| 1. |
- Abdurahman, Samir, 1965-, et al.
(author)
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Pattern of microbial translocation in patients living with HIV-1 from Vietnam, Ethiopia and Sweden
- 2014
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In: Journal of the International AIDS Society. - 1758-2652. ; 17, s. 18841-
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Journal article (peer-reviewed)abstract
- INTRODUCTION: The role of microbial translocation (MT) in HIV patients living with HIV from low- and middle-income countries (LMICs) is not fully known. The aim of this study is to investigate and compare the patterns of MT in patients from Vietnam, Ethiopia and Sweden.METHODS: Cross-sectional samples were obtained from treatment-naïve patients living with HIV-1 and healthy controls from Vietnam (n=83; n=46), Ethiopia (n=9492; n=50) and Sweden (n=51; n=19). Longitudinal samples were obtained from a subset of the Vietnamese (n=24) in whom antiretroviral therapy (ART) and tuberculostatics were given. Plasma lipopolysaccharide (LPS), sCD14 and anti-flagellin IgG were determined by the endpoint chromogenic Limulus Amebocyte Assay and enzyme-linked immunosorbent assay.RESULTS: All three biomarkers were significantly increased in patients living with HIV-1 from all countries as compared to controls. No differences were found between males and females. Vietnamese and Ethiopian patients had significantly higher levels of anti-flagellin IgG and LPS, as compared to Swedes. ART reduced these levels for the Vietnamese. Vietnamese patients given tuberculostatics at initiation of ART had significantly lower levels of anti-flagellin IgG and higher sCD14. The biomarkers were lower in Vietnamese who did not develop opportunistic infection.CONCLUSIONS: Higher MT is common in patients living with HIV compared to healthy individuals, and in patients from LMICs compared to patients from a high-income country. Treatment with tuberculostatics decreased MT while higher levels of MT are associated with a poorer clinical outcome.
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| 2. |
- Degu, Wondwossen Amogne
(author)
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Optimization of TB/HIV co-treatment in Ethiopian patients
- 2015
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Doctoral thesis (other academic/artistic)abstract
- Tuberculosis (TB) and HIV infection act with deadly synergy. HIV is the most important risk factor for latent TB reactivation and active TB progression following exposure or reinfection while TB accelerates HIV progression. TB is the most frequent cause of morbidity and mortality in HIV infection. Anti-TB therapy (ATT) must precede initiation of combination Antiretroviral Therapy (cART), TB being the most immediate threat. Undoubtedly cART benefits; however, important clinical challenges emerge when cART is initiated during TB therapy. Optimization TB and HIV cotreatment is therefore required. Paper II: We hypothesized that by initiating efavirenz (EFV)-based cART earlier than the second week of ATT in patients with CD4 counts < 200 cells/ µL; overall survival can be improved at 48 weeks. The study hypothesis was tested with randomized, open-label, clinical trial comparing efficacy and safety of EFV-based cART one week, four weeks and eight weeks after ATT in coinfected patients with baseline CD4 count < 200 cells/µL. The results showed that cART one week after TB therapy doesn’t improve overall survival at 48 weeks. All-cause mortality in subgroups with CD4 count below 50 cells/µL versus above was lowest in week one. However, compared with week four and eight, first line ATT interruption from severe Drug-Induced Liver Injury (DILI) was highest in week one deaths (P=0.03) and in the CD4 subgroup < 50 cells/µL (P=0.02). The key question for CD4 category < 50 cells/µL is striking the optimal balance between the potential survival benefits if cART is initiated one week after TB therapy as opposed to the increased morbidity and mortality due to DILI and risk of ATT interruption. Paper I and IV: We investigated DILI during TB/HIV cotreatment and HIV-treatment with EFV-based cART. DILI is the most important treatment limiting factor for continuation of both ATT and/or cART. Multiple evidences show that TB/HIV coinfected patients experience higher rate of adverse drug reactions than those without HIV. Both are prospective cohort studies and analysis was made with multivariate Cox regression model. Outcome measures were incidence rates for DILI, ATT and/or cART interruptions as well as assessment of risk factors. Paper I on EFV-based cART in HIV-infected patients with baseline CD4 counts < 200 cells/µL revealed high plasma EFV levels and CYP 2B6*6 genetic polymorphism predict DILI events in addition to baseline transaminitis, low CD4 count, low serum albumin and platelet values. Paper IV specifically addressed severe form of DILI during TB/HIV cotreatment compared with only TB treatment in HIV-negative patients as well as EFV-based cART in HIV-infected patients with baseline CD4 counts < 200 cells/µL inclusive of isoniazid preventive therapy. The findings from this study are: severe DILI risk is increased several folds with TB/HIV coinfection whereas concurrent cART timing doesn’t alter the risk. Incidence rate of ATT interruption is higher with CD4< 50 cells/µL. Independent risk factors for severe DILI in addition to TB/HIV coinfection were abnormal alanine aminotransferase and bilirubin values at baseline, CD4 < 50 cells/µL and positive HCV antibody result. In summary, the result concur earlier initiation of EFV-based cART during TB/HIV coinfection, though DILI remains as the most important challenge. It is more related to ATT than EFV-based cART and not affected by the timing of EFV-based cART within the first 8 weeks of TB therapy. Paper III evaluated Ethiopian HIV-1 subtype C virus (HIV-1CET) at near full length genome level for phylogenetic analysis, genotypic drug resistance and viral tropism. The results showed high diversity among HIV-1CET strains compared to other geographical locations suggesting introduction of HIV-1C in the country occurred in early phase of HIV- 1C epidemic. Primary drug resistant mutations were identified in < 5% of the cases and 95% of the viral strains had R-5 tropism.
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| 3. |
- Ekici, Halime, et al.
(author)
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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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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:10, s. e111042-
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Journal article (peer-reviewed)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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| 4. |
- Siddik, Abu Bakar, et al.
(author)
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Phenotypic co-receptor tropism and Maraviroc sensitivity in HIV-1 subtype C from East Africa
- 2018
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 8:1
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Journal article (peer-reviewed)abstract
- Genotypic tropism testing (GTT) for co-receptor usage is a recommended tool for clinical practice before administration of the CCR5-antagonist maraviroc. For some isolates, phenotypic tropism testing (PTT) revealed discordant results with GTT. In this study, we performed a comparative study between GTT and PTT in HIV-1C from East Africa (HIV-1C(EA)) and compared the data with HIV-1B and 01_AE and described the maraviroc susceptibility in the CCR5-tropic strains. Patient-derived HIV-1 envgp120 region was cloned into a modified pNL4-3 plasmid expressing the luciferase gene. rPhenotyping dissected single clones from 31 HIV-1C(EA) infected patients and four strains with known phenotype. Additionally, 68 clones from 18 patients (HIV-1B: 5, 01_AE: 7, HIV-1C(EA): 6) were used to determine the PTT in GHOST cell line. The respective V3-sequences were used for GTT. R5-tropic strains from HIV-1C(EA) (n = 20) and non-C (n = 12) were tested for maraviroc sensitivity in TZMbl cell line. The GTT falsely called a higher proportion of X4-tropic strains in HIV-1C(ET) compared to PTT by both rPhenotyping and the GHOST-cell assay. When multiple clones were tested in a subset of patients' samples, both dual-tropic and R5-tropic strains were identified for HIV-1C. Relatively higher EC50 values were observed in HIV-1C strains than the non-C strains (p = 0.002).
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