| 1. |
- Aderaye, Getachew
(författare)
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Pulmonary tuberculosis and Pneumocystis jiroveci pneumonia in HIV-infected patients in Ethiopia
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The objective of this study initially was to determine the prevalence of culture-verified pulmonary tuberculosis in TB suspects and investigate the impact of human immunodeficiency virus (HIV) infection on the prevalence, clinical and radiological presentation and diagnosis of tuberculosis. During the study, it soon became clear that the HIV sero-prevalence in tuberculosis (TB) suspects who could not be verified to be culture-positive was too high to deserve an explanation. The second objective, therefore, was to prospectively look for possible causes of other pulmonary opportunistic infections including pneumocystis pneumonia (PCP) to explain the excess HIV. In paper I, among 509 consecutive PTB suspects attending the outpatient department of a university hospital in Addis Ababa, 33% could be culture-verified as having PTB. PTB patients, non-TB patients (culture-negative PTB suspects) and controls were HIV-1 positive in 57.1%, 38.5% and 8.3% of cases respectively. Independent predictors of culture-verified TB were age <25yrs, male gender and the presence of HIV and fever whereas profound weight loss indicated HIV infection. Diagnosis of PTB based on clinical symptoms, direct sputum microscopy and chest radiography (CXR) was significantly less sensitive and specific in HIV+ patients. In paper II, a look at the relationship between disease pattern and disease burden by chest x-ray, mycobacterial load and HIV infection also demonstrated that: (1) atypical chest x-ray with interstitial infiltrates, pleural effusion, miliary mottling, normal CXR and absent cavitations occurred more frequently in HIV-infected than non-HIV-infected patients (2) Mycobacterial load as assessed by the number of colonies of Mycobacterium tuberculosis (MTB) culture was significantly less in HIV-infected patients than non-HIV-infected, (3) the occurrence of high number of culture-verified PTB cases with normal CXR was identified as one of the challenges in the diagnosis of PTB in patients with HIV infection. In paper III, amongst 119 culture-negative, HIV+ TB suspects, P. jiroveci was detected in 10.9% by single polymerase chain reaction (PCR) and immunofluorescence (IF) and 30.3% by nested PCR in expectorated sputum sample. In HIV- negative TB and Non-TB patients, the prevalence of P.carini was significantly lower. Besides, in the IF-positive and nPCR-positive HIV+ non-TB patients,more than 40% were interpreted as PTB by CXR whereas only one patient was diagnosed with clinical PCP. This observation prompted us to design a follow up prospective study to find out the relative importance of P. jiroveci and other pulmonary opportunistic diseases in smear-negative patients presenting with atypical chest x-rays. In paper IV, 131 consecutive HIV-1 infected patients presenting with respiratory symptoms and atypical chest x-rays who were sputum smear-negative for AFB and sero-reactive for HIV were enrolled into the study. They underwent clinical evaluation and investigation for P. jiroveci (using TBO and IF stain) and M. tuberculosis from expectorated sputum and BAL samples and fungal and bacterial culture from BAL alone. The results of this study showed that the prevalence of PCP was 29.8%, that of bacterial infection 33.6% and tuberculosis 23.7%. Pulmonary Kaposi sarcoma (PKS) and interstitial pneumonitis (NIP) occurred in 4 patients each. Double infection occurred in 18(13.7%) patients. Cryptococcal pneumonitis was conspicuously absent in this study population. In paper V, we evaluated the usefulness of a simple diagnostic method, Toluidine Blue O stain for the diagnosis of P. jiroveci in expectorated sputum sample and bronchoalveolar lavage (BAL) and compared it to immunofluorescence and PCR. Comparison of these diagnostic tests showed that the sensitivity of TBO in sputum and BAL samples was 71.4 % and 68% compared to immunofluorescence respectively. The overall sensitivity for the diagnosis of PJ was 42.7 % by PCR, 29.8% by IF and 20.6% by TBO. PCR was the most sensitive test and detected additional 18 patients than immunofluorescence. Considering cost, simplicity and efficacy, we recommend TBO as the most practical diagnostic test and expectorated sputum (ES) as the most practical biologic specimen for use in resource-constrained, high HIV-settings such as Ethiopia.
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| 2. |
- Ashenafi, S, et al.
(författare)
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Daily Nutritional Supplementation with Vitamin D₃ and Phenylbutyrate to Treatment-Naïve HIV Patients Tested in a Randomized Placebo-Controlled Trial
- 2019
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Poor nutritional status is common among human immunodeficiency virus (HIV)-infected patients including vitamin D (vitD3) deficiency. We conducted a double-blinded, randomized, and placebo-controlled trial in Addis Ababa, Ethiopia, to investigate if daily nutritional supplementation with vitD3 (5000 IU) and phenylbutyrate (PBA, 2 × 500 mg) could mediate beneficial effects in treatment-naïve HIV patients. Primary endpoint: the change in plasma HIV-1 comparing week 0 to 16 using modified intention-to-treat (mITT, n = 197) and per-protocol (n = 173) analyses. Secondary endpoints: longitudinal HIV viral load, T cell counts, body mass index (BMI), middle-upper-arm circumference (MUAC), and 25(OH)D3 levels in plasma. Baseline characteristics were detectable viral loads (median 7897 copies/mL), low CD4+ (median 410 cells/µL), and elevated CD8+ (median 930 cells/µL) T cell counts. Most subjects were vitD3 deficient at enrolment, but a gradual and significant improvement of vitD3 status was demonstrated in the vitD3 + PBA group compared with placebo (p < 0.0001) from week 0 to 16 (median 37.5 versus 115.5 nmol/L). No significant changes in HIV viral load, CD4+ or CD8+ T cell counts, BMI or MUAC could be detected. Clinical adverse events were similar in both groups. Daily vitD3 + PBA for 16 weeks was well-tolerated and effectively improved vitD3 status but did not reduce viral load, restore peripheral T cell counts or improve BMI or MUAC in HIV patients with slow progressive disease. Clinicaltrials.gov NCT01702974.
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| 3. |
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| 4. |
- Ekici, Halime, et al.
(författare)
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Minority drug-resistant HIV-1 variants in treatment Naive East-African and Caucasian patients detected by allele-specific real-time PCR
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:10, s. e111042-
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To assess the presence of two major non-nucleoside reverse transcriptase inhibitors (NNRTI) drug resistance mutations (DRMs), Y181C and K103N, in minor viral quasispecies of treatment naive HIV-1 infected East-African and Swedish patients by allele-specific polymerase chain reaction (AS-PCR).Methods: Treatment naive adults (n = 191) with three epidemiological backgrounds were included: 92 Ethiopians living in Ethiopia; 55 East-Africans who had migrated to Sweden; and 44 Caucasians living in Sweden. The pol gene was analysed by standard population sequencing and by AS-PCR for the detection of Y181C and K103N.Results: The Y181C was detected in the minority quasispecies of six Ethiopians (6.5%), in two Caucasians (4.5%), and in one East-African (1.8%). The K103N was detected in one East-African (1.8%), by both methods. The proportion of mutants ranged from 0.25% to 17.5%. Additional DRMs were found in all three treatment naive patient groups by population sequencing.Conclusions: Major NNRTI mutations can be found by AS-PCR in minor quasispecies of treatment naive HIV-1 infected Ethiopians living in Ethiopia, in East-African and Caucasian patients living in Sweden in whom population sequencing reveal wild-type virus only. Surveys with standard sequencing are likely to underestimate transmitted drug resistance and the presence of resistant minor quasispecies in treatment naive patients should be topic for future large scale studies.
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| 5. |
- Missailidis, C, et al.
(författare)
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Vitamin D and Phenylbutyrate Supplementation Does Not Modulate Gut Derived Immune Activation in HIV-1
- 2019
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Dysbiosis and a dysregulated gut immune barrier function contributes to chronic immune activation in HIV-1 infection. We investigated if nutritional supplementation with vitamin D and phenylbutyrate could improve gut-derived inflammation, selected microbial metabolites, and composition of the gut microbiota. Treatment-naïve HIV-1-infected individuals (n = 167) were included from a double-blind, randomized, and placebo-controlled trial of daily 5000 IU vitamin D and 500 mg phenylbutyrate for 16 weeks (Clinicaltrials.gov NCT01702974). Baseline and per-protocol plasma samples at week 16 were analysed for soluble CD14, the antimicrobial peptide LL-37, kynurenine/tryptophan-ratio, TMAO, choline, and betaine. Assessment of the gut microbiota involved 16S rRNA gene sequencing of colonic biopsies. Vitamin D + phenylbutyrate treatment significantly increased 25-hydroxyvitamin D levels (p < 0.001) but had no effects on sCD14, the kynurenine/tryptophan-ratio, TMAO, or choline levels. Subgroup-analyses of vitamin D insufficient subjects demonstrated a significant increase of LL-37 in the treatment group (p = 0.02), whereas treatment failed to significantly impact LL-37-levels in multiple regression analysis. Further, no effects on the microbiota was found in number of operational taxonomic units (p = 0.71), Shannon microbial diversity index (p = 0.82), or in principal component analyses (p = 0.83). Nutritional supplementation with vitamin D + phenylbutyrate did not modulate gut-derived inflammatory markers or microbial composition in treatment-naïve HIV-1 individuals with active viral replication.
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| 6. |
- Thulin, Petra, et al.
(författare)
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Keratin-18 and microRNA-122 complement alanine aminotransferase as novel safety biomarkers for drug-induced liver injury in two human cohorts
- 2014
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Ingår i: Liver international (Print). - : Wiley. - 1478-3223 .- 1478-3231. ; 34:3, s. 367-378
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Tidskriftsartikel (refereegranskat)abstract
- 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, microRNA-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 microRNA-122 levels were significantly increased at an earlier time point than ALT. Furthermore, the maximal elevation of M65 and microRNA-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 microRNA-122 are potential biomarkers of DILI superior to ALT with respect to sensitivity and specificity.
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