Evaluation of HIV-1 drug resistance among patients failing first-line antiretroviral therapy in Ethiopia

Background: High rates of disease progression and HIV drug resistance (HIVDR) among adults taking highly active antiretroviral treatment (HAART) in Sub-Saharan Africa were previously documented. However, children were generally not considered despite their greater risk. Hence, this study was aimed to evaluate HIV-1 disease progression and drug resistance mutation among children on first-line antiretroviral therapy in Ethiopia. Method: A longitudinal study was conducted among 551 HIV-positive children (<15 years old) recruited between 2017 and 2019 at 40 antiretroviral treatment delivery sites in Ethiopia. Disease progression was retrospectively measured over a 12-year (2007-2019) follow-up as the progress towards immunosuppression. Two consecutive viral load (VL) tests were conducted in 6-month intervals to assess virologic failure (VF). For children with VF, HIV-1 genotyping and sequencing was performed for the pol gene region using in-house assay validated at the Chinese Center for Disease Control and Prevention, and the Stanford HIVDB v9.0 algorithm was used for identification of drug resistance mutations. The Kaplan-Meier analysis and Cox proportional hazards regression model were used to estimate the rate and predictors of disease progression, respectively. Results: The disease progression rate was 6.3 per 100 person-years-observation (95% CI = 4.21-8.53). Overall immunosuppression (CD4 count < 200 cells/mm3) during the 12-year follow-up was 11.3% (95% CI = 7.5-15.1). Immunosuppression was significantly increased as of the mean duration of 10.5 (95% CI = 10.1-10.8) years (38.2%) to 67.8% at 12 years (p < 0.001). Overall, 14.5% had resistance to at least one drug, and 6.2% had multi-drug resistance. A resistance of 67.8% was observed among children with VF. Resistance to non-nucleotide reverse transcriptase inhibitors (NNRTI) and nucleotide reverse transcriptase inhibitors (NRTI) drugs were 11.4% and 10.1%, respectively. Mutations responsible for NRTI resistance were M184V (30.1%), K65R (12.1%), and D67N (5.6%). Moreover, NNRTI-associated mutations were K103N (14.8%), Y181C (11.8%), and G190A (7.7%). Children who had a history of opportunistic infection [AHR (95% CI) = 3.4 (1.8-6.2)], vitamin D < 20 ng/mL [AHR (95% CI) = 4.5 (2.1-9.9)], drug resistance [AHR (95% CI) = 2.2 (1.4-3.6)], and VF [AHR (95% CI) = 2.82 (1.21, 3.53)] had a higher hazard of disease progression; whereas, being orphan [AOR (95% CI) = 1.8 (1.2-3.1)], history of drug substitution [(AOR (95% CI) = 4.8 (2.1-6.5), hemoglobin < 12 mg/dL [AOR (95% CI) = 1.2 (1.1-2.1)] had higher odds of developing drug resistance. Conclusions: Immunosuppression was increasing over time and drug resistance was also substantially high. Enhancing routine monitoring of viral load and HIVDR and providing a vitamin-D supplement during clinical management could help improve the immunologic outcome. Limiting HAART substitution is also crucial for children taking HAART in Ethiopia.

Our study assesses human immunodeficiency virus (HIV) drug resistance (HIVDR) in patients failing first-line (1L) antiretroviral therapy (ART) with dual nucleoside analog reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) regimens in India. In this cross-sectional study, consecutive HIV-1-infected patients aged 13 years or older, failing 1L ART after at least 12 months exposure, underwent HIV genotyping and drug resistance testing (DRT) using the ViroSeq™ HIV-1 Genotyping System and the Stanford HIV-1 Database, with HIVDR classification based on a penalty score of ≥30. Among 115 eligible participants, 110 underwent DRT, revealing efavirenz (EFV) or nevirapine (NVP) resistance rates of 85.3% (n = 93/109) and 87.2% (n = 95/109), respectively, and substantial cross-resistance to rilpivirine (RPV) (37.6%, n = 41/109), etravirine (ETV) (30.3%, n = 33/109), and doravirine (DOR) (60.5%, n = 66/109). The cohort was categorized into 3 groups based on their previous ARV drug exposure: group A (36.4%, n = 40) with prior TA exposure (AZT or d4T) but no TFV exposure; group B (19.1%, n = 21) with prior nonconcomitant exposure to both TAs and TFV; and group C (44.5%, n = 49), exposed to TFV only. Despite group B's 1L ART regimen failure with TFV, the prevalence of AZT resistance was similar (difference in proportions, ∇P: 14.6%, p = 0.277) between group A [57.5% (n = 23/40)] and group B [42.9% (n = 9/21)]. TFV resistance was comparable (∇P: 0.8%, p = 0.947) between group A (32.5%, n = 13/40) and group B (33.3%, n = 7/21), despite group A's lack of TFV exposure, and was also similar to the TFV-only-exposed group (group C: 38.8%, n = 19/49). Regarding distinct DRM patterns, the prevalence of K65R DRM was higher (∇P: 22.4%, p = 0.060) among TFV-only-exposed patients (group C: 36.7%, n = 18/49) compared with PLH exposed to both TAs and TFV (group B: 14.3%, n = 3/21), whereas multiple TAMs occurred at similar rates (∇P: 12.1%, p = 0.367) among TA-exposed patients [group A: 55.0% (n = 22/40) vs group B: 42.9% (n = 9/21)]. The research provides insights into the complexities of HIVDR, emphasizing the interplay of resistance patterns and the role of drug exposure history, especially in the context of resistance to TFV and second-generation NNRTIs. Ensuring adequate drug exposure history in patients can prevent poor outcomes in PLH being treated with ART due to resistance. Resistance profiling is especially relevant following first-line ART failure.

The effect of dolutegravir (DTG)-based regimens on reducing attrition from care among women enrolled in the prevention of mother-to-child transmission (PMTCT) care program is unknown. Therefore, this study aimed to compare the incidence of attrition among women exposed to DTG-based with those exposed to efavirenz (EFV)-based first-line antiretroviral therapy (ART) in Ethiopia. An uncontrolled before-and-after study was conducted involving 932 women (with 466 on EFV-based and 466 on DTG-based regimens) who were enrolled in the PMTCT care program from September 2015 to February 2023. The outcome variable was attrition (i.e., maternal death or loss to follow-up before their infants' final HIV status was determined). A Kaplan-Meier estimator was employed to estimate the probability of attrition. The Cox proportional hazards regression model was fitted to identify predictor variables. The adjusted hazard ratio (aHR) with the corresponding 95% confidence interval (CI) was calculated to examine the risk difference in the comparison groups. The cumulative incidence of attrition among women was 5.2% (3.0% for those placed in the DTG-based regimen arm and 7.3% for those placed in the EFV-based regimen arm). Women on DTG-based regimens had a 57% (aHR: 0.43; 95% CI: 0.23-0.80) lower risk of attrition from care compared to those on EFV-based regimens. Women who delivered their infants at home (aHR: 2.35; 95% CI: 1.14-4.85), had poor/fair adherence (aHR: 3.23; 95% CI: 1.62-6.45), had unsuppressed/unknown viral load status (aHR: 2.61; 95% CI: 1.42-4.79), and did not disclose their status to partners (aHR: 2.56; 95% CI: 1.34-4.92) had a higher risk of attrition from PMTCT care compared to their counterparts. The cumulative incidence of attrition among women receiving PMTCT care is optimal. In addition, the risk of attrition among women receiving DTG-based regimens is lower than that among women receiving EFV-based regimens. Thus, DTG-based first-line ART regimen supplementation should be sustained to achieve a national retention target of 95% and above.

BackgroundPeople living with HIV/AIDS (PLWHA) are frequently confronted with severe social issues such as rejection, abandonment, criticism, and stigma. This would negatively affect their quality of life. Several studies have been conducted so far to assess factors affecting the health-related quality of life among people living with HIV/AIDS who are on antiretroviral therapy (ART) in Ethiopia. However, to our knowledge, there is no previous study that has summarized the results of the studies that investigated health-related quality of life (HRQOL) among PLWHA in Ethiopia. Therefore, the purpose of this review was to estimate the pooled prevalence of HRQOL and its association with social support among people living with HIV/AIDS (PLWHA) on ART in Ethiopia.MethodsA systematic search was carried out using several electronic databases (PubMed, Science Direct, Web of Science, and Cochrane electronic), Google Scholar, Google, and a manual search of the literature on health-related quality of life among people living with HIV/AIDS who are on ART. A Microsoft Excel data extraction sheet was used to extract pertinent data from an individual study. To assess the heterogeneity of primary articles, the Cochrane Q test statistics and the I2 test were carried out, and a random effects meta-analysis was used to estimate the pooled prevalence of HRQOL.ResultOut of the 493 articles reviewed, ten with a total of 3257 study participants were eligible for meta-analysis. The pooled prevalence of HRQOL among people living with HIV/AIDS who are on antiretroviral therapy in Ethiopia was 45.27%. We found that strong perceived social support was significantly associated with higher levels of subjectively perceived HRQOL. PLWHA who were on ART and had good social support were four times more likely to report higher HRQOL when compared to their counterparts [AOR = 4.01, 95% CI 3.07–5.23].ConclusionA substantial number of PLWHA had poor HRQOL in Ethiopia. Social support was significantly associated with HRQOL among people living with HIV/AIDS. Hence, it’s recommended to encourage suitable intervention at every follow-up visit, and psycho-social support is also warranted to improve the quality of life.

BackgroundOver 420,000 people have initiated life-saving antiretroviral therapy (ART) in Ethiopia; however, lost-to-follow-up (LTFU) rates continues to be high. A clinical decision tool is needed to identify patients at higher risk for LTFU to provide individualized risk prediction to intervention. Therefore, this study aimed to develop and validate a statistical risk prediction tool that predicts the probability of LTFU among adult clients on ART.MethodsA retrospective follow-up study was conducted among 432 clients on ART in Gondar Town, northwest, Ethiopia. Prognostic determinates included in the analysis were determined by multivariable logistic regression. The area under the receiver operating characteristic (AUROC) and calibration plot were used to assess the model discriminative ability and predictive accuracy, respectively. Individual risk prediction for LTFU was determined using both regression formula and score chart rule. Youden index value was used to determine the cut-point for risk classification. The clinical utility of the model was evaluated using decision curve analysis (DCA).ResultsThe incidence of LTFU was 11.19 (95% CI 8.95–13.99) per 100-persons years of observation. Potential prognostic determinants for LTFU were rural residence, not using prophylaxis (either cotrimoxazole or Isoniazid or both), patient on appointment spacing model (ASM), poor drug adherence level, normal Body mass index (BMI), and high viral load (viral copies > 1000 copies/ml). The AUROC was 85.9% (95% CI 82.0–89.6) for the prediction model and the risk score was 81.0% (95% CI 76.7–85.3) which was a good discrimination probability. The maximum sensitivity and specificity of the probability of LTFU using the prediction model were 72.07% and 83.49%, respectively. The calibration plot of the model was good (p-value = 0.350). The DCA indicated that the model provides a higher net benefit following patients based on the risk prediction tool.ConclusionThe incidence of LTFU among clients on ART in Gondar town was high (> 3%). The risk prediction model presents an accurate and easily applicable prognostic prediction tool for clients on ART. A prospective follow-up study and external validation of the model is warranted before using the model.

Time to overcome pretreatment HIV drug resistance

ObjectiveThis study aimed to pool the prevalence of virological failure and associated factors.DesignSystematic review and meta-analysis.Primary outcome measurePrevalence of virological failure.Secondary outcome measureFactors affecting virological failure.AnalysisThe extracted data were exported...

This study was aimed at developing a risk score prediction model for bacteriologically confirmed tuberculosis (TB) among adults with HIV receiving antiretroviral therapy in Ethiopia. An institutional-based retrospective follow-up study was conducted among 569 adults with HIV on ART. We used demographic and clinical prognostic factors to develop a risk prediction model. Model performance was evaluated by discrimination and calibration using the area under the receiver operating characteristic (AUROC) curve and calibration plot. Bootstrapping was used for internal validation. A decision curve analysis was used to evaluate the clinical utility. Opportunistic infection, functional status, anemia, isoniazid preventive therapy, and WHO clinical stages were used to develop risk prediction. The AUROC curve of the original model was 87.53% [95% confidence interval (CI): 83.88-91.25] and the calibration plot ( P -value = 0.51). After internal validation, the AUROC curve of 86.61% (95% CI: 82.92-90.29%) was comparable with the original model, with an optimism coefficient of 0.0096 and good calibration ( P -value = 0.10). Our model revealed excellent sensitivity (92.65%) and negative predictive value (NPV) (98.60%) with very good specificity (70.06%) and accuracy (72.76%). After validation, accuracy (74.85%) and specificity (76.27%) were improved, but sensitivity (86.76%) and NPV (97.66%) were relatively reduced. The risk prediction model had a net benefit up to 7.5 threshold probabilities. This prognostic model had very good performance. Moreover, it had very good sensitivity and excellent NPV. The model could help clinicians use risk estimation and stratification for early diagnosis and treatment to improve patient outcomes and quality of life.

Background: Treatment failure (TF) among patients receiving antiretroviral therapy (ART) against human immunodeficiency virus (HIV) impacts on treatment outcome and is becoming a public health concern globally. However, magnitude of TF and factors leading to it are poorly defined in the context of Ethiopia. Thus, the aim of this study was to determine the magnitude of TF and assess its determinants among HIV-infected patients on ART in Ethiopia. Methods: A prospective and retrospective study was conducted from March 2016 to 2017. Retrospective clinical and laboratory data were captured from patients’ medical record. Socio-demographics and explanatory variables of participants were collected using pre-tested structured questionnaire and study participants were followed for additional 6 month after baseline viral load has been done to classify virologic failure (VF). Multiple logistic regression was conducted to assess risk factors associated with TF. Statistical significance was set at P-value less than 0.05. Results: A total of 9,284 adults taking ART from a nationally representative 63 health facilities were included in the study. Viral Load Suppression (VLS) (VL1000 copies/ml at baseline of the study were re-suppressed after six months of enhanced adherence and counseling, leading TF among population on ART in Ethiopia to be 983 (11%). Immunologic and clinical failure was significantly improved from 21.5% and 16.5% at ART initiation to 576 (6.2%) and 470 (5.0%) at baseline of the study, respectively. Medication adherence, disclosure of HIV status, missed appointment to ART, history of ART exposure prior to initiation, residency and marital status had significant association with TF. Conclusions: The high level of VLS (88.1%) could explain the success of ART program in Ethiopia towards achieving the UNAIDS global target on viral suppression. TF among population taking ART in Ethiopia is still a public health concern, since 11% of virally failed population is maintained on failed first-line regimen. However, a significant improvement on immunologic and clinical outcome after ART initiation was maintained. Close follow-up of medication adherence, ensuring disclosure of HIV status, regular appointment follow-up to ART could significantly improve the treatment outcome of population on ART in Ethiopia.

BackgroundThe ongoing scale-up of antiretroviral therapy (ART) in sub-Saharan Africa has prompted the interest in surveillance of transmitted and acquired HIV drug resistance. Resistance data on virological failure and mutations in HIV infected populations initiating treatment in sub-Saharan Africa is sparse.MethodsHIV viral load (VL) and resistance mutations pre-ART and after 6 months were determined in a prospective cohort study of ART-naïve HIV patients initiating first-line therapy in Jimma, Ethiopia. VL measurements were done at baseline and after 3 and 6 months. Genotypic HIV drug resistance (HIVDR) was performed on patients exhibiting virological failure (>1000 copies/mL at 6 months) or slow virological response (>5000 copies/mL at 3 months and <1000 copies/mL at 6 months).ResultsTwo hundred sixty five patients had VL data available at baseline and at 6 months. Virological failure was observed among 14 (5.3%) participants out of 265 patients. Twelve samples were genotyped and six had HIV drug resistance (HIVDR) mutations at baseline. Among virological failures, 9/11 (81.8%) harbored one or more HIVDR mutations at 6 months. The most frequent mutations were K103N and M184VI.ConclusionsOur data confirm that the currently recommended first-line ART regimen is efficient in the vast majority of individuals initiating therapy in Jimma, Ethiopia eight years after the introduction of ART. However, the documented occurrence of transmitted resistance and accumulation of acquired HIVDR mutations among failing patients justify increased vigilance by improving the availability and systematic use of VL testing to monitor ART response, and underlines the need for rapid, inexpensive tests to identify the most common drug resistance mutations.

7.0 Managing virological failure

Objectives: To study the prevalence of drug resistance and genotype testing for HIV drug resistance on HIV/AIDS patients with first-line antiretroviral treatment failure at Dong Da Hospital, Hanoi, Vietnam.Patients and methods: Forty-seven patients in Dong Da Hospital, Hanoi, with confirmation of first-line antiretroviral therapy (ART) failure were enrolled in this study from June 2006 to December 2016. Both the protease and reverse transcriptase genes were amplified and sequenced using Trugene® HIV-1 Genotyping Kit and OpenGene® DNA system at the biomolecular laboratory of the National Institute of Hygiene and Epidemiology, Vietnam. The Stanford HIV database algorithm was used for interpretation of resistance data and genotyping.Results: Drug resistance mutations were 90.7% in patients with first-line treatment failure. Amongst patients with drug resistance mutation, 97.7% resisted to non-nucleoside reverse transcriptase inhibitors (NNRTIs), followed by nucleoside reverse transcriptase inhibitors (NRTIs, 95.3%) and protease inhibitors (PIs, 11.6%). Amongst the genetic mutations resistant to NNRTIs, G190S mutation was the highest (51.2%), K101HQ mutation was 39.5% and Y181I mutation was 34.9%. In genetic mutations to NRTIs, M184V mutation was 88.4%. In thymidine analogue mutations, K70R mutation was the most common (37.2%), followed by D67N, T215F and T69N mutations (27.9%, 27.9% and 25.6%, respectively). In genetic mutations in PIs, M36I and K20R mutations made up 9.3%. In NNRTIs, the prevalence of nevirapine resistance was 55.8%, and that of efavirenz resistance was 4.7%. In NRTIs, the ratio of lamivudine resistance was 93.0%, and that of zidovudine resistance was 9.3%. No lopinavir/ritonavir resistance was recorded.Conclusions: Drug resistance mutations in patients with first-line ART failure had a high prevalence of NNRTI and NRTI resistance but still susceptible to PIs.

To study the condition of HIV-1 drug resistance mutation among failures of first-line antiretroviral therapy in Henan province. The sub platform of China's legal infectious disease monitoring information reporting system-HIV/AIDS integrated prevention and control data information management system was used to collect the information of patients experiencing first-line antiretroviral treatment failure (virus load ≥ 1 000 copies/ml) more than one year among nine cities of Henan in 2011. A total of 40 cases with no information and 212 cases with incomplete drug resistance results were deleted, and 1 922 cases were included in this study and genotype resistance testing was carried out. Non-conditional logistic regression analysis was used to analyse the influencing factors of drug resistance mutation. A total of 1 922 cases were included in the analysis. 1 039 cases were males, 833 cases were females, the age was (45.7 ± 12.1) years, 82.73% (1 590) were married, and 87.93% (1 690) were transmitted by blood. 64.20% (1 234) patients acquired drug resistance. Nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI) resistance mutations were found in 62.59% (1 203), 49.74% (956) and 0.94% (18) of subjects, respectively. 42.09% (809) of patients harbored NRTI and NNRTI resistance mutations synchronously. ≥ 1TAM was the most commonly emerged NRTI resistance mutation (41.94% (806)), the prevalences of TAM-1 and TAM-2 were 8.48% (163) and 4.24% (81), respectively. K65R/N and Q151M complex existed in 23 and 4 patients, respectively. K103N/S was the most commonly emerged NNRTI resistance mutation (34.32% (659)). Non-conditional logistic regression analysis showed that, factors associated with high drug resistance were the following: transmitted by mother to child (OR = 9.05, 95% CI: 1.14-72.12), clinical stage was IV (OR = 1.70, 95% CI: 1.09-2.66) and 5-year-treated (OR = 1.59, 95% CI: 1.03-2.47). Factors associated with low drug resistance were the following: 1-year-treated (OR = 0.19, 95% CI: 0.13-0.27). Complex patterns of HIV-1 drug resistance mutations were identified among individuals experiencing failure of first-line antiretroviral therapy in Henan province. Factors associated with high drug resistance were lived in Luohe, Shangqiu, Nanyang, Xinyang, transmitted by mother to child, clinical stage was IV, and 5-year-treated.

BackgroundCryptococcal disease is estimated to be responsible for significant mortality in Sub-Saharan Africa; however, only scarce epidemiology data exists. We sought to evaluate the prevalence of and risk factors for cryptococcal antigenemia in Ethiopia.MethodsConsecutive adult HIV-infected patients from two public HIV clinics in Addis Ababa, Ethiopia were enrolled into the study. A CD4 count ≤200 cells/μl was required for study participation. Patients receiving anti-retroviral therapy (ART) were not excluded. A cryptococcal antigen test was performed for all patients along with an interview, physical exam, and medical chart abstraction. Logistic regression analysis was used to assess risk factors for cryptococcal antigenemia.Results369 HIV-infected patients were enrolled; mean CD4 123 cells/μl and 74% receiving ART. The overall prevalence of cryptococcal antigenemia was 8.4%; 11% in patients with a CD4 count <100 cells/μl, 8.9% with CD4 100 to 150 cells/μl and 5.7% with CD4150-200 cell/μl. 84% of patients with cryptococcal antigenemia were receiving ART. In multivariable analysis, increasing age, self reported fever, CD4 count <100 cells/μl, and site of screening were associated with an increased risk of cryptococcal antigenemia. No individual or combination of clinical symptoms had optimal sensitivity or specificity for cryptococcal antigenemia.ConclusionCryptococcal antigenemia is high in Ethiopia and rapid scale up of screening programs is needed. Screening should be implemented for HIV-infected patients with low CD4 counts regardless of symptoms or receipt of ART. Further study into the effect of location and environment on cryptococcal disease is warranted.

The emergence of HIV-1 drug resistance mutations has mainly been linked to the duration and composition of antiretroviral treatment (ART), as well as the level of adherence. This study reports the incidence and pattern of acquired antiretroviral drug resistance mutations and long-term outcomes of ART in a prospective cohort from Northwest Ethiopia. Two hundred and twenty HIV-1C infected treatment naïve patients were enrolled and 127 were followed-up for up to 38 months on ART. ART initiation and patients’ monitoring was based on the WHO clinical and immunological parameters. HIV viral RNA measurement and drug resistance genotyping were done at baseline (N = 160) and after a median time of 30 (IQR, 27–38) months on ART (N = 127). Viral suppression rate (HIV RNA levels ≤ 400 copies/ml) after a median time of 30 months on ART was found to be 88.2% (112/127), which is in the range for HIV drug resistance prevention suggested by WHO. Of those 15 patients with viral load >400 copies/ml, six harboured one or more drug resistant associated mutations in the reverse transcriptase (RT) region. Observed NRTIs resistance associated mutations were the lamivudine-induced mutation M184V (n = 4) and tenofovir associated mutation K65R (n = 1). The NNRTIs resistance associated mutations were K103N (n = 2), V106M, Y181S, Y188L, V90I, K101E and G190A (n = 1 each). Thymidine analogue mutations and major drug resistance mutations in the protease (PR) region were not detected. Most of the patients (13/15) with virologic failure and accumulated drug resistance mutations had not met the WHO clinical and/or immunological failure criteria and continued the failing regimen. The incidence and pattern of acquired antiretroviral drug resistance mutations is lower and less complex than previous reports from sub Saharan Africa countries. Nevertheless, the data suggest the need for virological monitoring and resistance testing for early detection of failure. Moreover, adherence reinforcement will contribute to improving overall treatment outcomes.