203 research outputs found
Incidence, predictors and biomarkers for antiretroviral and/or anti-tuberculosis drugs induced liver injury
No full textAnti-tuberculosis and/or antiretroviral drugs induced liver injury (DILI) is a major challenge when managing TB and/or HIV patients. The aims of this thesis were to identify incidence, risk factors, and management of DILI among 4 different treatment groups namely; HIV positive individuals with no TB co-infection and had a CD4 count of 200 cells/μl (taking anti-TB alone = arm 3), HIV negative TB patients (taking anti-TB alone = arm 4).Newly diagnosed TB and/or HIV patients were prospectively followed for 56-weeks after initiation of anti-TB and/or ARV treatment. All patients were evaluated clinically and biochemically for development of DILI in each visit. Laboratory tests performed include; hepatitis B surface antigen and anti-hepatitis C virus antibody. Liver enzymes and function tests were measured before and during therapy. Associations of DILI with CYP2B6, CYP3A5, NAT2 and UGT2B7, ABCB1, SLCO1B1 genotypes as well as plasma efavirenz and 8-hydroxyefavirenz concentrations were evaluated.In the pilot study which involved HIV positive and negative TB patients (n=197), who were taking anti-TB alone, the incidence of DILI was 17.3%. DILI was noted to have a statistically significant association with having a lower CD4 count and concomitant drug intake.The main study, which involved the 4 different arms (n=953) showed that incidence of DILI was still high and significantly associated with the specific arm the patient belonged to. The highest incidence was observed in arm-2 (23.5%) >arm-3 (11.6%) >arm-1 (8.1%) >arm-4 (2.8%). DILI was significantly associated with lower baseline platelet, albumin, and CD4 count. Moreover, higher plasma viral load, EFV level, baseline ALT, AST, ALP, and CYP2B6*6 were also good predictors for development of DILI among arm 1 patients. Similarly, a statistically significant association between 2 DILI and female sex, higher plasma efavirenz level, efavirenz/8-hydroxyefavirenz ratio, baseline AST, ALT, lower haemoglobin, and serum albumin was observed among participants in arm 2. NAT2 slow-acetylator, CYP2B6*6/*6, and ABCB1 3435TT genotype were also seen to contribute for development of DILI in arm 2 patients. The median time for development of DILI was 1-2 weeks after initiation of treatment, depending on the arm, with the majority developing it in the first 8 weeks.In conclusion anti-TB and/or ARV DILI is found to be a major problem among TB and/or HIV patients in Ethiopia. Hence, regular monitoring of liver enzymes during early therapy is recommended for better management. Particularly among those with an underlying risk factors; female, concurrent anti-TB and ART, advance HIV disease, elevated liver enzymes, lower haemoglobin, albumin and BMI at baseline, elevated plasma efavirenz level, having CYP2B6*6/*6 and ABCB13435TT genotype and slow acetylation status.List of scientific papersI. Getnet Yimer, Getachew Aderaye, Wondwossen Amogne, Eyasu Makonnen, Eleni Aklillu, Lars Lindquist, Lawrence Yamuah, Beniyam Feleke, and Abraham Aseffa. Anti-Tuberculosis Therapy-Induced Hepatotoxicity among Ethiopian HIV Positive and Negative Patients. PLoS ONE. 2008; 3(3): e1809. https://doi.org/10.1371/journal.pone.0001809 II. G Yimer, W Amogne, A Habtewold, E Makonnen, N Ueda, A Suda, A Worku, WE Haefeli, J Burhenne, G Aderaye, L Lindquist and E Aklillu. High plasma efavirenz level and CYP2B6*6 are associated with efavirenzbased HAART-induced liver injury in the treatment of naïve HIV patients from Ethiopia: a prospective cohort study. Pharmacogenomics J. 2011 Aug 23; 21862974. https://doi.org/10.1038/tpj.2011.34 III. Getnet Yimer, Nobuhisa Ueda, Abiy Habtewold, Wondwossen Amogne, Akira Suda, Klaus-Dieter Riedel, Jürgen Burhenne, Getachew Aderaye, Lars Lindquist, Eyasu Makonnen, Eleni Aklillu. Pharmacogenetic & Pharmacokinetic biomarker for efavirenz-based ARV and rifampicin-based anti-TB drug induced liver injury in TB-HIV infected patients. PLoS ONE. 2011; 6(12): e27810. https://doi.org/10.1371/journal.pone.0027810 IV. Getnet Yimer, Marcus Gry, Getachew Aderaye, Wondwossen Amogne, Abiy Habtewold, Eyasu Makonnen, Ina Schuppe-Koistinen, Lars Lindquist, Eleni Aklillu. TB-HIV co-infection and concomitant anti-TB and HAART increases the risk for drug induced liver injury: A prospective four arm cohort study. [Manuscript]</p
Satisfaction and associated factors of outpatient psychiatric service consumers in Ethiopia
No full textSolomon Yimer,1 Zegeye Yohannis,2 Wondale Getinet,3 Tesfa Mekonen,4 Wubalem Fekadu,4 Habte Belete,4 Melak Menberu,5 Asmamaw Getnet,6 Amsalu Belete7 1Psychiatry Department, College of Health Sciences and Medicine, Dilla University, Dilla, 2Amanuel Mental Specialized Hospital, Addis Ababa, 3Psychiatry Department, College of Health Science and Medicine, University of Gondar, Gondar, 4Psychiatry Department, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, 5Department of Nursing, College of Health Sciences, Mizan-Tepi University, Mizan, 6Finote Selam Hospital, Finote Selam, 7Department of Nursing, College of Health Sciences and Medicine, Debre Tabor University, Debre Tabor, Ethiopia Purpose: The purpose of this study was to assess the level of patient satisfaction and associated factors with psychiatric outpatient services in Ethiopia.Patients and methods: A cross-sectional study was performed from May 2015 to June 2015. A total of 454 participants selected by systematic random sampling were included in this study. Pretested and interviewer-administered questionnaire was used to collect the data. Patient satisfaction was measured using Charleston Psychiatric Outpatient Satisfaction Scale, and other validated tools were used to assess the associated variables. Multivariate logistic regressions with 95% confidence interval (CI) were used to assess the strength, and P-value <0.05 was used to indicate significance of association.Results: A total of 441 respondents were enrolled, with a response rate of 97.1% and magnitude of satisfaction of 61.2%. Being male (adjusted odds ratio [AOR] =0.612, 95% CI: 0.39, 0.94), being widowed (AOR =0.13, 95% CI: 0.05, 0.36), urban residence (AOR =0.49, 95% CI: 0.31, 0.78), diagnosed with schizophrenia (AOR =0.48, 95% CI: 0.28, 0.81), unfavorable attitude (AOR =0.49, 95% CI: 0.28, 0.86), and poor social functioning (AOR =0.52, 95% CI: 0.34, 0.80) were significantly associated with satisfaction.Conclusion: More than one-third of psychiatric service consumers were dissatisfied with the service they received. Integrating patients to their own treatment plan and regular service evaluation are important to improve satisfaction. Keywords: patient satisfaction, mental illness, social functionin
Anti-Tuberculosis Drug Induced Hepatotoxicity in HIV Positive and Negative Patients
No full textAnti-tuberculosis drug induced hepatotoxicity (DIH) is a common problem in the management of
tuberculosis. This study was intended to identify possible risk factors for development of DIH,
including degree of immunosuppression. In this prospective 2-month cohort study, 103 HIV
positive and 94 HIV negative newly diagnosed tuberculosis patients were followed after initiation
of DOTS (direct observed treatment short course). CD4 count was measured for the HIV positive
patients. All patients were also evaluated for different risk factors including HBsAg, Anti-HCV,
alcohol intake, use of other drugs including traditional medicines, acetylation status and presence
of chronic illness. Patients were monitored biochemically (by liver function tests) and clinically
for development of DIH weekly in the first month and bi-weekly in the second month after start
of therapy. Biochemical hepatotoxicity was seen in 17.3% of the patients. CD4 counts of these
patients were 0-50 for 7 (35%), 51-100 for 8 (40%), 101-200 for 4 (20%), and > 200 for 1 (5%).
Three patients were positive for HBsAg and none had anti-HCV. Five patients died of nonhepatic causes among the patients who developed DIH. Eight out of the 34 patients with
biochemical hepatotoxicity (23.5%) developed clinical hepatotoxicity that necessitated
discontinuation of their anti-TB drugs. Seven of the eight were HIV positive, seven were female,
and 2 were positive for HBsAg. Biochemical hepatotoxicity was significantly associated with
HIV co-infection (p=0.002), concomitant drug intake (p=0.008), decrease in CD4 count
(p=0.001), high mortality (p=0.001), and having Wt/Wt allele for acetylation status (p=0.026).
Clinical hepatotoxicity is also significantly associated with being female (p=0.027), HIV coinfection (p=0.043), concomitant drug intake (p=0.003), HBsAg (p=0.046), decrease in CD4
count (p=0.025), and high mortality (p=0.0001). No significant association was seen between
hepatotoxicity with alcohol intake, age, body mass index, type of TB and anti HCV positivity.
The findings would assist in selectively managing patients at risk. It is recommended to have a
regular biochemical and clinical follow up for those patients who are at risk of developing DIH
.These patients include HIV positive patients, with special emphasis to those with a lower CD4
count, and patients who take drugs other than their anti TB medication. We also recommend that
further work should be done to explore the reason for the observed association between DIH and
female sex, HBsAg positivity, and acetylation status
Quality of clinical trials for selected priority mental and neurological disorders in sub-Saharan Africa: a systematic review
No full textAnwar Mulugeta,1 Girmay Medhin,2 Getnet Yimer,1 Rahimush Jemal,3 Abebaw Fekadu,4,5 1Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University, 2Aklilu Lemma Institute of Pathobiology, Addis Ababa University, 3Department of Pharmacy, Tikur Anbesa Hospital, 4Department of Psychiatry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; 5Department of Psychological Medicine, Centre for Affective Disorders, Institute of Psychiatry, King’s College London, London, UK Background: There is a developing consensus on the effectiveness of various interventions for mental disorders in low- and middle-income countries, and it has been proposed that the main task is to scale up these interventions. In this context, we aimed to review the quality and extent of intervention trials for selected priority mental and neurological disorders in sub-Saharan Africa.Methods: Medline and African Journals Online databases were used for searching relevant articles. Both randomized and nonrandomized clinical trials for the treatment of schizophrenia, depression, maternal depression, bipolar disorder, and epilepsy/seizure disorders that involve pharmacotherapy, psychotherapy, and physical therapy were included. An extensive list of search terms that identified locations, disorders, interventions, and study types were employed. The qualities of the trials were appraised using the single-component quality assessment of the consolidated standards of reporting trials (CONSORT) statement and the Jadad scale.Results: From 1,136 studies identified, only 34 trials that fulfilled inclusion criteria were used for quality analysis. Most studies were clinical trials of treatments for epilepsy and were conducted after 2006. In terms of region, the majority of studies were conducted in South Africa (22 of the 34 studies). Approximately half of the trials (53%) were conducted in single center and the majority of the trials (71%) were pharmacotherapeutics-based intervention. In terms of methodological quality in relation to the Jadad scale, 82% fulfilled the criteria for good methodological quality with a score of 3−5. However, the methodological quality according to the CONSORT criteria was more mixed.Conclusion: The overall quality of clinical trials conducted in sub-Saharan Africa is encouraging despite the limited number of studies. However, important quality limitations remain and have not improved over time. Hence, establishing clinical trial centers in these countries may be one approach to improving quality and quantity of trials. Keywords: randomized controlled trial, schizophrenia, depression, epilepsy, drug therapy, psychotherapy, Afric
Anti-nociceptive and anti-inflammatory activities of crude root extract and solvent fractions of Cucumis ficifolius in mice model
No full textDesalegn Getnet Demsie,1,2 Ebrahim M Yimer,1 Abera Hadgu Berhe,1 Birhanetensay Masresha Altaye,3 Derbew Fikadu Berhe11Department of Pharmacology and Toxicology, College of Health Sciences, Mekelle University, Mekelle, Ethiopia; 2Department of Pharmacy, College of Medicine and Health Sciences, Adigrat University, Adigrat, Ethiopia; 3Department of Pharmacy, College of Medicine, Debre Berhan University, Debre Berhan, EthiopiaBackground: Societies in developing countries use traditional medicine as alternatives for management of pain and inflammation. The plant Cucumis ficifolius has been used in Ethiopia to treat many ailments including inflammation and pain. The objective of this study was to evaluate the antinociceptive and anti-inflammatory activities of the crude root extract and solvent fractions of C. ficifolius.Methods: The analgesic activity of crude extract and solvent fractions of C. ficifolius was evaluated with acetic acid-induced writhing, hot plate, and formalin-induced paw licking tests. The anti-inflammatory effect of crude methanolic root extract and solvent fractions of C. ficifolius was evaluated using carrageenan-induced paw edema. The crude extract was given at 200, 400 and 800 mg/kg. Butanol and aqueous fractions were given at 100 and 200 mg/kg doses. The negative control groups were treated with distilled water (10 mL/kg). Standard drugs used wereacetylsalicylic acid(ASA) in acetic acid, formalin tests and carrageenan-induced paw edema and morphine (20 mg/kg) in hot plate test.Results: The crude extract, at its maximum dose, produced comparable analgesic activity (72.5%) to ASA in acetic acid writhing test. In the hot plate test, both the crude extract and solvent fractions exhibited a significant prolongation of nociception reaction time. Formalin test result indicated a significant reduction of mean lick time with maximal protection of 64% (early phase) and 83% (late phase). Aqueous and butanol fractions showed good analgesic activity in the three models. Inflammation was decreased by 69% with butanol (200 mg/kg); 71% (800 mg/kg) of crude extract and by 41% and 56% with the use of aqueous fraction at 100 and 200 mg/kg, respectively (p<0.001).Conclusion: The present study indicates that the crude methanolic root extract, as well as butanol and aqueous solvent fractions, showed anti-nociceptive and anti-inflammatory activities.Keywords: hot plate test, writhing test, paw edema, formalin test, carrageenan, 80% methano
Optimization of TB/HIV co-treatment in Ethiopian patients
No full textTuberculosis (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 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 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 List of scientific papersI. G Yimer, W Amogne, A Habtewold, E Makonnen, N Ueda1, A Suda, A Worku, WE Haefeli, J Burhenne, G Aderaye, L Lindquist and E Aklillu. High plasma efavirenz level and CYP2B6*6 are associated with efavirenz-based HAARTinduced liver injury in the treatment of naïve HIV patients from Ethiopia: a prospective cohort study. The Pharmacogenomics Journal 2012 Dec;12(6):499-506. https://doi.org/10.1038/tpj.2011.34 II. Wondwossen Amogne, Getachew Aderaye, Abiy Habtewold, Getnet Yimer, Eyasu Makonnen, Alemayhu Worku, Anders Sonnerborg, Eleni Aklillu, Lars Lindquist. Efficacy and Safety of Antiretroviral Therapy Initiated One Week after Tuberculosis Therapy in Patients with CD4 Counts https://doi.org/10.1371/journal.pone.0122587 III. Wondwossen Amogne, Irene Bontell, Sebastian Grossmann, Getachew Aderaye, Lars Lindquist, Anders Sönnerborg, Ujjwal Neogi. Phylogenetic analysis of near full-length genome reveals high intra-HIV-1 subtype C diversity but a strong geographical cluster in Ethiopia abstain in subgenomic region. [Manuscript]IV. Wondwossen Amogne, Getachew Aderaye, Eleni Aklillu, Abiy Habtewold, Getnet Yimer, Eyasu Makonnen, Alemayhu Worku, Anders Sonnerborg, Lars Lindquist. Evaluation of severe antituberculosis Drug-Induced Liver Injury, the effect of concurrent antiretroviral therapy timing and Hy’s Law in Tuberculosis and HIV coinfected patients: A Prospective cohort study. [Manuscript]</p
The Role of Pharmacogenomics Studies for Precision Medicine Among Ethiopian Patients and Their Clinical Implications: A Scoping Review
No full textKefyalew Ayalew Getahun,1 Dessie Abebaw Angaw,2 Mezgebu Silamsaw Asres,3 Wubayehu Kahaliw,1 Zelalem Petros,4 Solomon Mequanente Abay,4 Getnet Yimer,5 Nega Berhane6 1Department of Pharmacology, School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; 2Department of Biostatistics and Epidemiology, Institute of Public Health, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; 3Department of Internal Medicine, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; 4Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; 5Department of Genetics and Center for Global Genomics and Health Equity, School of Medicine, University of Pennsylvania, Pennsylvania, US, USA; 6Department of Medical Biotechnology, Institute of Biotechnology, University of Gondar, Gondar, EthiopiaCorrespondence: Kefyalew Ayalew Getahun, Tel +251 946970462, Email [email protected]; [email protected]: Pharmacogenomics research is currently revolutionizing treatment optimization by discovering molecular markers. Medicines are the cornerstone of treatment for both acute and chronic diseases. Pharmacogenomics associated treatment response varies from 20% to 95%, resulting in from lack of efficacy to serious toxicity. Pharmacogenomics has emerged as a useful tool for therapy optimization and plays a bigger role in clinical care going forward. However, in Africa, in particular in Ethiopia, such studies are scanty and not generalizing. Therefore, the objective of this review was to outline such studies, generating comprehensive evidence and identify studied variants’ association with treatment responses in Ethiopian patients.Methods: The Joanna Briggs Institute’s updated 2020 methodological guidelines for conducting and guidance for scoping reviews were used. We meticulously adhered to the systemic review reporting items checklist and scoping review meta-analyses extension.Results: Two hundred twenty-nine possibly relevant studies were searched. These include: 64, 54, 21, 48 and 42 from PubMed, Scopus, Google Scholar, EMBASE, and manual search, respectively. Seventy-seven duplicate studies were removed. Thirty-nine papers were rejected with justification, whereas 58 studies were qualified for full-text screening. Finally 19 studies were examined. The primary pharmacogene that was found to have a significant influence on the pharmacokinetics of efavirenz was CYP2B6. Drug-induced liver injury has frequently identified toxicity among studied medications.Conclusion and Future Perspectives: Pharmacogenomics studies in Ethiopian populations are less abundant. The studies conducted focused on infectious diseases, specifically on HAART commonly efavirenz and backbone first-line anti-tuberculosis drugs. There is a high need for further pharmacogenomics research to verify the discrepancies among the studies and for guiding precision medicine. Systematic review and meta-analysis are also recommended for pooled effects of different parameters in pharmacogenomics studies.Keywords: Ethiopian, pharmacogenomics, single nucleotide polymorphisms, treatment outcome, pharmacogenetics, precision medicin
Importance of Ethnicity, CYP2B6 and ABCB1 Genotype for Efavirenz Pharmacokinetics and Treatment Outcomes: A Parallel-group Prospective Cohort Study in two sub-Saharan Africa Populations.
No full textWe evaluated the importance of ethnicity and pharmacogenetic variations in determining efavirenz pharmacokinetics, auto-induction and immunological outcomes in two African populations. ART naïve HIV patients from Ethiopia (n = 285) and Tanzania (n = 209) were prospectively enrolled in parallel to start efavirenz based HAART. CD4+ cell counts were determined at baseline, 12, 24 and 48 weeks. Plasma and intracellular efavirenz and 8-hydroxyefvairenz concentrations were determined at week 4 and 16. Genotyping for common functional CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 variant alleles were done. Patient country, CYP2B6*6 and ABCB1 c.4036A>G (rs3842A>G) genotype were significant predictors of plasma and intracellular efavirenz concentration. CYP2B6*6 and ABCB1 c.4036A>G (rs3842) genotype were significantly associated with higher plasma efavirenz concentration and their allele frequencies were significantly higher in Tanzanians than Ethiopians. Tanzanians displayed significantly higher efavirenz plasma concentration at week 4 (p<0.0002) and week 16 (p = 0.006) compared to Ethiopians. Efavirenz plasma concentrations remained significantly higher in Tanzanians even after controlling for the effect of CYP2B6*6 and ABCB1 c.4036A>G genotype. Within country analyses indicated a significant decrease in the mean plasma efavirenz concentration by week 16 compared to week 4 in Tanzanians (p = 0.006), whereas no significant differences in plasma concentration over time was observed in Ethiopians (p = 0.84). Intracellular efavirenz concentration and patient country were significant predictors of CD4 gain during HAART. We report substantial differences in efavirenz pharmacokinetics, extent of auto-induction and immunologic recovery between Ethiopian and Tanzanian HIV patients, partly but not solely, due to pharmacogenetic variations. The observed inter-ethnic variations in efavirenz plasma exposure may possibly result in varying clinical treatment outcome or adverse event profiles between populations
Pharmacokinetic and pharmacogenetic aspects of drug-drug interactions between antiretroviral and anti-tuberculosis drugs in Ethiopian patients : implication for optimization of TB-HIV co-treatment
No full textTB and HIV are immuno-pathologically interacting epidemic infectious diseases affecting the lives of millions globally & sub-Saharan African region accounts the highest burden of both diseases. Although effective therapies are available for the management of each, TB-HIV co-treatment has faced challenges mainly due to drug-drug interactions & overlapping drug toxicities. To overcome these, efavirenz (EFV) based highly active antiretroviral therapy (HAART) is the preferred regimen while rifampicin (RIF) based anti-TB treatment regimen is a choice to treat TB-HIV co-infection in resource-limited settings. RIF is a known enzyme & drug transporter inducer and/or inhibitor. The dose of EFV to be used in the presence of RIF is, however, controversial. This thesis is primarily carried out to investigate the pharmacogenetic and pharmacokinetic aspect of drug-drug interaction between RIF & EFV aiming to optimize the dose of EFV to be used in TB-HIV co-infected Ethiopian patients.This study was designed to be carried out in two sub-Saharan African countries (Ethiopia and Tanzania), owning to the heterogeneity of the region genetically and culturally. This thesis focuses on the Ethiopian population. The thesis was conducted by prospectively recruiting cohort of HIV infected individuals without TB (Arm 1; N = 285) in parallel to another cohort of HIV co-infected with active TB (Arm 2; N = 196). All study participants were adults with baseline CD4 count less than 200 cells per mm3 and were followed for a year. At baseline and follow up periods, clinical chemistry (liver and kidney function tests), hematological parameters (complete and differential blood cell counts) and HAART outcome monitoring (CD4 counts and HIV RNA viral load) were done. In addition, genotyping for CYP2B6*6, CYP3A5 (*3, *6, *7), UGT2B7*2, NAT2, ABCB1 (3435 C > T & 3842 A > G) & SLCO1B1 (*1b & *5) were also done. Pharmacokinetic variables such as plasma/intracellular concentrations of EFV, 8-hydroxyefavirenz (major metabolite) & metabolic ratio were determined at weeks 4 and/or 16, 16±1h post-dose. Besides, cholesterol, 4β-hydroxy-cholesterol (biomarker for CYP3A activity) & metabolic ratio at weeks 0, 4, 16 & 48 were also determined to investigate time-dependent effect of EFV on CYP3A enzyme. Socio-demographic factors (Age, sex, baseline body weight and BMI) were also recorded.This thesis reports paradoxical increase in plasma/intracellular EFV concentrations by RIF co-therapy; coherent to this is improved immunological outcomes among individuals co-treated for TB and HIV with comparable virologic success to HAART than those without RIF co-treatment. The thesis also shows wide between-subject variability in the long-term auto-induction by EFV based on CYP2B6 genotype. Between & within-subject variability in plasma EFV concentration and immunological outcome are shown to be influenced by RIF co-therapy, CYP2B6 genotype and baseline body weight. Besides, the thesis demonstrates the influence of CYP2B6 genotype on CYP3A autoinduction by EFV in a gene-dose dependent manner, CYP2B6 (*6/*6 > *1/*6 > *1/*1). Furthermore, the thesis reveals the importance of differences in ethnicity & environmental factors contributing to wide between-population variability in EFV auto-induction comparing Ethiopian & Tanzanian patients. In addition, associations of CYP2B6, ABCB1 (3842A >G), slow NAT2 metabolizing genotypes & plasma concentration of EFV with increased incidences of drug-induced liver injury (DILI) and correlation of plasma and intracellular concentrations of EFV are reported in the thesis. The thesis also shows the long-term but not short-term effects of sex and UGT2B7 genotype in predicting auto-induction as well as plasma concentration of EFV.In conclusion, EFV dose-escalation from 600mg to 800mg is not required during TB-HIV co-treatment in Ethiopian patients. CYP2B6*6 genotype is not only a strong predictor for EFV pharmacokinetics but also could predict EFVbased HAART outcomes, DILI & CYP3A auto-induction by EFV. In addition to pharmacogenetic variability, the importance of differences in ethnicity & environmental factors are highlighted to optimize HIV treatment across subSaharan Africa.List of scientific papersI. Habtewold A, Amogne W, Makonnen E, Yimer G, Riedel KD, Ueda N, Worku A, Haefeli WE, Lindquist L, Aderaye G, Burhenne J, Aklillu E. Long-term effect of efavirenz autoinduction on plasma/peripheral blood mononuclear cell drug exposure and CD4 count is influenced by UGT2B7 and CYP2B6 genotypes among HIV patients. J Antimicrob Chemother. 2011 Oct; 66(10): 2350-61. https://doi.org/10.1093/jac/dkr304 II. Habtewold A, Amogne W, Makonnen E, Yimer G, Nylén H, Riedel KD, Aderaye G, Bertilsson L, Burhenne J, Diczfalusy U, Aklillu E. Pharmacogenetic and pharmacokinetic aspects of CYP3A induction by efavirenz in HIV patients. Pharmacogenomics J. 2012 Oct 23. https://doi.org/10.1038/tpj.2012.46 III. Eliford Ngaimisi and Abiy Habtewold, Omary Minzi, Eyasu Makonnen, Sabina Mugusi, Wondwossen Amogne, Getnet Yimer, Klaus-Dieter Riedel, Philip Sasi, Mohammed Janabi, Getachew Aderaye, Ferdinand Mugusi, Leif Bertilsson, Eleni Aklillu and Juergen Burhenne. Importance of ethnicity, CYP2B6 and ABCB1 genotype for efavirenz pharmacokinetics and treatment outcomes: A parallel-group prospective cohort study in two Sub-Saharan Africa populations. [Submitted]IV. Yimer G, Ueda N, Habtewold A, Amogne W, Suda A, Riedel KD, Burhenne J, Aderaye G, Lindquist L, Makonnen E, Aklillu E. Pharmacogenetic & Pharmacokinetic Biomarker for Efavirenz Based ARV and Rifampicin Based AntiTB Drug Induced Liver Injury in TB-HIV Infected Patients. PLoS One. 2011; 6(12):e27810. https://doi.org/10.1371/journal.pone.0027810 V. Abiy Habtewold, Eyasu Makonnen, Wondwossen Amogne, Getnet Yimer, KlausDieter Riedel, Getachew Aderaye, Leif Bertilsson, Jürgen Burhenne, Eleni Aklillu. Paradoxical effect of rifampicin on plasma/intracellular efavirenz pharmacokinetics and increased immunologic outcome: No need for efavirenz dose escalation with rifampicin co-therapy in Ethiopian HIV patients. [Submitted]</p
Copy number variation of Fc gamma receptor genes in HIV-infected and HIV-tuberculosis co-infected individuals in Sub-Saharan Africa
No full textAIDS, caused by the retrovirus HIV, remains the largest cause of morbidity in sub-Saharan Africa yet almost all genetic studies have focused on cohorts from Western countries. HIV shows high co-morbidity with tuberculosis (TB), as HIV stimulates the reactivation of latent tuberculosis (TB). Recent clinical trials suggest that an effective anti-HIV response correlates with non-neutralising antibodies. Given that Fcγ receptors are critical in mediating the nonneutralising effects of antibodies, analysis of the extensive variation at Fcγ receptor genes is important. Single nucleotide variation and copy number variation (CNV) of Fcγ receptor genes affects the expression profile, activatory/inhibitory balance, and IgG affinity of the Fcγ receptor repertoire of each individual. In this study we investigated whether CNV of FCGR2C, FCGR3A and FCGR3B as well as the HNA1 allotype of FCGR3B is associated with HIV load, response to highly-active antiretroviral therapy (HAART) and co-infection with TB. We confirmed an effect of TB-co-infection status on HIV load and response to HAART, but no conclusive effect of the genetic variants we tested. We observed a small effect, in Ethiopians, of FCGR3B copy number, where deletion was more frequent in HIV-TB co-infected patients than those infected with HIV alone
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