Nucleoside Reverse Transcriptase Inhibitor Backbone Research Articles

Pharmacokinetics of once-daily darunavir/ritonavir in second-line treatment in African children with HIV.

Darunavir is a potent HIV protease inhibitor with a high barrier to resistance. We conducted a nested pharmacokinetic sub-study within CHAPAS-4 to evaluate darunavir exposure in African children with HIV, taking once-daily darunavir/ritonavir for second-line treatment. We used data from the CHAPAS-4 pharmacokinetic sub-study treating children with once-daily darunavir/ritonavir (600/100 mg if 14-24.9 kg and 800/100 mg if ≥25 kg) with either tenofovir alafenamide fumarate (TAF)/emtricitabine (FTC), abacavir/lamivudine or zidovudine/lamivudine. Steady-state pharmacokinetic sampling was done at 0, 1, 2, 4, 6, 8, 12 and 24 hours after observed darunavir/ritonavir intake. Non-compartmental and population pharmacokinetic analyses were used to describe the data and identify significant covariates. Reference adult pharmacokinetic data were used for comparison. We simulated the World Health Organization (WHO) recommended 600/100 mg darunavir/ritonavir dose for the 25-34.9 kg weight band. Data from 59 children with median age and weight 10.9 (range 3.8-14.7) years and 26.0 (14.5-47.0) kg, respectively, were available. A two-compartment disposition model with transit absorption compartments and weight-based allometric scaling of clearance and volume best described darunavir data. Our population achieved geometric mean (%CV) darunavir AUC0-24h, 94.3(50) mg·h/L and Cmax, 9.1(35) mg/L, above adult reference values and Ctrough, 1.5(111) mg/L, like adult values. The nucleoside reverse-transcriptase inhibitor backbone was not found to affect darunavir concentrations. Simulated WHO-recommended darunavir/ritonavir doses showed exposures equivalent to adults. Higher alpha-1-acid glycoprotein increased binding to darunavir and decreased apparent clearance of darunavir. Darunavir exposures achieved in our trial are within safe range. Darunavir/ritonavir can safely be co-administered with TAF/FTC. Both WHO-recommended 600/100 mg and CHAPAS-4 800/100 mg darunavir/ritonavir doses for the 25-34.9 kg weight band offer favourable exposures. The choice between them can depend on tablet availability.

Switch to fixed-dose ainuovirine, lamivudine, and tenofovir DF versus elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed people living with HIV-1: the 48-week results of the SPRINT trial, a multi-centre, randomised, double-blind, active-controlled, phase 3, non-inferiority trial

We compared the efficacy and safety profiles of ainuovirine (ANV), a new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), with boosted elvitegravir (EVG), both coformulated with two nucleoside reverse transcriptase inhibitors (NRTIs), in people living with HIV-1 (PLWH) who had achieved virological suppression on previous NNRTI-based antiretroviral (ARV) regimen. This study was a multi-centre, randomised, double-blind, active-controlled, non-inferiority trial recruiting PLWH from 10 clinical centres across China. Main inclusion criteria included age of 18-65 years (inclusive), and stably staying on an ARV regimen combining an NNRTI with a two-drug NRTI backbone for at least 12 months. Eligible participants must have maintained plasma HIV-1 ribonucleic acid (RNA) titre below 50 copies per mL confirmed on two successive tests at an interval of at least one month prior to randomisation. Participants were randomly assigned to receive ANV 150mg plus lamivudine (3TC) 300mg, and tenofovir disoproxil fumarate (TDF) 300mg (ANV/3TC/TDF), or cobicistat (Cobi) 150mg boosted EVG plus emtricitabine (FTC) 200mg, and tenofovir alafenamide (TAF) 10mg. The primary efficacy endpoint was the proportion of participants with HIV-1 RNA titre at 50 copies per mL or above at week 48 using the US Food and Drug Administration snapshot algorithm, with a non-inferiority margin of 4 percentage points at a two-side 95% confidence level. This trial is active, but not recruiting, and is registered with Chinese Clinical Trial Registry (ChiCTR), number ChiCTR2100051605. Between October 2021 and February 2022, 923 patients were screened for eligibility, among whom 762 participants were randomized and had received at least one dose of ANV/3TC/TDF (n=381) or EVG/Cobi/FTC/TAF (n=381). At week 48, 7 (1.8%) participants on ANV/3TC/TDF and 6 (1.6%) participants on EVG/Cobi/FTC/TAF had plasma HIV-1 RNA titre at 50 copies per mL or above, including missing virological data within the time window (the Cochran-Mantel-Haenszel method, estimated treatment difference [ETD], 0.3%, 95% CI-1.6 to 2.1), establishing the non-inferiority of ANV/3TC/TDF to EVG/Cobi/FTC/TAF. The proportions of participants experiencing at least one treatment-emergent adverse events (AEs) were comparable between the two arms (97.6% versus 97.6%). A small proportion of participants discontinued study drug due to AEs (0.3% versus 0.3%). Serious AEs occurred in 11 (2.9%) participants on ANV/3TC/TDF and 9 (2.4%) participants on EVG/Cobi/FTC/TAF, respectively, none of which was considered related to study drug at the jurisdiction of the investigator. At week 48, participants on ANV/3TC/TDF showed a significantly less weight gain from baseline compared to those on EVG/Cobi/FTC/TAF (least square mean, 1.16 versus 2.05kg, ETD-0.90kg, 95% CI,-1.43 to-0.37). The changes in serum lipids from baseline also favoured ANV/3TC/TDF over EVG/Cobi/FTC/TAF. In virologically suppressed PLWH on previous NNRTI-based ARV regimen, switch to ANV/3TC/TDF resulted in less weight gain, and improved lipid metabolism while maintaining virological suppression non-inferior to that to EVG/Cobi/FTC/TAF. Jiangsu Aidea Pharmaceutical & the National "Thirteenth Five-year Period" Major Innovative Drugs Research and Development Key Project of the People's Republic of China Ministry of Science and Technology.

Perinatal exposure to atazanavir-based antiretroviral regimens in a mouse model leads to differential long-term motor and cognitive deficits dependent on the NRTI backbone.

Combination antiretroviral therapy (ART) use in pregnancy has been pivotal in improving maternal health and reducing perinatal HIV transmission. However, children born HIV-exposed uninfected fall behind their unexposed peers in several areas including neurodevelopment. The contribution of in utero ART exposure to these deficits is not clear. Here we present our findings of neurocognitive outcomes in adult mice exposed in utero to ART. Dams were treated with a combination of ritonavir-boosted atazanavir with either abacavir plus lamivudine (ABC/3TC + ATV/r) or tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC + ATV/r), or water as a control, administered daily from day of plug detection to birth. Offspring underwent a battery of behavioral tests that investigated motor performance and cognition starting at 6-weeks of age and ending at 8 months. Changes in brain structure were assessed using magnetic resonance imaging and immunohistochemistry. Expression of genes involved in neural circuitry and synaptic transmission were assessed in the hippocampus, a region strongly associated with memory formation, using qPCR. Pups exposed to TDF/FTC + ATV/r showed increased motor activity and exploratory drive, and deficits in hippocampal-dependent working memory and social interaction, while pups exposed to ABC/3TC + ATV/r showed increased grooming, and deficits in working memory and social interaction. Significant volumetric reductions in the brain were seen only in the ABC/3TC + ATV/r group and were associated with reduced neuronal counts in the hippocampus. Altered neurotransmitter receptor mRNA expression as well as changes in expression of the neurotrophic factor BDNF and its receptors were observed in both ART-exposed groups in a sex-dependent manner. In our model, in utero ART exposure had long-term effects on brain development and cognitive and motor outcomes in adulthood. Our data show that neurological outcomes can be influenced by the type of nucleoside reverse transcriptase inhibitor backbone of the regimen and not just the base drug, and display sex differences.

The rollout of paediatric dolutegravir and virological outcomes among children living with HIV in Mozambique.

In 2022, Mozambique introduced Dolutegravir 10mg (pDTG), as part of paediatric antiretroviral therapy for children weighing < 20 kg. Understanding real-world challenges during national rollout can strengthen health systems in resource-limited settings. We described the transition rate to, and new initiation of, pDTG, viral load suppression (VLS) post-pDTG, and factors associated with VLS among children living with HIV. We conducted a retrospective cohort study involving children aged < 9 years and abstracted data from clinical sources. We used logistic regression to assess VLS and pDTG initiation predictors. Of 1353 children, 1146 initiated pDTG; 196 (14.5%) had no recorded weight. Post-pDTG switch, 98.9% (950/961) of children maintained the same nucleoside reverse transcriptase inhibitor backbone. After initiating Abacavir/Lamivudine+pDTG, 834 (72.8%) children remained on the regimen, 156 (13.6%) switched off (majority to Dolutegravir 50mg), 22 (1.9%) had ≥ 2 anchor drug switches; 134 (11.7%) had no documented follow-up regimen. Factors associated with pDTG initiation or switch were younger age (adjusted odds ratio [AOR] = 0.71 [0.63-0.80]) and a recorded weight (AOR = 55.58 [33.88-91.18]). VLS among the 294 children with a viral load (VL) test after ≥ 5 months post-pDTG was 75.5% (n = 222/294). Pre-pDTG VLS rate among treatment-experienced children was 56.5% (n = 130/230). Factors associated with VLS were older age (AOR = 1.18 [1.03-1.34]) and previous VLS (AOR = 2.27 [1.27-4.06]). Most eligible children initiated pDTG per guidelines, improving post-pDTG VLS. Challenges included unexplained switches off pDTG after initiation, low VL coverage and inadequate documentation in clinic records.

Revisiting efavirenz in the era of dolutegravir: Low-dose efavirenz, a viable alternative capable of holding its own against dolutegravir-based regimens

ABSTRACT Background: First-line dual NRTI + NNRTI-based ART has shown good virological effectiveness; however, toxicity is common and is often the most common reason for modification of first-line ART. Aims: The purpose of this study is to revisit low-dose efavirenz (EFV) in the era of dolutegravir (DTG) by investigating anti-retroviral therapy (ART) switch strategies for outcomes of virological effectiveness and safety in virologically suppressed Indian persons living with HIV (PLH) on first-line dual nucleoside reverse transcriptase inhibitors (NRTI) + non-NRTI (NNRTI)-based ART. Methods: A phase-IV comparative study of consecutive cases who switched their first-line NNRTI-based ART to either EFV-400 or DTG with a dual NRTI backbone between October 2020 to December 2021 and underwent at least 48 weeks of follow-up. The study is a non-randomised trial, wherein ART regimens were based on physician choice, patient preference and drug availability. Results: A total of 102 [DTG arm: 52; EFV-400 arm: 50; intention-to-treat (ITT) population] participants met the inclusion criteria. At 48-week follow-up, virological failure was not observed in either arm. Virological suppression to &lt; 200 cp/mL was attained in 97.9% (n = 48/49; 95% confidence interval [CI]: 89.1–99.9) and 95.9% (n = 47/49; 95% CI: 86.02–99.5) of patients, respectively, in the DTG and-EFV-400 arm (ITT-populations). There was no significant difference in mean change from baseline in body weight and body mass index between DTG and-EFV-400 arms. The proportion of patients who gained ≥ 10% of their baseline body weight at 24 weeks of exposure to DTG was 16% (n = 8, 95% CI: 5.8 to 26.2) and that to EFV-400 was 10% (n = 5, 95% CI: 1.7 to 18.3) with a difference in proportions: 6.0% (95% CI: −7.1–19.1)]. There was a significant decrease at 24 weeks in mean fasting levels of lipid fractions in the DTG arm as compared to EFV-400 [total cholesterol: − 24.3 mg/dL, 95% CI: −35.2 to − 13.3 vs. −6.9 mg/dL, 95% CI: −17.9–4.1 (P = 0.029) and triglycerides:−35.9 mg/dL, 95% CI: −60.9 to − 10.9 vs. 8.6 mg/dL, 95% CI: −16.6 to 33.8 (P = 0.014)]. Adverse events (AEs) of any grade including laboratory derangements to DTG were experienced by 6% (n = 3, 95% CI: −0.6 to 12.6) and that to EFV-400 by 8% (n = 4, 95% CI: 0.5 to 15.5) with a difference in proportions: 2.0% (95% CI: −7.9 to 11.9). Grades 3–4-AE occurred in two patients, both in the EFV-400 arm. Central nervous system AEs were not observed in the DTG arm and occurred in two patients in the EFV-400 arm. Two patients in the EFV-400 arm discontinued the regimen due to AEs. Conclusion: Both DTG and EFV-400-based first-line ART show good virological effectiveness and safety profiles in patients who are virologically suppressed on dual NRTI + NNRTI-based first-line ART.

Virologic Outcomes and ARV Switch Profiles 2 Years After National Rollout of Dolutegravir to Children Less Than 15 Years in Southern Mozambique.

Dolutegravir (DTG) was scaled up globally to optimize treatment for children living with HIV. We evaluated the rollout and virological outcomes after DTG introduction in Mozambique. Data from children 0-14 years with visits from September 2019 to August 2021 were extracted from records in 16 facilities in 12 districts. Among children ever on DTG, we report treatment switches, defined as changes in anchor drug, regardless of changes to nucleoside reverse transcriptase inhibitor (NRTI) backbones. Among those on DTG for ≥6 months, we described viral load suppression rates by children newly initiating and switching to DTG and by the NRTI backbone at the time of the DTG switch. Overall, 3,347 children were ever on DTG-based treatment (median age 9.5 years; 52.8% female). Most children (3,202, 95.7%) switched to DTG from another antiretroviral regimen. During the 2-year follow-up, 9.9% never switched from DTG; 52.7% had 1 regimen change, of which 97.6% were switched to DTG. However, 37.2% of children experienced ≥2 anchor drug changes. Overall median time on DTG was 18.6 months; nearly all children ≥5 years (98.6%) were on DTG at the last visit. Viral suppression was 79.7% (63/79) for children newly initiating DTG and 85.8% (1,775/2,068) for those switching to DTG. Suppression rates were 84.8% and 85.7% among children who switched and maintained NRTI backbones, respectively. Viral suppression rates of ≥80% with minor variations by backbone were achieved during the 2-year DTG rollout. However, there were multiple anchor drug switches for over one-third of children, which may be attributable in part to drug stockouts. Long-term pediatric HIV management will only be successful with immediate and sustainable access to optimized child-friendly drugs and formulations.

Contribution of Low CD4 Cell Counts and High Human Immunodeficiency Virus (HIV) Viral Load to the Efficacy of Preferred First-Line Antiretroviral Regimens for Treating HIV Infection: A Systematic Review and Meta-Analysis.

We assessed whether low CD4 count and high viral load (VL) affect the response to currently preferred ART. We performed a systematic review of randomized, controlled clinical trials that analyzed preferred first-line ART and a subgroup analysis by CD4 count (≤ or >200 CD4/μL) or VL (≤ or >100 000 copies/mL). We computed the odds ratio (OR) of treatment failure (TF) for each subgroup and individual treatment arm. Patients with ≤200 CD4 cells or VL ≥100 000 copies/mL showed an increased likelihood of TF at 48 weeks: OR, 1.94; 95% confidence interval (CI): 1.45-2.61 and OR, 1.75; 95% CI: 1.30-2.35, respectively. A similar increase in the risk of TF was observed at 96 weeks. There was no significant heterogeneity regarding integrase strand transfer inhibitor or nucleoside reverse transcriptase inhibitor backbone. Our results show that CD4 <200 cells/μL and VL ≥100,000 copies/mL impair ART efficacy in all preferred regimens.

Determinants of therapy failure among adults on first-line antiretroviral therapy in Asmara, Eritrea: a multicenter retrospective matched case–control study

BackgroundInformation on treatment failure (TF) in People living with HIV in a data-poor setting is necessary to counter the epidemic of TF with first-line combined antiretroviral therapies (cART) in sub-Saharan Africa (SSA). In this study, we examined the risk factors associated with TF in Asmara, Eritrea from 2001 to 2020.MethodsA multicenter, retrospective 1:2 matched (by age and gender) case–control study was conducted in four major hospitals in Asmara, Eritrea on adults aged ≥ 18 years who were on treatment for at least 6 months. Cases were patients who fulfills at least one of the WHO therapy failure criterion during the study period. Controls were randomly selected patients on first-line treatment and plasma viral load < 1000 copies/ml in their latest follow-up measurement. Multivariable logistic regression analysis was conducted to identify risk factors for TF. All P-values were 2-sided and the level of significance was set at P < 0.05 for all analyses.ResultsOf the 1068 participants (356 cases; 712 controls), 585 (54.7%) were females. The median age at treatment initiation was 46 years [interquartile range (IQR): 39–51]. Median time to combined antiretroviral therapy (cART) failure was 37 months (IQR = 24–47). In the multivariate analysis, factors associated with increased likelihood of TF included initial nucleoside reverse transcriptase inhibitors (NRTI) backbone (Zidovudine + Lamivudine (AZT + 3TC): adjusted odds ratio (aOR) = 2.70, 95% Confidence interval (CI): 1.65–4.41, P-value < 0.001), (Abacavir + lamivudine (ABC + 3TC): aOR = 4.73, 95%CI: 1.18–18.92, P-value = 0.028], and (Stavudine + Lamivudine (D4T + 3TC): aOR = 5.00; 95% CI: 3.03–8.20, P-value < 0.001) in comparison to Emtricitabine and Tenofovir diproxil fumarate (FTC + TDF). Additional associations included prior exposure to cART (aOR = 2.28, 95%CI: 1.35–3.86; P- value = 0.002), record of sub-optimal drug adherence (aOR = 3.08, 95%CI: 2.22–4.28; P < 0.001), ambulatory/bedridden at presentation (aOR = 1.61, 95%CI: 1.12–4.28; P-value = 0.010), presence of comorbidities (aOR = 2.37; 95%CI: 1.36–4.10, P-value = 0.002), duration of cART (< 5 years: aOR: 5.90; 95% CI: 3.95–8.73, P-value < 0.001), and use of SMX-TMP prophylaxis (aOR = 2.00, 95%CI, 1.44–2.78, P-value < 0.001).ConclusionOur findings underscore the importance of optimizing cART adherence, diversification of cART regimens, and interventions directed at enhancing early HIV diagnosis, prompt initiations of treatment, and improved patient-focused monitoring of treatment response.

Trends in Use of Combination Antiretroviral Therapy and Treatment Response from 2000 to 2016 in the Canadian Observational Cohort (CANOC): A Longitudinal Cohort Study.

Advances in treatment have turned HIV from a terminal illness to a more manageable condition. Over the past 20 years, there have been considerable changes to HIV treatment guidelines, including changes in preferred antiretrovirals and timing of initiation of combination antiretroviral therapy (cART). To examine real-world trends in cART utilization, viral control, and immune reconstitution among people living with HIV in Canada. Data were obtained from the Canadian Observational Cohort (CANOC). CANOC participants were eligible if they were antiretroviral therapy-naive at entry and initiated 3 or more antiretrovirals on or after January 1, 2000; if they were at least 18 years of age at treatment initiation; if they were residing in Canada; and if they had at least 1 viral load determination and CD4 count within 1 year of CANOC entry. Baseline and annual mean CD4 counts were categorized as less than 200, 200-350, 351-500, and more than 500 cells/mm3. Annual mean viral loads were reported as suppressed (< 50 copies/mL), low (50-199 copies/mL), or high detectable (≥ 200 copies/mL). The cART regimens were reported yearly. All CANOC participants were included (n = 13 040). Over the study period, the proportion of individuals with an annual mean CD4 count above 500 cells/mm3 increased from 16.3% to 65.8%, while the proportion of individuals with an undetectable mean viral load increased from 10.6% to 83.2%. As of 2007, the most commonly prescribed 2-agent nucleoside reverse transcriptase inhibitor backbone was tenofovir disoproxil fumarate and emtricitabine. In terms of third agents, non-nucleoside reverse transcriptase inhibitors were the most common class in the periods 2000-2003 and 2014-2015, protease inhibitors were most common in the period 2004-2013, and integrase inhibitors were most common in 2016. Concordance with treatment guidelines was demonstrated over time with respect to cART prescribing and immunologic and virologic response.

Class-Based Antiretroviral Exposure and Cognition Among Women Living with HIV.

Neurologic complications of the human immunodeficiency virus (HIV) are common in treated individuals, and toxicity of certain antiretroviral therapies (ART) may contribute to cognitive impairment. We investigated exposures to specific ART and cognition among women living with HIV (WLWH). Virologically suppressed (viral load <200 copies/mL during at least two semi-annual visits) WLWH and age/race matched HIV-seronegative controls enrolled in the Women's Interagency HIV Study who completed at least two biennial cognitive assessments were included. Analysis of WLWH was restricted to those with exposure to the drug class of interest and a nucleoside reverse transcriptase inhibitor (NRTI) backbone. Generalized estimating equations were used to evaluate repeated measures of cognition over time in association with ART class exposure. Among 1,242 eligible WLWH, 20% (n = 247) had isolated drug exposure to non-nucleoside reverse transcriptase inhibitors (NNRTI), 18% (n = 219) to protease inhibitors (PIs), and 6% (n = 79) to integrase inhibitors with a NRTI backbone. Cognitive assessments were performed at a median of 3 biennial visits {IQR 2-4 visits}. At the index assessment, 21% of WLWH demonstrated global cognitive impairment versus 29% at their last cognitive assessment. In multivariable analyses adjusted for hypertension, depression, diabetes mellitus, history of AIDS-defining illness, alcohol use, number of medications, and time on ART, WLWH exposed to NNRTIs demonstrated verbal learning improvements (mean T-score change 1.3, p = .020) compared to other treated women. Compared to HIV-seronegative women, WLWH exposed to PIs had worse verbal learning (mean T-score difference -2.62, p = .002) and verbal memory performance (mean T-score difference -1.74, p = .032) at baseline. Compared to HIV-seronegative women, WLWH exposed to PIs had improvements in verbal learning (mean T-score slope difference 0.36, p = .025) and verbal memory (mean T-score slope difference 0.32, p = .042). The index T-score and slope of change in the T-score were similar among other treated groups and the HIV-seronegative group. We noted emerging trends in cognition in WLWH exposed to specific drug classes. Ongoing study of this relatively young group is important to characterize long-term cognitive outcomes and effect of antiretrovirals as treatment guidelines evolve.

Impact of nucleos(t)ide reverse transcriptase inhibitor resistance on dolutegravir and protease-inhibitor-based regimens in children and adolescents in Kenya.

We assessed the impact of using dolutegravir or a protease inhibitor with an inactive nucleoside-reverse transcriptase inhibitor (NRTI) in children and adolescents. We observed high-levels of viral suppression among those on tenofovir-lamivudine-dolutegravir even in presence of an inactive NRTI backbone but lower levels among those on protease inhibitors, especially those retained on an inactive abacavir. Although tenofovir may be recycled with dolutegravir, more studies are needed to determine if abacavir can be reused with dolutegravir or protease inhibitors.

Is tenofovir disoproxil fumarate associated with weight loss?

Recent clinical trials have shown weight gain associated with newer antiretrovirals. It is unclear how the nucleoside reverse transcriptase inhibitor backbone affects weight. Recent evidence suggests greater weight gain with tenofovir alafenamide (TAF) compared with tenofovir disoproxil fumarate (TDF). However, it is not fully understood whether TDF contributes to weight suppression. A systematic search of PubMed, Embase and clinicaltrials.gov was conducted to identify all randomized control trials comparing TDF/FTC or TDF to control in HIV-negative individuals. The primary endpoint included the number of events of 5% weight loss. Mantel-Haenszel test with random-effects modelling was used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI). Further analyses of gastrointestinal (GI) adverse events were also undertaken. Seven PrEP trials: PARTNERS, VOICE, TDF-2, Bangkok PrEP, iPrEX, FEM-PrEP and HPTN 084 were included in the analysis of weight loss, with a total sample size of 19 359. One study (HPTN 084) compared TDF/FTC to cabotegravir (CAB). HIV-negative individuals taking TDF were more likely to experience weight loss compared with control [odds ratio (OR) 1.44; 95% CI 1.12-1.85; P = 0.005). Exposure to TDF was also linked to greater odds of vomiting (OR 1.81; 95% CI 1.20-2.73; P < 0.005). There were no increased odds of nausea, diarrhoea or loss of appetite. There is evidence in HIV-negative individuals that TDF may be associated with weight loss. Further research should be carried out in HIV-positive individuals, and clinical trials of TDF/FTC should publish weight data to widen the evidence base.

882. Use of Tenofovir Disoproxil Fumarate Shows Weight Loss vs Placebo: A Meta-Analysis of 7 Clinical Trials in 19,359 HIV-negative Individuals

Abstract Background Recent clinical trials have shown weight gain associated with newer antiretrovirals. It is unclear how the nucleoside reverse transcriptase inhibitor backbone affects weight. Recent evidence suggests greater weight gain with tenofovir alafenamide (TAF) compared to tenofovir disoproxil fumarate (TDF). However, it is not fully understood whether TDF contributes to weight suppression or weight loss. Methods A systematic search of PubMed, Embase and clinicaltrials.gov was conducted to identify all randomised control trials comparing TDF/FTC or TDF to control in HIV-negative individuals. The primary endpoint included the number of events of ‘5% weight loss’ or ‘abnormal loss of weight’. The Mantel-Haenszel test with random-effects modelling was used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI). Further analyses of gastrointestinal (GI) adverse events (AEs) were undertaken, including the number of reported adverse events of nausea, vomiting, loss of appetite and diarrhoea. Results Seven PrEP trials: PARTNERS, VOICE, TDF-2, Bangkok PrEP, iPrEX, FEM-PrEP and HPTN 084 were included in the analysis of weight loss, with a total sample size of 19,359. One study (HPTN 084) compared TDF/FTC to cabotegravir (CAB). The remaining compared either TDF or TDF/FTC or placebo. HIV-negative individuals taking TDF were more likely to experience weight loss compared to control (OR 1.44 95% CI 1.12 – 1.85 p = 0.005 (table 1)). In a separate analysis of GI AEs, exposure to TDF was also linked to greater odds of vomiting (OR 1.81 95% CI (1.20, 2.73) p &amp;lt; 0.005). There were no increased odds of nausea, diarrhoea, or loss of appetite. Weight loss events in PrEP trials. Conclusion There is evidence in HIV-negative individuals that TDF may be associated weight loss when compared to placebo. Further research should be carried out in HIV positive individuals, and clinical trials of TDF/FTC should publish weight data to widen the evidence base Disclosures All Authors: No reported disclosures

Retrospective evaluation of an observational cohort by the Central and Eastern Europe Network Group shows a high frequency of potential drug-drug interactions among HIV-positive patients receiving treatment for coronavirus disease 2019(COVID-19).

The aim of this international multicentre study was to review potential drug-drug interactions (DDIs) for real-life coadministration of combination antiretroviral therapy (cART) and coronavirus disease 2019 (COVID-19)-specific medications. The Euroguidelines in Central and Eastern Europe Network Group initiated a retrospective, observational cohort study of HIV-positive patients diagnosed with severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) infection. Data were collected through a standardized questionnaire and DDIs were identified using the University of Liverpool's interaction checker. In total, 524 (94.1% of 557) patients received cART at COVID-19 onset: 117 (22.3%) were female, and the median age was 42 (interquartile range 36-50) years. Only 115 (21.9%) patients were hospitalized, of whom 34 required oxygen therapy. The most frequent nucleoside reverse transcriptase inhibitor (NRTI) backbone was tenofovir disoproxil fumarate (TDF)/tenofovir alafenamide (TAF) with lamivudine or emtricitabine (XTC) (79.3%) along with an integrase strand transfer inhibitor (INSTI) (68.5%), nonnucleoside reverse transcriptase inhibitor (NNRTI) (17.7%), protease inhibitor (PI) (13.7%) or other (2.5%). In total, 148 (28.2%) patients received COVID-19-specific treatments: corticosteroids (15.7%), favipiravir (7.1%), remdesivir (3.1%), hydroxychloroquine (2.7%), tocilizumab (0.6%) and anakinra (0.2%). In total, 62 DDI episodes were identified in 58 patients (11.8% of the total cohort and 41.9% of the COVID-19-specific treatment group). The use of boosted PIs and elvitegravir accounted for 43 DDIs (29%), whereas NNRTIs were responsible for 14 DDIs (9.5%). In this analysis from the Central and Eastern European region on HIV-positive persons receiving COVID-19-specific treatment, it was found that potential DDIs were common. Although low-dose steroids are mainly used for COVID-19 treatment, comedication with boosted antiretrovirals seems to have the most frequent potential for DDIs. In addition, attention should be paid to NNRTI coadministration.

Differentiated service delivery for people using second-line antiretroviral therapy: clinical outcomes from a retrospective cohort study in KwaZulu-Natal, South Africa.

IntroductionEvidence is needed to guide the inclusion of broader groups of people living with HIV (PLHIV) in differentiated service delivery (DSD) programmes. We assessed treatment outcomes among PLHIV on second‐line regimens in a community antiretroviral therapy (ART) delivery programme, compared to those who remained at clinics.MethodsUsing data from 61 public clinics, we did a retrospective cohort study among PLHIV receiving second‐line ART following rollout of the Centralized Chronic Medicines Dispensing and Distribution (CCMDD) programme in KwaZulu‐Natal, South Africa. We included PLHIV from the timepoint when they were first eligible, though not necessarily referred, for community ART within CCMDD and followed them for 18 months. We used multivariable logistic regression to compare 12‐month attrition and viraemia between clients referred for community ART and those remaining in clinic care.ResultsAmong 209,744 PLHIV aged ≥ 18 years who collected ART between October 2016 and December 2018, 7511 (3.6%) received second‐line ART. Of these, 2575 (34.3%) were eligible for community ART. The median age was 39.0 years (interquartile range 34.0–45.0) and 1670 (64.9%) were women. Five hundred and eighty‐four (22.7%) were referred for community ART within 6 months of meeting eligibility criteria. Overall, 4.5% [95% confidence interval (CI) 3.0–6.6%] in community ART and 4.4% (95% CI 3.5–5.4%) in clinic care experienced attrition at 12 months post eligibility for community ART. Two thousand one hundred and thirty‐eight (83.0%) had a viral load recorded 6–18 months after becoming eligible, and of these, 10.3% (95% CI 7.7–13.3%) in community ART and 11.3% (95% CI 9.8–12.9%) in clinic care had viraemia > 200 copies/ml. In separate regressions adjusted for age, gender, district, time on second‐line ART, nucleoside reverse transcriptase inhibitor backbone and year of eligibility, no differences in the odds of attrition [adjusted odds ratio (aOR) 1.02, 95% CI 0.71–1.47] or viraemia (aOR 0.91, 95% CI 0.64–1.29) were observed between those in community ART and those remaining in clinic care.ConclusionsWe found good outcomes among PLHIV who were stable on second‐line regimens and referred for community ART. Efforts to expand DSD access among this group should be prioritized.

Lactic acidosis and hyperlactatemia associated with lamivudine accumulation and sepsis in a kidney transplant recipient\u2014a case report and review of the literature

BackgroundWe report a case of sudden, lethal metabolic acidosis in a 70-year-old man on long-term nucleoside reverse transcriptase inhibitor (NRTI) -based antiretroviral therapy (ART) who had developed atypical necrotizing fasciitis 1 month after kidney transplantation.Case presentationThe HIV infection of the patient was treated for the last four months with an integrase strand inhibitor (dolutegravir 50 mg/d) plus a NRTI backbone including lamivudine (150 mg/d) and abacavir (600 mg/d). In this renal transplant patient we hypothesize that the co-existence of sepsis, renal failure and an accumulation of lamivudine led to the development of fatal metabolic acidosis and hyperlactatemia. Although lamivudine is only rarely associated with hyperlactatemia, there is evidence that overdose may be a risk factor for developing it. In our patient the lamivudine concentration two days after stopping and during hemodiafiltration was more than 50 times higher than therapeutic target trough concentrations. Likely reasons for this were renal impairment and concurrent treatment with trimethoprim, known to inhibit the renal elimination of lamivudine.ConclusionsNRTIs could trigger the development of hyperlactatemia in septic patients. The use of NRTI sparing regimens might be considered in the presence of this critical condition.

Virologic efficacy of tenofovir, lamivudine and dolutegravir as second-line antiretroviral therapy in adults failing a tenofovir-based first-line regimen.

ObjectiveRecycling tenofovir and lamivudine/emtricitabine (XTC) with dolutegravir would provide a more tolerable, affordable, and scalable second-line regimen than dolutegravir with an optimized nucleoside reverse transcriptase inhibitor (NRTI) backbone. We evaluated efficacy of tenofovir/lamivudine/dolutegravir (TLD) in patients failing first-line tenofovir/XTC/efavirenz or nevirapine.DesignSingle arm, prospective, interventional studySettingTwo primary care clinics in Khayelitsha, South AfricaParticipants60 adult patients with two viral loads (VL)>1000 copies/mLInterventionParticipants were switched to TLD with additional dolutegravir (50mg) for two weeks to overcome efavirenz induction.Primary outcomeProportion achieving VL<50 copies/mL at week 24 using the FDA snapshot algorithm.ResultsBaseline median CD4 count was 248 cells/mm3, VL 10580 copies/mL and 48/54 (89%) had resistance (Stanford score ≥15) to one or both of tenofovir and XTC. No participants were lost to follow-up. At week 24, 51/60 (85%, 95% CI 73-93%) were virologically suppressed, six had VL 50-100 copies/mL, one VL 100-1000 copies/mL, one no VL in window, and one switched due to tenofovir-related adverse event. No integrase mutations were detected in the one participant meeting criteria for resistance testing. Virological suppression was achieved by 29/35 (83%, 95% CI 66-93%) with resistance to tenofovir and XTC, 11/13 (85%, 95% CI 55-98%) with resistance to XTC, and 6/6 (100%, 95% CI 54-100%) with resistance to neither.ConclusionA high proportion of adults switching to second-line TLD achieved virologic suppression despite substantial baseline NRTI resistance and most not suppressed had low-level viraemia (≤100 copies/mL). This suggests recycling tenofovir and XTC with dolutegravir could provide an effective second-line option.

New Insights on Long-Term Hepatitis B Virus Responses in HIV-Hepatitis B virus Co-infected Patients: Implications for Antiretroviral Management in Hepatitis B virus-Endemic Settings.

WHO treatment guidelines recommend tenofovir plus lamivudine or emtricitabine as the nucleoside reverse transcriptase inhibitor backbone in first-line regimens for HIV-infected adults. Lamivudine alone is not recommended, because of the risk of hepatitis B virus (HBV) resistance. We studied HBV responses in a large cohort of co-infected patients in a resource-limited setting. Clinical centers in Uganda and Zimbabwe. DART was a randomized trial of monitoring practices in HIV-infected adults starting antiretroviral therapy. Baseline samples were tested retrospectively for HBV serological markers and HBV DNA. Longitudinal HBV DNA testing at 48 weeks and the last available sample before HBV-relevant modification of antiretroviral therapy was performed on patients with detectable HBV DNA at baseline. Two hundred twenty-four hepatitis B surface antigen-positive patients were followed for up to 4.8 years. Of the drugs with anti-HBV activity, 166 were prescribed lamivudine-tenofovir and 58 lamivudine alone. Ninety-eight percent (96/98) patients with baseline HBV DNA <6 log10 IU/mL achieved viral suppression at 48 weeks (HBV DNA <48 IU/mL), regardless of regimen, compared with 50%(26/52) for HBV DNA >6 log10 IU/mL. Of the 83 patients suppressed at 48 weeks and with follow-up data, only 7(8%) experienced viral rebound (range 200-3460 IU/mL). Of the 20 patients not suppressed at 48 weeks and with follow-up data, HBV DNA levels generally declined with lamivudine-tenofovir, but increased with lamivudine alone. Alanine transaminase flares were not observed in any patient who experienced viral rebound. The suppressive effect of lamivudine alone was highly durable (up to 5 years) in HIV-HBV co-infected patients with baseline HBV DNA <6 log10 IU/mL. It may be feasible to develop stratified approaches using lamivudine as the only drug with anti-HBV activity.

Pregnancy and neonatal outcomes in women with HIV-1 exposed to integrase inhibitors, protease inhibitors and non-nucleoside reverse transcriptase inhibitors: an observational study.

Recommended regimens for pregnant women with HIV-1 are composed of two nucleoside reverse transcriptase inhibitors (NRTI) plus either a ritonavir-boosted protease inhibitor (PI) or an integrase strand transfer inhibitor (ISTI), with non-nucleoside reverse transcriptase inhibitors (NNRTI) representing an alternative drug class. The study's purpose was to compare these three options in terms of pregnancy outcomes. Data from a national observational study of pregnant women with HIV-1 were used. The analysis included all pregnancies reported between 2008 and 2018, ending in live births and exposed within 32weeks of gestation to three-drug regimens composed of a NRTI backbone plus a PI, a NNRTI or a ISTI, without class switching during pregnancy. Clinical and laboratory outcomes were evaluated in univariate and multivariable analyses. Overall, 794 exposed pregnancies were analyzed (PI 78.4%, NNRTI 15.4%, ISTI 6.2%). Almost all outcomes had similar rates in the three groups. Women who received PI in pregnancy were less likely to be virologically suppressed at third trimester. PI use was associated with higher bilirubin and triglyceride levels, and ISTI use with a lower rate of low birthweight. The differences in viral suppression at third trimester and in low birthweight were not maintained in multivariable analyses that were adjusted for confounders. We found no major differences in a wide range of outcomes relevant for pregnant women with HIV. Such results are reassuring, and this information may be helpful in a context of preconception counseling when therapeutic choices for pregnancy are discussed between women and care providers.

Nucleoside reverse transcriptase inhibitor backbones and pregnancy outcomes.

The aim of this study was to investigate whether specific nucleoside reverse transcriptase inhibitor (NRTI) backbones are associated with risk of adverse pregnancy outcomes among pregnant women starting antiretroviral therapy (ART). Seven observational studies across eight European countries of pregnancies in HIV-positive women. Individual-level data were pooled on singleton pregnancies conceived off-ART in which a single combination ART regimen was initiated at least 2 weeks before delivery, and ending in a live birth in 2008-2014. Preterm delivery (PTD) was defined as less than 37 gestational weeks and small-for-gestational-age (SGA) as less than 10th percentile according to INTERGROWTH standards. Poisson regression models were fitted to investigate associations between NRTI backbones and PTD/SGA. Out of 7193 pregnancies, 45% (3207) were in UK/Ireland, 44% (3134) in Ukraine. 10% (722/7193) of deliveries were preterm and 11.1% (785/7089) of newborns SGA. The most common NRTI backbones were zidovudine (ZDV)-lamivudine (3TC) (71%), tenofovir (TDF)-XTC (16%) and abacavir (ABC)-3TC (10%) with TDF-containing backbone use increasing over time. Overall, 77% of regimens contained ritonavir-boosted lopinavir (LPV/r). There was no association between NRTI backbone and PTD in main adjusted analyses [adjusted prevalence ratios (aPRs) 0.97 (95% confidence interval, 95% CI 0.73-1.28] for ABC-3TC and aPR 1.06 (95% CI 0.83-1.35) for TDF-XTC, both vs. ZDV-3TC) or in 4720 pregnancies on LPV/r [aPR 1.03 (95% CI 0.74-1.43) for ABC-3TC and aPR 1.16 [0.85-1.57] for TDF-XTC, both vs. ZDV-3TC]. Infants exposed to ABC-3TC or TDF-XTC in utero were less likely to be SGA than those exposed to ZDV-3TC [aPR 0.72 (95% CI 0.53-0.97) and aPR 0.70 (95% CI 0.53-0.93), respectively]. Results support the safety of TDF-XTC backbones initiated in pregnancy with respect to gestation length and birthweight.