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Background: The aim of this observational cohort study was to determine the incidence and risk factors of active tuberculosis (TB) in persons living with HIV in a low endemic setting over a 17-year time period when combination antiretroviral therapy (ART) has been available. We thereby aimed to understand the usefulness of TB chemoprophylaxis among HIV patients with latent TB., Methods: All 2127 adult patients diagnosed with HIV January 1996-December 2013 at the Karolinska University Hospital in Stockholm County were eligible. After exclusion of 259 patients transferred to other clinics, 1868 were followed until TB diagnosis, death or end of study period (December 2013). The median follow-up time was 7.9 years (interquartile range, 3.9-11.5)., Results: Active TB was diagnosed in 92 patients, corresponding to an incidence rate of 6.2 cases (95% CI 5.1-7.6) per 1000 person-years with a significant decline over time. The majority (52%) of TB cases were diagnosed within 1 month from HIV diagnosis. Being a migrant from a TB-endemic region, was the only patient characteristic associated with significantly higher risk of active TB (Hazard Ration, HR: 8.54, 95% confidence interval, CI: 3.09-23.61 in a multivariate regression analysis controlling for route of HIV transmission, year of HIV diagnosis and CD4-cell count and viral load at HIV diagnosis. The number needed to treat to prevent one case of TB among patients in this high-risk group was 22 (95% CI 26-47)., Conclusion: The incidence of active TB in persons living with HIV in Stockholm County declined significantly after the introduction of ART but was still 80 times higher than in the general population at the end of the study period. The therapeutic gain of chemoprophylaxis in low endemic settings should be weighed against costs and side effects.

Background: Given the high death rate the first two months of tuberculosis (TB) therapy in HIV patients, it is critical defining the optimal time to initiate combination antiretroviral therapy (cART)., Methods: A randomized, open-label, clinical trial comparing efficacy and safety of efavirenz-based cART initiated one week, four weeks, and eight weeks after TB therapy in patients with baseline CD4 count < 200 cells/μL was conducted. The primary endpoint was all-cause mortality rate at 48 weeks. The secondary endpoints were hepatotoxicity-requiring interruption of TB therapy, TB-associated immune reconstitution inflammatory syndrome, new AIDS defining illnesses, CD4 counts, HIV RNA levels, and AFB smear conversion rates. All analyses were intention-to-treat., Results: We studied 478 patients with median CD4 count of 73 cells/μL and 5.2 logs HIV RNA randomized to week one (n = 163), week four (n = 160), and week eight (n = 155). Sixty-four deaths (13.4%) occurred in 339.2 person-years. All-cause mortality rates at 48 weeks were 25 per 100 person-years in week one, 18 per 100 person-years in week four and 15 per 100 person-years in week eight (P = 0.2 by the log-rank test). All-cause mortality incidence rate ratios in subgroups with CD4 count below 50 cells/μL versus above were 2.8 in week one (95% CI 1.2-6.7), 3.1 in week four (95% CI 1.2-8.6) and 5.1 in week eight (95% CI 1.8-16). Serum albumin < 3 gms/dL (adjusted HR, aHR = 2.3) and CD4 < 50 cells/μL (aHR = 2.7) were independent predictors of mortality. Compared with similar subgroups from weeks four and eight, first-line TB treatment interruption was high in week one deaths (P = 0.03) and in the CD4 subgroup <50 cells/μL (P = 0.02)., Conclusions: Antiretroviral therapy one week after TB therapy doesn't improve overall survival. Despite increased mortality with CD4 < 50 cells/μL, we recommend cART later than the first week of TB therapy to avoid serious hepatotoxicity and treatment interruption., Trial Registration: ClinicalTrials.gov NCT 01315301.

Background: The aim of this study was to describe risk factors for mortality and clinical characteristics of HIV-infected patients with and without tuberculosis (TB) coinfection., Methods: A cohort of HIV-infected patients with CD4(+) T-cell counts of ≤200 cells/μl was recruited, consisting of 255 HIV-infected patients without active TB and 231 patients with active TB. All received a well-supervised treatment with an efavirenz-based HAART, and those coinfected with TB received appropriate anti-TB treatment. They were followed up for 48 weeks after HAART initiation., Results: Common presenting symptoms in HIV-only patients were fever (36.5%), headache (34.5%), skin rash (34.5%) and weight loss (32%), while in HIV-TB patients the symptoms were weight loss (58%), cough (57.6%), night sweats (44.6%) and fever (34.2%). HIV-TB patients had significantly lower body mass index, Karnofsky scores and haemoglobin levels compared to those infected with HIV only, despite similar baseline CD4(+) T-cell counts. Overall, 12 (4.7%) HIV patients developed TB and 7 (3%) HIV-TB patients had worsening of their TB symptoms during the study period. Mortality was similar in the two groups, being 10.9% (16 deaths per 100 person years) and 11.3% (17 deaths per 100 person years) in HIV-only and HIV-TB patients, respectively. Overall, more males (13.1%) died compared to females (9.6%). Predictors of mortality were presence of oral candidiasis, Kaposi's sarcoma, low Karnofsky score, and low baseline white blood cell and CD4(+) T-cell counts., Conclusions: The outcomes following well-supervised treatment of HIV-TB patients are similar to those in patients with HIV alone. Predictors of mortality were those of advanced disease.

Objectives: To investigate the timing, incidence, clinical presentation, pharmacokinetics and pharmacogenetic predictors for antiretroviral and anti-tuberculosis drug induced liver injury (DILI) in HIV patients with or without TB co-infection., Methods and Findings: A total of 473 treatment naïve HIV patients (253 HIV only and 220 with HIV-TB co-infection) were enrolled prospectively. Plasma efavirenz concentration and CYP2B6*6, CYP3A5*3, *6 and *7, ABCB1 3435C/T and SLCO1B1 genotypes were determined. Demographic, clinical and laboratory data were collected at baseline and up to 48 weeks of antiretroviral therapy. DILI case definition was according to Council for International Organizations of Medical Sciences (CIOMS). Incidence of DILI and identification of predictors was evaluated using Cox Proportional Hazards Model. The overall incidence of DILI was 7.8% (8.3 per 1000 person-week), being non-significantly higher among patients receiving concomitant anti-TB and HAART (10.0%, 10.7 per 1000 person-week) than those receiving HAART alone (5.9%, 6.3 per 1000 person-week). Frequency of CYP2B6*6 allele (p = 0.03) and CYP2B6*6/*6 genotype (p = 0.06) was significantly higher in patients with DILI than those without. Multivariate cox regression model indicated that CYP2B6*6/*6 genotype and anti-HCV IgG antibody positive as significant predictors of DILI. Median time to DILI was 2 weeks after HAART initiation and no DILI onset was observed after 12 weeks. No severe DILI was seen and the gain in CD4 was similar in patients with or without DILI., Conclusions: Antiretroviral and anti-tuberculosis DILI does occur in our setting, presenting early following HAART initiation. DILI seen is mild, transient and may not require treatment interruption. There is good tolerance to HAART and anti-TB with similar immunological outcomes. Genetic make-up mainly CYP2B6 genotype influences the development of efavirenz based HAART liver injury in Tanzanians.

Background: Implication of pharmacogenetic variations and efavirenz pharmacokinetics in concomitant efavirenz based antiviral therapy and anti-tubercular drug induced liver injury (DILI) has not been yet studied. We performed a prospective case-control association study to identify the incidence, pharmacogenetic, pharmacokinetic and biochemical predictors for anti-tubercular and antiretroviral drugs induced liver injury (DILI) in HIV and tuberculosis (TB) co-infected patients., Methods and Findings: Newly diagnosed treatment naïve TB-HIV co-infected patients (n = 353) were enrolled to receive efavirenz based ART and rifampicin based anti-TB therapy, and assessed clinically and biochemically for DILI up to 56 weeks. Quantification of plasma efavirenz and 8-hydroxyefaviernz levels and genotyping for NAT2, CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 genes were done. The incidence of DILI and identification of predictors was evaluated using survival analysis and the Cox Proportional Hazards Model. The incidence of DILI was 30.0%, or 14.5 per 1000 person-week, and that of severe was 18.4%, or 7.49 per 1000 person-week. A statistically significant association of DILI with being of the female sex (p = 0.001), higher plasma efavirenz level (p = 0.009), efavirenz/8-hydroxyefavirenz ratio (p = 0.036), baseline AST (p = 0.022), ALT (p = 0.014), lower hemoglobin (p = 0.008), and serum albumin (p = 0.007), NAT2 slow-acetylator genotype (p = 0.039) and ABCB1 3435TT genotype (p = 0.001)., Conclusion: We report high incidence of anti-tubercular and antiretroviral DILI in Ethiopian patients. Between patient variability in systemic efavirenz exposure and pharmacogenetic variations in NAT2, CYP2B6 and ABCB1 genes determines susceptibility to DILI in TB-HIV co-infected patients. Close monitoring of plasma efavirenz level and liver enzymes during early therapy and/or genotyping practice in HIV clinics is recommended for early identification of patients at risk of DILI.

Background: To assess and compare the prevalence, severity and prognosis of anti-TB drug induced hepatotoxicity (DIH) in HIV positive and HIV negative tuberculosis (TB) patients in Ethiopia., Methodology/principal Findings: In this study, 103 HIV positive and 94 HIV negative TB patients were enrolled. All patients were evaluated for different risk factors and monitored biochemically and clinically for development of DIH. Sub-clinical hepatotoxicity was observed in 17.3% of the patients and 8 out of the 197 (4.1%) developed clinical hepatotoxicity. Seven of the 8 were HIV positive and 2 were positive for HBsAg., Conclusions/significance: Sub-clinical hepatotoxicity was significantly associated with HIV co-infection (p = 0.002), concomitant drug intake (p = 0.008), and decrease in CD4 count (p = 0.001). Stepwise restarting of anti TB treatment was also successful in almost all the patients who developed clinical DIH. We therefore conclude that anti-TB DIH is a major problem in HIV-associated TB with a decline in immune status and that there is a need for a regular biochemical and clinical follow up for those patients who are at risk.

Objectives: To evaluate the incidence, type, severity and predictors of antiretroviral and/or anti-tuberculosis drugs induced liver injury (DILI). Methods: A total of 1,060 treatment naive patients were prospectively enrolled into four treatment groups: HIV patients receiving efavirenz based HAART alone (Arm-1); TB-HIV co-infected patients with CD4≤200 cells/μL, receiving concomitant rifampicin based anti-TB and efavirenz based HAART (Arm-2); TB-HIV co-infected patients with CD4>200 cells/μL, receiving anti-TB alone (Arm-3); TB patients taking rifampicin based anti-TB alone (Arm-4). Liver enzyme levels were monitored at baseline, 1st, 2nd, 4th, 8th, 12th and 24th weeks during treatment. CD4 and HIV viral load was measured at baseline, 24th and 48th weeks. Data were analyzed using multivariate Cox Proportional Hazards Model. Results: A total of 159 patients (15%) developed DILI with severity grades 1, 2, 3 and 4 of 53.5%, 32.7%, 11.3% and 2.5% respectively. The incidence of cholestatic, hepatocellular or mixed pattern was 61%, 15% and 24%, respectively. Incidence of DILI was highest in Arm-2 (24.2%)>Arm-3 (10.8%)>Arm-1 (8.8%)>Arm-4 (2.9%). Concomitant anti-TB-HIV therapy increased the risk of DILI by 10-fold than anti-TB alone (p<0.0001). HIV co-infection increased the risk of anti-TB DILI by 4-fold (p = 0.004). HAART associated DILI was 3-fold higher than anti-TB alone, (p = 0.02). HAART was associated with cholestatic and grade 1 DILI whereas anti-TB therapy was associated with hepatocellular and grade ≥ 2. Treatment type, lower CD4, platelet, hemoglobin, higher serum AST and direct bilirubin levels at baseline were significant DILI predictors. There was no effect of DILI on immunologic recovery or virologic suppression rate of HAART. Conclusion: HAART associated DILI is mainly cholestatic and mild whereas hepatocellular or mixed pattern with high severity grade is more common in anti-tuberculosis DILI. TB-HIV co-infection, disease severity and concomitant treatment exacerbates the risk of DILI. [ABSTRACT FROM AUTHOR]

Background & Aims There is a demand for more sensitive, specific and predictive biomarkers for drug-induced liver injury ( DILI) than the gold standard used today, alanine aminotransferase ( ALT). The aim of this study was to qualify novel DILI biomarkers (keratin-18 markers M65/M30, micro RNA-122, glutamate dehydrogenase and alpha-foetoprotein) in human DILI. Methods Levels of the novel biomarkers were measured by enzyme-linked immunosorbent assay or real-time quantitative reverse-transcription PCR ( qRT-PCR) in two human DILI cohorts: a human volunteer study with acetaminophen and a human immunodeficiency virus (HIV)/tuberculosis (TB) study. Results In the acetaminophen study, serum M65 and micro RNA-122 levels were significantly increased at an earlier time point than ALT. Furthermore, the maximal elevation of M65 and micro RNA-122 exceeded the increase in ALT. In the HIV/ TB study, all the analysed novel biomarkers increased after 1 week of treatment. In contrast to ALT, the novel biomarkers remained stable in a human cohort with exercise-induced muscular injury. Conclusions M65 and micro RNA-122 are potential biomarkers of DILI superior to ALT with respect to sensitivity and specificity. [ABSTRACT FROM AUTHOR]

Pneumocystis pneumonia (PCP) has been considered a rare disease in sub-Saharan Africa. However, a rising prevalence has been noted recently. The objective of this study was to determine the relative prevalence of PCP and other pulmonary opportunistic diseases in patients infected with HIV in Ethiopia. 131 consecutive patients with respiratory symptoms and atypical chest X-ray, who were sputum smear-negative for AFB and seroreactive for HIV, underwent clinical evaluation and investigation for Pneumocystis jiroveci and Mycobacterium tuberculosis from sputum and bronchoalveolar lavage (BAL), and fungal and bacterial pathogens from BAL alone. Bacterial infections, Pneumocystis pneumonia (PCP) and pulmonary tuberculosis (PTB) occurred in 44 (33.6%), 39 (29.7%) and 31 (23.7%) patients, respectively. Pulmonary Kaposi sarcoma and non-specific interstitial pneumonitis occurred in 4 patients each. In a multivariate regression model, predictors of PCP were typical chest X-ray and low CD4 count while purulent sputum predicted bacterial infection. The sensitivity of physicians and chest X-ray diagnosis was particularly low for PTB and bacterial infections. We conclude that chronic bacterial infection and Pneumocystis pneumonia are important differential diagnoses in HIV-infected, smear-negative PTB patients presenting with atypical chest X-ray. We therefore need to escalate the use of preventive and highly active antiretroviral (HAART) treatment in order to prevent a PCP epidemic. [ABSTRACT FROM AUTHOR]

In a setting with a high prevalence of HIV we studied (i) the prevalence of pulmonary tuberculosis (PTB) and HIV; (ii) clinical and epidemiological characteristics of PTB; and (iii) the usefulness of standard procedures for diagnosing PTB. Of 509 consecutive outpatients evaluated on clinical suspicion of PTB in Addis Ababa, 33.0% were culture-verified as having PTB. PTB patients, non-TB patients and controls were HIV-1-positive in 57.1%, 38.5% and 8.3% of cases, respectively. Predictors for culture-verified PTB were age < 25 y, male gender and the presence of HIV and fever, whereas profound weight loss indicated HIV infection. Diagnosis of PTB based on clinical symptoms, sputum microscopy for acid-fast bacilli and chest radiography was sensitive (86.7%) but unspecific (64.1%). In HIV-positive patients both sensitivity and specificity were significantly lower (p < 0.05). HIV-related pulmonary infections are often misinterpreted as smear-negative PTB. HIV screening is therefore warranted not only in cases of verified TB but also as part of the diagnostic work-up in patients with respiratory symptoms suggestive of PTB. Also, increased awareness of, and improved diagnostic tools for, HIV-related pulmonary infections other than PTB are required, together with algorithms for patients with suspected PTB. [ABSTRACT FROM AUTHOR]