, 0.35-0.83). CONCLUSIONS: Enrollment in a clinic offering primary isoniazid preventive therapy to HIV-infected adults reduced tuberculosis incidence by 38% overall and by 46% among individuals with no history of tuberculosis prior to the study. Tuberculosis incidence remained high despite isoniazid preventive therapy, and further work is needed to determine how to use additional interventions most effectively to reduce morbidity and mortality due to tuberculosis in HIV-infected persons