Optimization of TB/HIV co-treatment in Ethiopian patients

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

Knowledge and adherence to antiretroviral therapy among adult people living with HIV/AIDS at Tikur Anbessa Specialized Hospital, Ethiopia

Background: Adherence to antiretroviral therapy (ART) is necessary to achieve best virological response, lower the risk of drug resistance, and reduce morbidity and mortality. The objectives of the current study were to assess the extent of knowledge of patients on treatment plan and regimen, determine the rate of adherence and identify factors related to non-adherence to ART.Methods: A cross-sectional study was conducted at Tikur Anbessa Specialized Teaching Hospital, Addis Ababa, Ethiopia, using data from both semi-structured interview (self-report) and ART database (pharmacy refill) during the months of March and April 2013 using a total 350 participants.Results: The results indicated that 33% of the participants had good knowledge on the treatment plan and regimen. Using self-report and pharmacy refill record, 79.1% and 72.9% respectively showed adherence rate of ≥95%. Younger people were found to be less likely to adhere to ART (AOR [95%] = 0.51 [0.30, 0.85]) using pharmacy refill record. Risk factors for ART non-adherence using self-report were use of memory aids (AOR [95%] = 3.46 [1.72, 6.98]), treatment satisfaction (AOR [95%] = 2.33 [1.22, 4.07]), taking co-medication (AOR [95%] = 0.56 [0.32, 0.98]), and regimen switch (AOR [95%] = 0.41 [0.19, 0.85]). Whereas using pharmacy refill record risk factors were, knowledge on treatment plan and regimen (AOR [95%] = 2.50 [1.39, 4.51]), use of memory aids (AOR [95%] = 2.71 [1.34, 5.47]), treatment satisfaction (AOR [95%] = 3.78 [1.47, 9.71]), and regimen switch (AOR [95%] = 0.50 [0.27, 0.92]).Conclusion: Older age, good knowledge on treatment plan and regimen, use of memory aids, treatment satisfaction, and not having co-medications and regimen switch showed more adherence to ART

Interrogating the Impact of Intestinal Parasite-Microbiome on Pathogenesis of COVID-19 in Sub-Saharan Africa

Intestinal parasitic infections affect more than 2 billion people throughout the world with disproportionately high prevalence rates in Low- and Middle-Income Countries (LMICs) (Herricks et al., 2017). Multicellular and highly complex parasites such as Ascaris, hook worm, Trichuris, Enterobius and Schistosoma, as well as unicellular organisms including Entamoeba, Giardia, Toxoplasma, Cyclospora, and Cryptosporidium are among major pathogens that contribute to the global intestinal parasitic disease burden. Parasites can cause persistent infection due to their ability to resist immune-mediated expulsion by modulating the host's immune response (McSorley and Maizels, 2012; Wammes et al., 2014; Chabé et al., 2017; Burrows et al., 2019; Ryan et al., 2020). There is a complex interaction between parasites and human microbiota which can triangulate with host's immune homeostasis and host responses to bystander antigens, vaccines or other unrelated diseases, both infectious and non-communicable diseases (McSorley and Maizels, 2012; Wammes et al., 2014). Recently, the world has grappled with an unprecedented pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that causes coronavirus disease 2019 (COVID-19) (WHO, 2020). The pathogenesis of severe disease in COVID-19 has been linked to the phenomenon of immune hyperactivation (Sinha et al., 2020; Tay et al., 2020). Here, we propose that the interplay between intestinal parasites and microbiome may have a potential direct or indirect effects on the pathogenesis of SARS-CoV-2 infection, in particular in the context of LMICs

MiDRMpol: A High-Throughput Multiplexed Amplicon Sequencing Workflow to Quantify HIV-1 Drug Resistance Mutations against Protease, Reverse Transcriptase, and Integrase Inhibitors

The detection of drug resistance mutations (DRMs) in minor viral populations is of potential clinical importance. However, sophisticated computational infrastructure and competence for analysis of high-throughput sequencing (HTS) data lack at most diagnostic laboratories. Thus, we have proposed a new pipeline, MiDRMpol, to quantify DRM from the HIV-1 pol region. The gag-vpu region of 87 plasma samples from HIV-infected individuals from three cohorts was amplified and sequenced by Illumina HiSeq2500. The sequence reads were adapter-trimmed, followed by analysis using in-house scripts. Samples from Swedish and Ethiopian cohorts were also sequenced by Sanger sequencing. The pipeline was validated against the online tool PASeq (Polymorphism Analysis by Sequencing). Based on an error rate of &lt;1%, a value of &gt;1% was set as reliable to consider a minor variant. Both pipelines detected the mutations in the dominant viral populations, while discrepancies were observed in minor viral populations. In five HIV-1 subtype C samples, minor mutations were detected at the &lt;5% level by MiDRMpol but not by PASeq. MiDRMpol is a computationally as well as labor efficient bioinformatics pipeline for the detection of DRM from HTS data. It identifies minor viral populations (&lt;20%) of DRMs. Our method can be incorporated into large-scale surveillance of HIV-1 DRM

Clinical and Socio-demographic Profile of the First 33 COVID-19 Cases Treated at Dedicated Treatment Center in Ethiopia

BACKGROUND:Severe respiratory tract infection caused by family of Corona viruses has become world pandemic. The purpose of this study was to describe the first few COVID 19 cases in Ethiopia.METHOD: Descriptive study was conducted on the first 33 consecutive RT-PCR confirmed COVID 19 cases diagnosed and managed at Ekka-Kotebe COVID Treatment Center in Addis Ababa, Ethiopia.RESULT: The median age of the cases was 36 years. Cough, headache and fever were the most frequent symptoms. Diarrhea, sore throats, loss of taste and/or smell sensation were among the rare symptoms. Most (84.8%) had mild to moderate disease, and 15.2%(n=5) were critical at the time of admission. Among the five ICU admissions, four patients required invasive mechanical ventilation. Thirty cases were discharged after two pairs of nasopharyngeal and oropharyngeal samples turned negative for SARS CoV2. Three cases from the ICU died while on mechanical ventilator. The age of the two deaths was 65 years, and one was 60 years. With the exception of three, all cases were either imported from abroad or had contact with confirmed cases.CONCLUSION: Most of our patients were in the younger age group with male predominance and few with comorbidities. Cough was the commonest symptom followed by headache and fever. As it was in the early stage of the pandemic, observation of more cases in the future will reveal further clinical and demographic profiles of COVID-19 cases in Ethiopia

Etiquette of the antibiotic decision-making process for surgical prophylaxis in Ethiopia: a triangulated ethnographic study

BackgroundProphylactic antibiotics reduce surgery-associated infections and healthcare costs. While quantitative methods have been widely used to evaluate antibiotic use practices in surgical wards, they fall short of fully capturing the intricacies of antibiotic decision-making in these settings. Qualitative methods can bridge this gap by delving into the often-overlooked healthcare customs that shape antibiotic prescribing practices.AimThis study aimed to explore the etiquette of the antibiotic decision-making process of surgical prophylaxis antibiotic use at Tikur Anbessa Specialized Hospital (TASH).MethodsThe observational study was carried out at TASH, a teaching and referral hospital in Addis Ababa, Ethiopia, from 26 August 2021 to 1 January 2022. Overall, 21 business ward rounds, 30 medical record reviews, and 11 face-to-face interviews were performed sequentially to triangulate and cross-validate the qualitative observation. The data were collected until saturation. The data were cleaned, coded, summarized, and analyzed using the thematic analysis approach.ResultSurgical antibiotic prophylaxis (SAP) discussions were infrequent during surgical ward rounds in TASH, leading to practices that deviated from established recommendations. Clear documentation differentiating SAP from other antibiotic uses was also lacking, which contributed to unjustified extended SAP use in the postoperative period. Missed SAP documentation was common for emergency surgeries, as well as initial dose timing and pre-operative metronidazole administration. Importantly, there was no standardized facility guideline or clinical protocol for SAP use. Furthermore, SAP prescriptions were often signed by junior residents and medical interns, and administration was typically handled by anesthesiologists/anesthetists at the operating theater and by nurses in the wards. This suggests a delegation of SAP decision-making from surgeons to senior residents, then to junior residents, and finally to medical interns. Moreover, there was no adequate representation from pharmacy, nursing, and other staff during ward rounds.ConclusionDeeply ingrained customs hinder evidence-based SAP decisions, leading to suboptimal practices and increased surgical site infection risks. Engaging SAP care services and implementing antimicrobial stewardship practices could optimize SAP usage and mitigate SSI risks

Genotype characterization of Epstein–Barr virus among adults living with human immunodeficiency virus in Ethiopia

BackgroundEpstein–Barr virus (EBV) is a human lymphotropic herpesvirus with a causative agent in cancer. There are two genotypes of EBV (EBV genotype 1 and EBV genotype 2) that have been shown to infect humans. This study aimed to characterize the EBV genotype among people with human immunodeficiency virus (PWH) and HIV-negative individuals in Ethiopia.MethodsDNA was extracted from peripheral blood mononuclear cells (PBMCs). Conventional polymerase chain reaction (cPCR) targeting EBNA3C genes was performed for genotyping. A quantitative real-time PCR (q-PCR) assay for EBV DNA (EBNA1 ORF) detection and viral load quantification was performed. Statistical significance was determined at a value of p &lt; 0.05.ResultIn this study, 155 EBV-seropositive individuals were enrolled, including 128 PWH and 27 HIV-negative individuals. Among PWH, EBV genotype 1 was the most prevalent (105/128, 82.0%) genotype, followed by EBV genotype 2 (17/128, 13.3%), and mixed infection (6/128, 4.7%). In PWH, the median log10 of EBV viral load was 4.23 copies/ml [interquartile range (IQR): 3.76–4.46], whereas it was 3.84 copies/ml (IQR: 3.74–4.02) in the HIV-negative group. The EBV viral load in PWH was significantly higher than that in HIV-negative individuals (value of p = 0.004). In PWH, the median log10 of EBV viral load was 4.25 copies/ml (IQR: 3.83–4.47) in EBV genotype 1 and higher than EBV genotype 2 and mixed infection (p = 0.032).ConclusionIn Ethiopia, EBV genotype 1 was found to be the most predominant genotype, followed by EBV genotype 2. Understanding the genotype characterization of EBV in PWH is essential for developing new and innovative strategies for preventing and treating EBV-related complications in this population

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.

We 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

Anti-Tuberculosis Therapy-Induced Hepatotoxicity among Ethiopian HIV-Positive and Negative Patients

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

Pharmacogenetic & Pharmacokinetic Biomarker for Efavirenz Based ARV and Rifampicin Based Anti-TB Drug Induced Liver Injury in TB-HIV Infected Patients

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