First-line Antiretroviral Therapy Research Articles

Geospatial and temporal mapping of detectable HIV-1 viral loads amid dolutegravir rollout in KwaZulu-Natal, South Africa.

South Africa rolled out dolutegravir (DTG) as first-line antiretroviral therapy (ART) in December 2019 to overcome high rates of pretreatment non-nucleoside reverse transcriptase inhibitor drug resistance. In the context of transition to DTG-based ART, this study spatiotemporally analysed detectable HIV viral loads (VLs) prior to- and following DTG rollout in public-sector healthcare facilities in KwaZulu-Natal (KZN) province, the epicentre of the HIV epidemic in South Africa. We retrospectively curated a HIV VL database using de-identified routine VL data obtained from the National Health Laboratory Service for the period January 2018 to June 2022. We analysed trends in HIV viraemia and mapped median log10 HIV VLs per facility on inverse distance weighted interpolation maps. We used Getis-Ord Gi* hotspot analysis to identify geospatial HIV hotspots. We obtained 7,639,978 HIV VL records from 736 healthcare facilities across KZN, of which 1,031,171 (13.5%) had detectable VLs (i.e., VLs ≥400 copies/millilitre (mL)). Of those with detectable VLs, we observed an overall decrease in HIV VLs between 2018 and 2022 (median 4.093 log10 copies/mL; 95% confidence interval (CI) 4.087-4.100 to median 3.563 log10 copies/mL; CI 3.553-3.572), p<0.01 (median test). The downward trend in proportion of HIV VLs ≥1000 copies/mL over time was accompanied by an inverse upward trend in the proportion of HIV VLs between 400 and 999 copies/mL. Moreover, specific coastal and northern districts of KZN had persistently higher VLs, with emergent hotspots demonstrating spatial clustering of high median log10 HIV VLs. The overall decrease in HIV VLs over time shows good progress towards achieving UNAIDS 95-95-95 targets in KZN, South Africa. The DTG-transition has been associated with a reduction in VLs, however, there is a need for pre-emptive monitoring of low-level viraemia. Furthermore, our findings highlight that specific districts will need intensified HIV care despite DTG rollout.

Population Effectiveness of Dolutegravir Implementation in Uganda - A Prospective Observational Cohort Study (DISCO): 48-week Results.

Tenofovir/lamivudine/dolutegravir (TLD) is the preferred first-line antiretroviral therapy (ART) regimen for people with HIV (PWH), including those who were previously virologically suppressed on non-nucleoside reverse transcriptase inhibitors (NNRTIs). We sought to estimate the real-world effectiveness of the TLD transition in Ugandan public-sector clinics. We conducted a prospective cohort study of PWH ≥18 years who were transitioned from NNRTI-based ART to TLD. Study visits were conducted on the day of TLD transition and 24- and 48- weeks later. The primary endpoint was viral suppression (<200 copies/mL) at 48-weeks. We collected blood for retrospective viral load (VL) assessment and conducted genotypic resistance tests for specimens with VL >500 copies/mL. We enrolled 500 participants (median age of 47 years; 41% women). At 48-weeks after TLD transition, 94% of participants were in care with a VL <200 copies/mL (n = 469/500); 2% (n = 11/500) were lost from care or died; and only 2% (n = 9/500) had a VL >500 copies/mL. No incident resistance to DTG was identified. Few participants (2%, n = 9/500) discontinued TLD due to adverse events. High rates of viral suppression, high tolerability, and lack of emergent drug resistance support use of TLD as the preferred first-line regimen in the region.

Effectiveness of double-dose dolutegravir in people receiving rifampin-based tuberculosis treatment: an observational, cohort study of people with HIV from six countries.

Tenofovir-lamivudine-dolutegravir (TLD) is the preferred first-line antiretroviral therapy (ART) regimen. An additional 50 mg dose of dolutegravir (TLD + 50) is required with rifampin-containing tuberculosis (TB) co-treatment. There are limited data on the effectiveness of TLD + 50 in individuals with TB/HIV. Prospective, observational cohort study at 12 sites in Haiti, Kenya, Malawi, South Africa, Uganda, Zimbabwe. Participants starting TLD and rifampin-containing TB treatment were eligible. Primary outcome was HIV-1 RNA ≤1000 copies/mL at end of TB treatment. We enrolled 91 participants with TB/HIV: 75 (82%) ART-naïve participants starting TLD after a median 15 days on TB treatment, 10 (11%) ART-naïve participants starting TLD and TB treatment, 5 (5%) starting TB treatment after a median 3.3 years on TLD, and 1 (1%) starting TB treatment and TLD after changing from efavirenz/lamivudine/tenofovir. Median age was 37 years, 35% female, median CD4 count 120 cells/mm3 (IQR 50-295), 87% had HIV-1 RNA >1000 copies/mL. Two participants died during TB treatment. Among 89 surviving participants, 80 were followed to TB treatment completion, including 7 who had no HIV-1 RNA result due to missed visits. Primary virologic outcome was assessed in 73 participants, of whom 69 (95%, 95% CI 89-100%) had HIV-1 RNA ≤1000 copies/mL. No dolutegravir resistance mutations were detected among four participants with HIV-1 RNA >1000 copies/mL. In routine programmatic settings, concurrent rifampin-containing TB treatment and TLD + 50 was feasible, well-tolerated, and achieved high rates of viral suppression in a cohort of predominantly ART-naïve people with TB/HIV.

The Incidence of Type 2 Diabetes Mellitus and Weight Gain in People Living with HIV Receiving a Dolutegravir-Based Antiretroviral Therapy in Addis Ababa, Ethiopia: A Pilot Single-Arm Historical Cohort Study

The Incidence of Type 2 Diabetes Mellitus and Weight Gain in People Living with HIV Receiving a Dolutegravir-Based Antiretroviral Therapy in Addis Ababa, Ethiopia: A Pilot Single-Arm Historical Cohort Study

Factors Affecting Virological Failure in Children Receiving First-Line Antiretroviral Therapy in Ethiopian Healthcare Facilities: A Retrospective Analysis.

The causes of virological failure are poorly recognized and investigated. This study aimed to identify determinant factors of viral failure in children taking first-line ART at a randomly selected federal hospital in Addis Ababa, Ethiopia. A facility-based unmatched case-control study was carried out from May 10, 2022, to July 20, 2022, G.C. among HIV-infected children on first-line antiretroviral therapy. There were 209 HIV-positive youngsters in the study's overall sample size, comprising 53 cases and 156 controls. Data was gathered by chart review using an organized checklist in English. The data were entered using Epi-data 4.2 and exported into SPSS version 24 for analysis. The relationship between each explanatory variable and the result variable was described using both bivariate and multivariate analysis. An adjusted odds ratio with 95% confidence intervals was conducted, and a p-value <0.05 was considered statistically significant. Being male (AOR= 4.504; 95% CI: 1.498, 13.539), duration on ART exceeding 47 months (AOR=40.6; 95% CI:9.571,172.222), fair and poor drug adherence (AOR=16.348; 95% CI:4.690,56.990), missed clinical appointments (AOR = 3.177; 95% CI: 1.100-9.174), and baseline WHO clinical stage 4 disease (AOR = 6.852; 95% CI: 1.540-30.49) were associated with an increased risk of virological failure. Conversely, a history of drug change and a CD4 count ranging from 250 to 500 cells/mm3 were significantly protective factors (AOR = 0.071; 95% CI: 0.024-0.214 and AOR=0.118; 95% CI: 0.030, 0.464, respectively). Being male, duration on ART >47 months, fair and poor adherence, missed clinical appointments, and baseline WHO Stage 4 are factors that increase the odds of virological failure. History of ART Drug change and a CD4 count between 250 and 500 cells/mm3 are factors that decrease the odds of virological failure.

Low-Level Viremia among Adults Living with HIV on Dolutegravir-Based First-Line Antiretroviral Therapy Is a Predictor of Virological Failure in Botswana.

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.

Effect of dolutegravir on ferritin, iron, and C-reactive protein among people living with HIV and co-infections.

Dolutegravir-based antiretroviral therapy (ART) is currently recommended as the preferred first-line ART in many resource-limited settings. However, little is known about the clinical experience of dolutegravir within a context of prevalent co-infections. To assess virological outcomes, and iron, ferritin and C-reactive protein (CRP) levels among people living with HIV (PLWH) and co-infections after initiating or re-initiating dolutegravir-based ART. This prospective study was conducted between August 2022 and August 2023. Study participants were recruited from an HIV opportunistic infection clinic. Screening for co-infections (syphilis, hepatitis B virus, cytomegalovirus and herpes simplex virus) was performed at baseline, prior to ART initiation. Plasma HIV viral load (VL), CRP, ferritin and iron levels were measured at baseline and at the 6-month follow-up period. A total of 100 participants (51 women and 49 men) were enrolled in this study. The median age of the participants was 39 years. The prevalence of co-infections was 30%. Prior to ART initiation, participants with co-infections had higher VL, CRP and ferritin, and lower iron levels, compared to those without co-infections (P < 0.001). Following 6 months of ART, CRP and ferritin levels decreased while iron levels increased, regardless of co-infection status. However, CRP and ferritin remained significantly higher in those with co-infections despite similar and high rates of virologic suppression in both groups. The presence of co-infections in PLWH is associated with higher VL and with chronic inflammation. Ferritin and CRP decreased on dolutegravir-based ART but remained higher in people with co-infections despite similar rates of virologic suppression.

Estimating the cost due to resistance against antiretroviral therapies in individuals with HIV: Perspective of the Kingdom of Saudi Arabia

ObjectivesThe emergence of resistance to antiretroviral therapy (ART) has an impact on the cost of HIV care. This study aimed to estimate the direct and indirect costs associated with the first episode of drug resistance in individuals with HIV receiving first-line ART. MethodsWe developed a cost calculator to estimate the cost of drug resistance over a period of 12 months in the Kingdom of Saudi Arabia. The model inputs (estimated using expert opinion and publicly available sources) included costs associated with testing for resistance, adverse events of a new regimen, and indirect costs. ResultsThe direct and indirect medical expenses for the year resistance developed were 6980 Saudi Arabian riyal (SAR) and SAR 2862, respectively. The addition of the cost of new ARTs would increase the total annual costs (between SAR 5174 and SAR 34,265 per patient). One-way sensitivity analysis also reported significant impact of initial and switching therapies used after resistance develops on the total costs of resistance per year. ConclusionsThere is a significant cost burden associated with drug resistance, which emphasizes the need to select an appropriate initial ART regimen that has a strong genetic barrier and conduct pre-treatment resistance tests (if possible).

Cardiometabolic Differences in People Living with HIV Receiving Integrase Strand Transfer Inhibitors Compared to Non-nucleoside Reverse Transcriptase Inhibitors: Implications for Current ART Strategies.

In people living with HIV (PLHIV), integrase strand transfer inhibitors (INSTIs) are part of the first-line combination antiretroviral therapy (cART), while non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens are alternatives. Distinct cART regimens may variably influence the risk for non-AIDS comorbidities. We aimed to compare the metabolome and lipidome of INSTI and NNRTI-based regimens. The 2000HIV study includes asymptomatic PLHIV (n = 1646) on long-term cART, separated into a discovery cohort with 730 INSTI and 617 NNRTI users, and a validation cohort encompassing 209 INSTI and 90 NNRTI users. Baseline plasma samples from INSTI and NNRTI users were compared using mass spectrometry-based untargeted metabolomic (n = 500) analysis. Perturbed metabolic pathways were identified using MetaboAnalyst software. Subsequently, nuclear magnetic resonance spectroscopy was used for targeted lipoprotein and lipid (n = 141) analysis. Metabolome homogeneity was observed between the different types of INSTI and NNRTI. In contrast, higher and lower levels of 59 and 45 metabolites, respectively, were found in the INSTI group compared to NNRTI users, of which 77.9% (81/104) had consistent directionality in the validation cohort. Annotated metabolites belonged mainly to 'lipid and lipid-like molecules', 'organic acids and derivatives' and 'organoheterocyclic compounds'. In pathway analysis, perturbed 'vitamin B1 (thiamin) metabolism', 'de novo fatty acid biosynthesis', 'bile acid biosynthesis' and 'pentose phosphate pathway' were detected, among others. Lipoprotein and lipid levels in NNRTIs were heterogeneous and could not be compared as a group. INSTIs compared to individual NNRTI types showed that HDL cholesterol was lower in INSTIs compared to nevirapine but higher in INSTIs compared to doravirine. In addition, LDL size was lower in INSTIs and nevirapine compared to doravirine. NNRTIs show more heterogeneous cardiometabolic effects than INSTIs, which hampers the comparison between these two classes of drugs. Targeted lipoproteomic and lipid NMR spectroscopy showed that INSTI use was associated with a more unfavorable lipid profile compared to nevirapine, which was shifted to a more favorable profile for INSTI when substituting nevirapine for doravirine, with evidently higher fold changes. The cardiovascular disease risk profile seems more favorable in INSTIs compared to NNRTIs in untargeted metabolomic analysis using mass-spectrometry.

Viremia and HIV Drug Resistance Among People Receiving Dolutegravir Versus Efavirenz-Based First-Line Antiretroviral Therapy.

Viremia and HIV Drug Resistance Among People Receiving Dolutegravir Versus Efavirenz-Based First-Line Antiretroviral Therapy.

Incidence and predictors of virological failure among children receiving first-line anti-retroviral treatment in public comprehensive specialized hospitals found in Northeast Ethiopia: a retrospective follow-up study.

Despite anti-retroviral treatment coverage in resource-limited countries being highly appreciated, the occurrence of first-line virological failure remains a priority agenda. Therefore, this study serves as an input for evidence of virological failure among children. This study aimed to assess the incidence and predictors of virological failure among children receiving first-line anti-retroviral treatment in public comprehensive specialized hospitals found in Northeast Ethiopia through a retrospective follow-up study. A multicenter institution-based retrospective follow-up study was conducted on the medical records of 481 human immunodeficiency virus (HIV)-infected children who were on first-line anti-retroviral therapy from 1 January 2017 to 31 December 2021. Data were retrieved from 15 May to 15 June 2022 at three public comprehensive specialized hospitals. Study participants were recruited using a simple random sampling technique. STATA-14 was used to analyze the data, which was entered using EpiData version 4.6.2.0. The Kaplan-Meier estimator was used to estimate the survival. Both bivariable and multivariable Cox regression models were fitted to identify predictors. Finally, adjusted hazards ratios (AHRs) with 95% confidence intervals (CIs) were computed, and variables with a P-value of <0.05 were considered statistically significant predictors of virological failure. A total of 481 children records were included in the final analysis, with an observed follow-up period of 16,379 person-months. Among these, 60 (12.47%) had developed virological failure, resulting in an overall incidence density rate of 3.67 (95% CI; 2.84, 4.73) per 1000 person-month observations. The hazards of virological failure (VF) among children were found to be increased by being in recent WHO stages III and IV (AHR = 3.688; 95% CI: 1.449-6.388), poor adherence to anti-retroviral treatment (ART) (AHR = 3.506; 95% CI: 1.711-7.234), and living in a rural environment (AHR = 5.013; 95% CI: 1.958-8.351). Conversely, the hazard of VF was reduced by 60% when the age of caregivers was less than 40 years (AHR = 0.405; 0.003-0.449). The incidence rate of virological failure was relatively high. Living in a rural area, poor adherence to ART, being in a recent advanced WHO clinical stage, and having a caregiver of 40 years of age or older were all independent predictors of virological failure in children. Patients or parents (caregivers) need to be aware of the importance of strictly adhering to treatment regimens to prevent virological failure.

Relationship Between Tenofovir Diphosphate Concentrations in Dried Blood Spots and Virological Outcomes After Initiating Tenofovir-Lamivudine-Dolutegravir as First-Line or Second-Line Antiretroviral Therapy.

Tenofovir diphosphate (TFV-DP) concentration in dried blood spots is a marker of long-term adherence. We investigated the relationship between TFV-DP concentrations and virological outcomes in participants initiating tenofovir-lamivudine-dolutegravir (TLD) as first-line or second-line antiretroviral therapy. Three primary care clinics in Khayelitsha, Cape Town, South Africa. We conducted a post hoc analysis of 2 randomized controlled trials of participants initiating TLD. TFV-DP concentrations and viral loads were measured at 12, 24, and 48 weeks. Multivariable logistic regression was performed to assess the association with virological suppression (<50 copies/mL) per natural logarithm increase in TFV-DP concentration. Generalized estimating equations with logit link were used to assess associations with virological rebound. The Akaike Information Criterion and Quasi-likelihood Information Criteria were used to compare models built on continuous TFV-DP data to 4 previously defined concentration categories. We included 294 participants in the analysis, 188 (64%) of whom initiated TLD as second-line therapy. Adjusted odds ratios (95% CIs) of virological suppression were 2.12 (1.23, 3.75), 3.11 (1.84, 5.65), and 4.69 (2.81, 8.68) per natural logarithm increase in TFV-DP concentration at weeks 12, 24, and 48, respectively. In participants with virological suppression at week 12, the adjusted odds ratio for remaining virologically suppressed was 3.63 (95% CI: 2.21 to 5.69) per natural logarithm increase in TFV-DP concentration. Models using continuous TFV-DP data had lower Akaike Information Criterion and Quasi-likelihood Information Criteria values than those using categorical data for predicting virological outcomes. TFV-DP concentrations in dried blood spots exhibit a dose-response relationship with viral load. Analyzing TFV-DP concentrations as continuous variables rather than conventional categorization may be appropriate.

Voluntariness of consent in paediatric HIV clinical trials: a mixed-methods, cross-sectional study of participants in the CHAPAS-4 and ODYSSEY trials in Uganda

ObjectivesTo examine the voluntariness of consent in paediatric HIV clinical trials and the associated factors.DesignMixed-methods, cross-sectional study combining a quantitative survey conducted concurrently with indepth interviews.Setting and participantsFrom January 2021...

Determinants of early change in serum creatinine after initiation of dolutegravir-based antiretroviral therapy in South Africa.

Dolutegravir increases serum creatinine by inhibiting its renal tubular secretion and elimination. We investigated determinants of early changes in serum creatinine in a southern African cohort starting first-line dolutegravir-based antiretroviral therapy (ART). We conducted a secondary analysis of data from participants in a randomized controlled trial of dolutegravir, emtricitabine and tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) (ADVANCE, NCT03122262). We assessed clinical, pharmacokinetic and genetic factors associated with change in serum creatinine from baseline to Week 4 using linear regression models adjusted for age, sex, baseline serum creatinine, HIV-1 RNA concentration, CD4 T-cell count, total body weight and co-trimoxazole use. We included 689 participants, of whom 470 had pharmacokinetic data and 315 had genetic data. Mean change in serum creatinine was 11.3 (SD 9.9)μmol.L-1. Factors that were positively associated with change in serum creatinine at Week 4 were increased log dolutegravir area under the 24-h concentration-time curve (change in creatinine coefficient [β] = 2.78 μmol.L-1 [95% confidence interval (CI) 0.54, 5.01]), TDF use (β = 2.30 [0.53, 4.06]), male sex (β = 5.20 [2.92, 7.48]), baseline serum creatinine (β = -0.22 [-0.31, -0.12]) and UGT1A1 rs929596 A→G polymorphism with a dominant model (β = -2.33 [-4.49, -0.17]). The latter did not withstand correction for multiple testing. Multiple clinical and pharmacokinetic factors were associated with early change in serum creatinine in individuals initiating dolutegravir-based ART. UGT1A1 polymorphisms may play a role, but further research on genetic determinants is needed.

Dolutegravir based therapy showed CD4+ T cell count recovery and viral load suppression among ART naïve people living with HIV AIDS: a pilot evaluation

Recently, dolutegravir (DTG)-based combined therapy, a more effective and safer first-line antiretroviral therapy (ART), has been recommended by the World Health Organization for the treatment of Human Immunodeficiency Virus (HIV) since July 2018. However, its effectiveness in CD4+ T-cells count recovery and viral load suppression has not been studied yet in Ethiopia, where HIV is endemic. Therefore, we aimed to conduct a pilot assessment on the effect of DTG-based therapy on CD4+ T-cell count and viral load count among people living with HIV (PLWH) in Ethiopia. A longitudinal prospective cohort study was conducted from July 2020 to February 2021. 109 PLWH who are ART naive but plan to initiate DTG-based therapy were recruited. HIV viral ribonucleic acid (RNA) copies were determined using polymerase chain reaction. To compute the difference in viral load and CD4+ T-cell counts between the baseline, 3rd, and 6th months, a Friedman test was used. The study included 109 PLWH who had never received antiretroviral medication. Participants taking DTG-based treatment showed significantly decreasing median (IQR) values of viral load count (copies/mL) from 446,812 (237649.5–732994.5) at baseline to 34 (23.5–46) at 3 months and 0.0 (0–19) at 6 months of treatment follow-up. Although the treatment increases the proportion of participants with HIV-1 RNA 50 copies/mL from 0 (0% at baseline) to 87 (79.8%) and 100 (91.7%) at the 3rd and 6th months of treatment, respectively, On the other hand, the CD4+ T-cell count increased significantly during treatment: median (IQR): 209 (81.5–417.5) versus 291 (132–522) versus 378 (181–632.5) cells/L at baseline, the 3rd and 6th months of the treatment follow-up period, respectively. We found dolutegravir-based therapy was a promising option with high virological suppression rates and CD4+ T-cell count recovery, demonstrating a restoration of cellular immunity. Moreover, Viral load suppression rates were high after the initiation of the treatment. We recommend further research should be conducted with a larger number of participants to acquire greater awareness of the treatment outcomes.

Comprehensive Analysis of HIV-1 Integrase Resistance-Related Mutations in African Countries.

The growing emergence of non-nucleoside reverse transcriptase inhibitor (NNRTI) HIV drug resistance in sub-Saharan Africa (SSA) led to the World Health Organization (WHO) recommending, in 2018, a transition to dolutegravir (DTG) as a first-line antiretroviral therapy (ART) in SSA. The broad HIV-1 genetic diversity in SSA could shape DTG effectiveness and the pattern of drug resistance mutations (DRMs) in this region. This study evaluated HIV-1 integrase (IN) DRMs and conserved regions among published groups M, N, O, and P HIV-1 sequences spanning forty years of the HIV epidemic during the transition of DTG-based ART. Overall, we found low levels of integrase strand transfer inhibitor (INSTI)-DRMs (<1%) across HIV groups between the years 1983 and 2023; however, it was unexpected to detect DRMs at statistically significantly higher frequencies in pre-INSTI (1983-2007) than in the INSTI (2008-2023) era. The variability of accessory INSTI-DRMs depended on the HIV subtypes, with implications for susceptibility to DTG. Our findings provide new perspectives on the molecular epidemiology and drug resistance profiles of INSTIs in SSA, emphasizing the need for ongoing surveillance and customized treatment approaches to address the continent's varied HIV subtypes and changing resistance patterns.

Distribution of the Prevalence of Human Leukocyte Antigen (HLA)-B*57:01 Positivity in HIV-1 Infected Individuals and Its Effects on Treatment: Türkiye Map-Buhasder Working Group

Human immunodeficiency virus (HIV)/acquired immundeficiency syndrome (AIDS) is a critical global public health problem that significantly affects both life expectancy and the overall quality of life of individuals in all age groups. The landscape of HIV infection has changed significantly in recent years due to the introduction of effective combination antiretroviral therapies (ART). A key component of first-line ART regimens for HIV treatment is abacavir, a nucleoside HIV reverse transcriptase inhibitor. Although abacavir is effective in suppressing viral replication and managing disease, its clinical utility is overshadowed by the potential for life-threatening hypersensitivity reactions in HLA-B*57:01-positive patients. In our country, local data obtained from various centers regarding the prevalence of HLA-B*57:01 in HIV-1-infected patients are available. In this study, it was aimed to determine the prevalence of the HLA-B*57:01 genotype in HIV-infected patients who were followed up and treated in many regions of our country. This retrospective study consists of the data of the patients aged 18 years and over diagnosed with HIV-1 infection between 01.01.2019 and 31.07.2022. Age, gender, place of birth, mode of transmission of the disease, death status, CD4+ T cell count and HIV RNA levels at the first clinical presentation, HLA-B*57:01 positivity, and the method used, clinical stage of the disease, virological response time with the treatment they received were recorded from the patient files. Data were collected from 16 centers and each center used different methods to detect HLA-B*57:01. These methods were sequence-specific oligonucleotide probe hybridization (SSOP), DNA sequence-based typing (SBT), single-specific primer-polymerase chain reaction (SSP-PCR), allele-specific PCR (AS-PCR) and quantitative PCR (Q-PCR). A total of 608 HIV-infected individuals, 523 males (86%) and 85 females (14%), were included in the study. The mean age of the patients was 36.9 ± 11.9 (18-73) years. The prevalence of HLA-B*57:01 allele was found to be 3.6% (22 patients). The number of CD4+ T lymphocytes in HLA-B*57:01 allele-positive patients was > 500/ mm3 in 10 patients (45.5%), while the number of CD4+ T lymphocytes in HLA-B*57:01 negative patients was > 500/mm3 in 216 patients (36.9%) (p> 0.05). Viral load at the time of diagnosis was found to be lower in patients with positive HLA-B*57:01 allele but it was not statistically significant (p> 0.05). Although different treatment algorithms were used in the centers following the patients, it was observed that the duration of virological response was shorter in HLA-B*57:01 positive patients (p= 0.006). Although the presence of the HLA-B*57:01 allele has a negative impact due to its association with hypersensitivity, it is likely to continue to attract interest due to its association with slower progression of HIV infection and reduced risk of developing AIDS. In addition, although the answer to the question of whether it is cost-effective to screen patients for HLA-B*57:01 before starting an abacavir-containing ART regimen for the treatment of HIV infection is being sought, it seems that HIV treatment guidelines will continue to recommend screening to identify patients at risk in this regard.

Incidence and Predictors of Severe Adverse Drug Reactions among Patients on Antiretroviral Drugs in Harari Regional State, Eastern Ethiopia.

The introduction of combination antiretroviral therapy improves the quality and longevity of people living with HIV/AIDS. However, adverse drug reactions associated with antiretroviral therapy compromise the resulting benefits and have been reported differently worldwide, including Ethiopia. Severe adverse drug reactions are one of the major public health concerns for the reason that they can potentially impede the benefit of antiretroviral therapy and put the patient's survival at risk. Despite many successes achieved with the introduction of the combined antiretroviral therapy, the majority of the patients on antiretroviral therapy experience adverse drug reactions associated with the drugs. Consequently, little is known about the problem in the current study area. This is, therefore, to study incidence and predictors of severe adverse drug reactions among patients on antiretroviral drugs in the Harari region, Eastern Ethiopia. The aim of this study was to assess the incidence and predictors of severe adverse drug reactions among patients on antiretroviral therapy from February 25, 2022, to March 25, 2022, in the Harari region, Eastern Ethiopia. A hospital-based retrospective cohort study was conducted among 449 randomly selected medical records of people living with HIV on first-line antiretroviral therapy. Collected data were entered into EpiData version 3.1 and exported to STATA version 15 for analysis. Kaplan-Meier survival curve with log-rank test was used to compare survival curves for categorical independent variables. A p value ≤0.05 was declared as significant, and an adjusted hazard ratio was used to report the effect size using the multivariate Cox proportional hazard model. The overall incidence density of the severe adverse reactions was 7.22 per 1000 months (95% CI: 5.5, 9.6). After adjusting for all potential confounders using multivariable Cox proportional hazard ratio, advanced clinical diseases (AHR = 3.44; 95% CI: 1.54, 7.65), HIV/tuberculosis confections (AHR = 2.38; 95% CI: 1.23, 4.62), and being female (AHR = 3.12; 95% CI: 1.57, 6.18) were significantly associated with the experience of severe adverse drug reactions. In this study, the incidence of severe adverse reactions was consistent with the previous studies, and advanced World Health Organization (WHO) clinical stage, HIV/TB confection, and being female were the independent predictors of the severe adverse drug reactions.

Virological, weight, and drug resistance outcomes among patients initiating a dolutegravir-based first-line antiretroviral therapy regimen in Zimbabwe.

Dolutegravir (DTG)-based antiretroviral therapy (ART) is being scaled up in Africa. However, clinical experience with DTG and patterns of HIV drug resistance (HIVDR) are sparse in Zimbabwe. We assessed virological, weight, and HIVDR outcomes among individuals initiating on a DTG-based ART. We conducted a prospective cohort study among HIV-infected adult (≥18 years old) individuals attending care at Parirenyatwa hospital, Harare, Zimbabwe between October 2021 and April 2023. Viral load and weight were assessed at both baseline and follow-up (≥24weeks) visits. HIVDR genotyping was performed by Sanger sequencing among participants with virological failure (viral load ≥1000 copies/ml) at follow-up visit. Factors associated with weight gain were determined using logistic regression analysis on STATA 17.0. One hundred and seventy-two participants were enrolled in the study. The median [interquartile range (IQR) age was 39 (29-48)] years whilst the median (IQR) CD4 + cell count and log 10 viral load at enrolment was 175 (58-328) cells/μl and 5.41 (4.80-5.74), respectively. After a median (IQR) duration of 27 (25-30) weeks on DTG, of the 131 participants with follow-up viral load data available, 129 (98%) had viral load less than 1000 copies/ml and among the 2 (2%) participants with viral load at least 1000 copies/ml, no emergent HIVDR was detected. We observed a significant increase in weight among the participants. The average weight gain was 5.25 kgs ( P < 0.0001). Baseline CD4 + cell count at least 200 cells/μl was significantly associated with at a smaller weight gain [odds ratio (OR) = 0.26; 95% confidence interval (CI) 0.12-0.58, P = 0.001]. We found high virological suppression and an increased weight among people initiating on DTG in a resource-limited setting. Encouragingly, HIVDR to DTG remains rare.

Cocaine regulates antiretroviral therapy CNS access through pregnane-x receptor-mediated drug transporter and metabolizing enzyme modulation at the blood brain barrier

BackgroundAppropriate interactions between antiretroviral therapies (ART) and drug transporters and metabolizing enzymes at the blood brain barrier (BBB) are critical to ensure adequate dosing of the brain to achieve HIV suppression. These proteins are modulated by demographic and lifestyle factors, including substance use. While understudied, illicit substances share drug transport and metabolism pathways with ART, increasing the potential for adverse drug:drug interactions. This is particularly important when considering the brain as it is relatively undertreated compared to peripheral organs and is vulnerable to substance use-mediated damage.MethodsWe used an in vitro model of the human BBB to determine the extravasation of three first-line ART drugs, emtricitabine (FTC), tenofovir (TFV), and dolutegravir (DTG), in the presence and absence of cocaine, which served as our illicit substance model. The impact of cocaine on BBB integrity and permeability, drug transporters, metabolizing enzymes, and their master transcriptional regulators were evaluated to determine the mechanisms by which substance use impacted ART central nervous system (CNS) availability.ResultsWe determined that cocaine had a selective impact on ART extravasation, where it increased FTC’s ability to cross the BBB while decreasing TFV. DTG concentrations that passed the BBB were below quantifiable limits. Interestingly, the potent neuroinflammatory modulator, lipopolysaccharide, had no effect on ART transport, suggesting a specificity for cocaine. Unexpectedly, cocaine did not breach the BBB, as permeability to albumin and 4 kDa FITC-dextran, as well as tight junction proteins and adhesion molecules remained unchanged. Rather, cocaine selectively decreased the pregnane-x receptor (PXR), but not constitutive androstane receptor (CAR). Consequently, drug transporter expression and activity decreased in endothelial cells of the BBB, including p-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 4 (MRP4). Further, cytochrome P450 3A4 (CYP3A4) enzymatic activity increased following cocaine treatment that coincided with decreased expression. Finally, cocaine modulated adenylate kinases that are required to facilitate biotransformation of ART prodrugs to their phosphorylated, pharmacologically active counterparts.ConclusionOur findings indicate that additional considerations are needed in CNS HIV treatment strategies for people who use cocaine, as it may limit ART efficacy through regulation of drug transport and metabolizing pathways at the BBB.