Search Results (18)

HIV drug resistance (HIVDR) presents a significant challenge to antiretroviral therapy (ART) success, particularly in resource-limited settings like Ethiopia. This cross-sectional study investigated viral suppression rates and resistance patterns among patients on second-line ART across 28 Ethiopian health facilities. Blood samples collected from 586 participants were analyzed to measure CD4 count and viral load and assess HIVDR in patients experiencing virological failure (VF) (viral load ≥ 1000 copies/mL). Demographic and clinical data were analyzed using logistic regression to identify factors associated with VF. Results showed that 13.82% of participants experienced VF, with 67.57% of genotyped samples exhibiting at least one drug resistance mutation. Resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) was detected in 48.64%, 64.86%, and 18.92% of cases, respectively. Dual-class resistance was identified in 48.64% of patients, while triple-class resistance was detected in 18.92%. VF was more likely among students and those with CD4 counts below 200 cells/mm³, but less likely in patients on second-line treatment for 12 months or more. Our findings highlight a substantial HIVDR burden among patients on second-line ART with VF, emphasizing the need for comprehensive HIV care, including adherence support, regular viral load monitoring, and HIVDR testing. Full article

Real-world data on HIV drug resistance (HIVDR) after transitioning to tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) are limited. We assessed HIVDR rates and patterns in clients with virological failure (VF) after switching from an NNRTI-based regimen to TLD. A cross-sectional study was conducted in Gaza, Mozambique (August 2021–February 2022), including adults on first-line ART for ≥12 months who transitioned to TLD and had unsuppressed viral load (VL) ≥ 1000 copies/mL six months post-transition. After three adherence counseling sessions, participants with VF underwent genotyping for drug resistance mutations (DRMs) using the Stanford HIVdb Program. Of 717 participants (median age 39.2 years, 70.7% female), 217 (30.2%) had VF, 193 (88.9%) underwent genotyping, with 183 (94.8%) successfully genotyped. Intermediate–high dolutegravir (DTG) resistance was found in 19.6% (36/183). Unsuppressed VL before DTG transition was independently associated with VF (aOR: 2.14). Resistance patterns included 33.3% (12/36; 95% CI: 14.6–46.3) to all three TLD drugs, 55.6% (20/36; 95% CI: 39.3–71.9) to DTG and 3TC, and 11% (4/36; 95% CI: 0.8–21.3) to DTG only. Major drug resistance mutations to DTG included G118R (9.3%), R263K (6.6%), and Q148H/R/K (4.4%). This study highlights the need to consider virologic status before transitioning PLHIV to TLD and suggests that adherence counseling may not prevent resistance in those with unknown or prior VF. Full article

M184V is a single-base mutation in the YMDD domain of reverse transcriptase (RT). The M184V resistance-associated mutation (RAM) is related to virological unresponsiveness to lamivudine (3TC) and emtricitabine (FTC) and induces high-level resistance to these two antiretroviral agents. M184V is rapidly selected in the setting of non-suppressive antiretroviral therapy (ART) and accumulates in the HIV reservoir. There were continuous efforts to evaluate the impact of the M184V mutation on the treatment outcomes in people living with HIV (PLWH). Since 3TC remains an extensively used part of recommended antiretroviral combinations, M184V is commonly detected in patients with virological failure (VF). ART guidelines do not recommend the use of drugs impacted by RAMs as they have been confirmed to comprise a risk factor for VF. However, there is evidence that 3TC/FTC can remain active even in the presence of M184V. Given the potential benefits of 3TC in ART combinations, the investigation of M184V remains of high interest to clinicians and researchers, especially in certain regions with limited resources, and especially for its unusual effects. This is a review of the literature on the challenges in treating both naïve and experienced individuals carrying the M184V mutation, including virological failure, virological suppression, and resistance to ART. Full article

We evaluated subsequent virologic outcomes in individuals experiencing low-level virem ia (LLV) on dolutegravir (DTG)-based first-line antiretroviral therapy (ART) in Botswana. We used a national dataset from 50,742 adults who initiated on DTG-based first-line ART from June 2016–December 2022. Individuals with at least two viral load (VL) measurements post three months on DTG-based first-line ART were evaluated for first and subsequent episodes of LLV (VL:51–999 copies/mL). LLV was sub-categorized as low-LLV (51–200 copies/mL), medium-LLV (201–400 copies/mL) and high-LLV (401–999 copies/mL). The study outcome was virologic failure (VF) (VL ≥ 1000 copies/mL): virologic non-suppression defined as single-VF and confirmed-VF defined as two-consecutive VF measurements after an initial VL < 1000 copies/mL. Cox regression analysis identified predictive factors of subsequent VF. The prevalence of LLV was only statistically different at timepoints >6–12 (2.8%) and >12–24 (3.9%) (p-value < 0.01). LLV was strongly associated with both virologic non-suppression (adjusted hazards ratio [aHR] = 2.6; 95% CI: 2.2–3.3, p-value ≤ 0.001) and confirmed VF (aHR = 2.5; 95% CI: 2.4–2.7, p-value ≤ 0.001) compared to initially virally suppressed PLWH. High-LLV (HR = 3.3; 95% CI: 2.9–3.6) and persistent-LLV (HR = 6.6; 95% CI: 4.9–8.9) were associated with an increased hazard for virologic non-suppression than low-LLV and a single-LLV episode, respectively. In a national cohort of PLWH on DTG-based first-line ART, LLV > 400 copies/mL and persistent-LLV had a stronger association with VF. Frequent VL testing and adherence support are warranted for individuals with VL > 50 copies/mL. Full article

The continuous pharmacological advances in antiretroviral treatment (ART) and the increasing understanding of HIV drug resistance has led to a change in the paradigm of ART optimization in the setting of the viral suppression of treatment-experienced patients with the emerging evidence of the effectiveness and safety of dual therapies. The aim of this study is to determine the antiviral efficacy and safety of switching to Dolutegravir + Lamivudine in people living with HIV, and to analyze the rate of patients with virologic failure (VF). A total of 200 patients were included with a median age of 51 years, 189 cells/µL of nadir CD4+, 13 years on ART and four previous ART regimens. Among the 168 patients who completed a follow-up at 48 weeks, a total of five VFs occurred, resulting in a 2.98% (5/168) VF rate. The results of the intention-to-treat analysis were a VF rate of 2.54% (5/197), and the rate of patients/year with viral suppression was 98.3% (298/303) in the observed data analysis. We observed a significant improvement in mean CD4 lymphocytes, the CD4/CD8 ratio and lipid profiles. The optimization of ART to DTG plus 3TC is a cost-effective switch option for treatment-experienced HIV patients, and also improves their lipid profiles. Full article

Despite the progress in contemporary antiretroviral therapy (ART) and the continuous changes in treatment guidelines, virological failure (VF) is still an ongoing concern. The goal of this study was to assess factors related to VF after first-line ART. A longitudinal cohort retrospective study of individuals on first-line ART diagnosed with HIV-1 in 2010–2018 and followed-up for a median of two years was conducted. Demographics, baseline and longitudinal CD4 counts, treatment regimens, adherence and VF were recorded. The Cox proportional hazards regression and mixed models were used. A cohort of 1130 patients were included. Overall, 80% were males and 62% were Israeli-born individuals. Compared to individuals diagnosed in 2010–2014, when treatment was initiated according to CD4 levels, those diagnosed in 2015–2018 were older and had lower baseline CD4 counts. VF was recorded in 66 (5.8%) patients. Diagnosis with CD4 <200 cells/mmᶟ with AIDS-defining conditions (HR = 2.75, 95%CI:1.52–4.97, p < 0.001) and non-integrase strand transfer inhibitor regimens (non-INSTI, HR = 1.80, 95%CI:1.01–3.24, p = 0.047) increased VF risk. No impact of baseline resistance was observed. We concluded that the early detection of HIV-1 infection and usage of INSTI-based regimens are recommended to reduce VF. Full article

Increasing HIV drug resistance (DR) among children with HIV (CHIV) on antiretroviral treatment (ART) is concerning. CHIV ages 1–14 years enrolled from March 2019 to December 2020 from five facilities in Kisumu County, Kenya, were included. Children were randomized 1:1 to control (standard-of-care) or intervention (point-of-care viral load (POC VL) testing every three months with targeted genotypic drug resistance testing (DRT) for virologic failure (VF) (≥1000 copies/mL)). A multidisciplinary committee reviewed CHIV with DRT results and offered treatment recommendations. We describe DR mutations and present logistic regression models to identify factors associated with clinically significant DR. We enrolled 704 children in the study; the median age was 9 years (interquartile range (IQR) 7, 12), 344 (49%) were female, and the median time on ART was 5 years (IQR 3, 8). During the study period, 106 (15%) children had DRT results (84 intervention and 22 control). DRT detected mutations associated with DR in all participants tested, with 93 (88%) having major mutations, including 51 (54%) with dual-class resistance. A history of VF in the prior 2 years (adjusted odds ratio (aOR) 11.1; 95% confidence interval (CI) 6.3, 20.0) and less than 2 years on ART at enrollment (aOR 2.2; 95% CI 1.1, 4.4) were associated with increased odds of major DR. DR is highly prevalent among CHIV on ART with VF in Kenya. Factors associated with drug resistance may be used to determine which children should be prioritized for DRT. Full article

Background: Dolutegravir (DTG)-based antiretroviral therapy (ART) rarely leads to virological failure (VF) and drug resistance in integrase strand transfer inhibitor (INSTI)-naïve persons living with HIV (PLWH). As a result, limited data are available on INSTI-associated drug resistance mutations (DRMs) selected by DTG-containing ART regimens. Methods: We reviewed studies published through July 2023 to identify those reporting emergent major INSTI-associated DRMs in INSTI-naïve PLWH receiving DTG and those containing in vitro DTG susceptibility results using a standardized assay. Results: We identified 36 publications reporting 99 PLWH in whom major nonpolymorphic INSTI-associated DRMs developed on a DTG-containing regimen and 21 publications containing 269 in vitro DTG susceptibility results. DTG-selected DRMs clustered into four largely non-overlapping mutational pathways characterized by mutations at four signature positions: R263K, G118R, N155H, and Q148H/R/K. Eighty-two (82.8%) viruses contained just one signature DRM, including R263K (n = 40), G118R (n = 24), N155H (n = 9), and Q148H/R/K (n = 9). Nine (9.1%) contained ≥1 signature DRM, and eight (8.1%) contained just other DRMs. R263K and G118R were negatively associated with one another and with N155H and Q148H/K/R. R263K alone conferred a median 2.0-fold (IQR: 1.8–2.2) reduction in DTG susceptibility. G118R alone conferred a median 18.8-fold (IQR:14.2–23.4) reduction in DTG susceptibility. N155H alone conferred a median 1.4-fold (IQR: 1.2–1.6) reduction in DTG susceptibility. Q148H/R/K alone conferred a median 0.8-fold (IQR: 0.7–1.1) reduction in DTG susceptibility. Considerably higher levels of reduced susceptibility often occurred when signature DRMs occurred with additional INSTI-associated DRMs. Conclusions: Among INSTI-naïve PLWH with VF and treatment emergent INSTI-associated DRMs, most developed one of four signature DRMs, most commonly R263K or G118R. G118R was associated with a much greater reduction in DTG susceptibility than R263K. Full article

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. Full article

Background: Clinical trials and real-life studies have granted the efficacy and safety of dolutegravir and lamivudine (DTG/3TC) in naïve and experienced people living with HIV (PLWH), but there are no long-term data in elderly people. We herein describe our real-life cohort of PLWH who were ≥65 years of age (PLWH ≥ 65) who started or were switched to DTG/3TC, single-tablet regimen, or DTG plus 3TC. Methods: We considered laboratory/clinical parameter changes from the baseline to the last follow-up time point available for each person by the paired Wilcoxon test and analyzed factors associated with virological failure (VF) and discontinuation. Results: We included 112 PLWH with a median age of 66 (IQR: 65–70) years, 77.6% males; 84.8% of people had multimorbidity, 34.8% were on polypharmacy, and only 5.4% were naïve to treatment. Reasons to be switched to DTG/3TC were: abacavir removal (38.7%), treatment simplification (33.1%), and PI discontinuation (28.2%). The median treatment durability was 6 (IQR: 5.4–7) years. No significant changes were detected in metabolic, renal, immunological, or cardiovascular biomarkers during follow-up. HIV RNA undetectability was maintained in 104 (92.8%) individuals for whom follow-up evaluation was available. We observed eight discontinuations (two deaths, two VFs, two early intolerances, one significant weight gain, and one switch to long-acting therapy). No factors were significantly associated with VF or discontinuation. Conclusions: This is the first study on DTG/3TC in PLWH ≥ 65 with a follow-up longer than 5 years. DTG/3TC was found to be safe and effective, neutral on metabolic parameters, and with a low discontinuation rate for toxicity or VF. Full article

Low-frequency mutations associated with drug resistance have been related to virologic failure in subjects with no history of pre-treatment and recent HIV diagnosis. In total, 78 antiretroviral treatment (ART)-naïve subjects with a recent HIV diagnosis were selected and followed by CD4+ T lymphocytes and viral load tests to detect virologic failure. We sequenced the basal samples retrospectively using next-generation sequencing (NGS), looking for low-frequency mutations that had not been detected before using the Sanger sequencing method (SSM) and describing the response to ART. Twenty-two subjects developed virologic failure (VF), and thirteen of them had at least one drug-resistance mutation associated with Reverse Transcriptase Inhibitors (RTI) and Protease Inhibitors (PIs) at frequency levels ≤ 1%, not detected previously in their basal genotyping test. No resistance mutations were observed to Integrase Strand Transfer Inhibitors (INSTIs). We identified a possible cause of VF in ART-naïve subjects with low-frequency mutations detected. To our knowledge, this is the first evaluation of pre-existing drug resistance for HIV-1 minority variants carried out on ART-naïve people living with HIV/AIDS (PLWHA) by analyzing the HIV-1 pol gene using NGS in the country. Full article

Background: Since limited data are available, we aimed to compare the efficacy and durability of dolutegravir and darunavir in advanced naïve patients. Methods: Retrospective multicenter study including AIDS- or late-presenting (def. CD4 ≤ 200/µL) HIV-infected patients starting dolutegravir or ritonavir/cobicistat-boosted darunavir+2NRTIs. Patients were followed from the date of first-line therapy initiation (baseline, BL) to the discontinuation of darunavir or dolutegravir, or for a maximum of 36 months of follow-up. Results: Overall 308 patients (79.2% males, median age 43 years, 40.3% AIDS-presenters, median CD4 66 cells/µL) were enrolled; 181 (58.8%) and 127 (41.2%) were treated with dolutegravir and darunavir, respectively. Incidence of treatment discontinuation (TD), virological failure (VF, defined as a single HIV-RNA > 1000 cp/mL or two consecutive HIV-RNA > 50 cp/mL after 6 months of therapy or after virological suppression had been achieved), treatment failure (the first of TD or VF), and optimal immunological recovery (defined as CD4 ≥ 500/µL + CD4 ≥ 30% + CD4/CD8 ≥ 1) were 21.9, 5.2, 25.6 and 1.4 per 100 person-years of follow-up, respectively, without significant differences between dolutegravir and darunavir (p > 0.05 for all outcomes). However, a higher estimated probability of TD for central nervous system (CNS) toxicity (at 36 months: 11.7% vs. 0%, p = 0.002) was observed for dolutegravir, whereas darunavir showed a higher probability of TD for simplification (at 36 months: 21.3% vs. 5.7%, p = 0.046). Conclusions: Dolutegravir and darunavir showed similar efficacy in AIDS- and late-presenting patients. A higher risk of TD due to CNS toxicity was observed with dolutegravir, and a higher probability of treatment simplification with darunavir. Full article

Background: The high effectiveness and safety of the two-drug (2DRs) strategy using dolutegravir (DTG) plus lamivudine (3TC) have led to international guidelines recommending their use for treatment-naive HIV patients. In virologically suppressed patients, de-escalating from 3DRs to DTG plus either rilpivirine (RPV) or 3TC has shown high rates of virological suppression. Objectives: This study aimed to compare the real-life data of two multicenter Spanish cohorts of PLWHIV treated with DTG plus 3TC (SPADE-3) or RPV (DORIPEX) as a switch strategy, not only in terms of virological suppression, safety, and durability but also in terms of immune restoration. The primary endpoint was the percentage of patients with virological suppression on DTG plus 3TC and DTG plus RPV at weeks 24 and 48. The secondary outcomes included the proportion of patients who experienced the protocol-defined loss of virological control by week 48; changes in immune status in terms of CD4+ and CD8+ T lymphocyte counts and the CD4+/CD8+ ratio; the rate, incidence, and reasons for discontinuation of treatment over the 48-week study period; and safety profiles at weeks 24 and 48. Methods: We conducted a retrospective, observational, multicenter study of 638 and 943 virologically suppressed HIV-1-infected patients in two cohorts who switched to 2DRs with DTG plus RPV or DTG plus 3TC. Results: The most frequent reasons for starting DTG-based 2DRs were treatment simplification/pill burden or drug decrease. The virological suppression rates were 96.9%, 97.4%, and 99.1% at weeks 24, 48, and 96, respectively. The proportion of patients with virological failure over the 48-week study period was 0.01%. Adverse drug reactions were uncommon. Patients treated with DTG+3TC increased CD4, CD8, and CD4/CD8 parameters at 24 and 48 weeks. Conclusions: We conclude that DTG-based 2DRs (combined with 3TC or RPV) in clinical practice were effective and safe as a switching strategy, with a low VF and high viral suppression rates. Both regimens were well tolerated, and ADR rates were low, including neurotoxicity and induced treatment discontinuations. Full article

In this observational study, we aimed to evaluate whether bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) administered 5 or 4 days a week is able to maintain viral suppression in people living with HIV (PLHIV). We enrolled 85 patients who initiated intermittent B/F/TAF between 28 November 2018 and 30 July 2020: median (IQR) age 52 years (46–59), duration of virological suppression 9 years (3–13), CD4 633/mm³ (461–781). Median follow-up was 101 weeks (82–111). The virological success rate (no virological failure [VF]: confirmed plasma viral load [pVL] ≥ 50 copies/mL, or single pVL ≥ 200 copies/mL, or ≥50 copies/mL with ART change) was 100% (95%CI 95.8–100) and the strategy success rate (pVL < 50 copies/mL with no ART regimen change) was 92.9% (95%CI 85.3–97.4) at W48. Two VF occurred at W49 and W70, in 2 patients self-reporting poor compliance. No resistance mutation emerged at time of VF. Eight patients presented strategy discontinuation for adverse events. There was no significant change in the CD4 count, residual viraemia rate, neither body weight during follow-up, but a slight increase in CD4/CD8 ratio (p = 0.02). In conclusion, our findings suggest that B/F/TAF administered 5 or 4 days a week could maintain the control of HIV replication in virologically suppressed PLHIV while reducing cumulative exposition of ART. Full article

Background: Dolutegravir (DTG)-based first-line regimens have shown superior efficacy versus darunavir (DRV)-based ones in randomized trials. We compared these two strategies in clinical practice, particularly considering the role of pre-treatment drug resistance mutations (DRMs) and of the HIV-1 subtype. Materials and methods: The multicenter Antiretroviral Resistance Cohort Analysis (ARCA) database was queried to identify HIV-1-positive patients starting a first-line therapy with 2NRTIs plus either DTG or DRV between 2013 and 2019. Only adult (≥18 years) patients with a genotypic resistance test (GRT) prior to therapy and with HIV-1 RNA ≥1000 copies/mL were selected. Through multivariable Cox regressions, we compared DTG- versus DRV-based regimens in the time to virological failure (VF) stratifying for pre-treatment DRMs and the viral subtype. Results: A total of 649 patients was enrolled, with 359 (55.3%) and 290 (44.7) starting DRV and DTG, respectively. In 11 months of median follow-up time, there were 41 VFs (8.4 in 100 patient-years follow-up, PYFU) and 15 VFs (5.3 per 100 PYFU) in the DRV and DTG groups, respectively. Compared with a fully active DTG-based regimen, the risk of VF was higher with DRV (aHR 2.33; p = 0.016), and with DTG-based regimens with pre-treatment DRMs to the backbone (aHR 17.27; p = 0.001), after adjusting for age, gender, baseline CD4 count and HIV-RNA, concurrent AIDS-defining event and months since HIV diagnosis. Compared with patients harboring a B viral subtype and treated with a DTG-based regimen, patients on DRV had an increased risk of VF, both in subtype B (aHR 3.35; p = 0.011), C (aHR 8.10; p = 0.005), CRF02-AG (aHR 5.59; p = 0.006) and G (aHR 13.90; p < 0.001); DTG also demonstrated a reduced efficacy in subtypes C (versus B, aHR 10.24; p = 0.035) and CRF01-AE (versus B; aHR 10.65; p = 0.035). Higher baseline HIV-RNA and a longer time since HIV diagnosis also predicted VF. Conclusions: In line with randomized trials, DTG-based first-line regimens showed an overall superior efficacy compared with DRV-based regimens. GRT may still play a role in identifying patients more at risk of VF and in guiding the choice of an antiretroviral backbone. Full article