Reverse Transcriptase Inhibitor Backbone Research Articles

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.

1522. Predictors of Weight Gain in People Living with HIV

Abstract Background Highly effective antiretroviral therapy (ART) and longer life expectancy in people living with HIV (PLWH) has led to increased incidence of lifestyle associated risk factors including overweight and obesity. ART is considered to play an important role in this tendency. Excess weight gain has been reported in PLWH treated with and integrase strand transfer inhibitors (INSTI). For nucleoside/nucleotid reverse transcriptase inhibitor (NRTI) backbone components tenofoviralafenamid (TAF) is associated with higher weight gain compared to tenofovir disoproxil (TDF) and abacavir (ABC). This study aims to investigate ART as predictors of weight gain in a prospective cohort using a target trial emulation. Methods The protocol for the target trial was established to evaluate the impact of baseline backbone treatment and various third components on weight gain over a 2-year follow-up period using the Copenhagen Co-Morbidity in HIV Infection Study (COCOMO) cohort. Data was collected from March 2015 to December 2016 in the Capital Region of Denmark. Adult PLWH were included. Subjects were divided into four different treatment groups according to their backbone components: Lamivudine/emtricitabin (XTC)/TDF, XTC/ABC, XTC/TAF or “other”. Regression standardization was applied to the linear regression outcome adjusted for relevant confounders. Results In total 704 subject were included in the analysis. Overall median weight gain in the 2-years follow up period was 0.7 IQR[-22.4, 26.0] with the largest weight gain in subjects with XTC/TDF at baseline (median 1.0 IQR[-12.6, 26.0]). Regression standardization of the adjusted linear regression model showed no significant difference in weight gain between backbone groups. In the third-component analysis including subjects with XTC/TDF or XTC/ABC backbone, subjects receiving an integrase inhibitor based regimen at baseline tended to have a 0.75 kg higher weight gain compared to NNRTI- and PI-based regimens, but this was not significant S.E. 0.474, (0.17;1.67 95%CI). Conclusion The results suggest that while antiretroviral therapy may contribute to weight gain, the choice of backbone components may not be a significant predictor. Further studies are needed to confirm these findings. Disclosures All Authors: No reported disclosures

Antiretroviral therapy among people with HIV with comorbidities in the United States: a retrospective cohort study

Objectives To describe patterns of antiretroviral medications among people with HIV (PWH) who also have common comorbid conditions in a United States cohort. Methods This retrospective cohort study used Optum Research Database claims data from 01/01/2017 through 01/31/2019 to identify adult PWH (≥18 years) based on pharmacy claims for ART during 2018. The index date was defined as the first date of an ART claim. Study inclusion required ≥1 HIV/AIDS diagnosis code during the study period, and continuous health plan enrollment 12 months prior to and at least 30 days after the index date. Descriptive statistics were used to report study results. Results The study population consisted of 17,694 PWH; mean (SD) age 52.2 (12.8) years; 62.0% were ≥ 50 years old. About 50.6% of the study sample had ≥2 comorbidities at baseline. The most prevalent comorbid conditions were hypertension (33.2%), hyperlipidemia (29.7%), neuropsychiatric conditions (26.9%), and cardiovascular disease (11.5%). Most (93.5%) of PWH received a nucleotide reverse transcriptase inhibitor (NRTI) backbone regimen, including tenofovir alafenamide (41.6%), tenofovir disoproxil fumarate (28.1%), and abacavir (22.0%). The most commonly used anchor agents, 62.6%, were integrase strand transfer inhibitors (INSTIs): dolutegravir (30.4%), elvitegravir (24.2%), and raltegravir (7.3%). The proportion of PWH using specific ARTs did not vary significantly with the presence and type of comorbidities. Conclusion From our analyses, ART prescribing did not appear to vary with the presence of comorbidities and potential medication contraindications. ART regimens may have comparable efficacy profiles; however, selection should be guided by each patient’s comorbidities to prevent potential comedication drug toxicities.

Use of integrase inhibitors vs protease inhibitors is associated with improved HIV viral suppression

Current guidelines for antiretroviral therapy in pregnancy include the use of a dual-nucleoside reverse transcriptase inhibitor with either an integrase strand transfer inhibitor or a ritonavir-boosted protease inhibitor, although there is no designation of which is the preferred option. This study aimed to compare viral suppression at delivery among patients on dual-nucleoside reverse transcriptase inhibitors combined with either an integrase strand transfer inhibitor or a protease inhibitor. A hypothesis was made that the incidence of viral suppression is higher with the use of a dual-nucleoside reverse transcriptase inhibitor backbone combined with an integrase strand transfer inhibitor than with the use of a dual-nucleoside reverse transcriptase inhibitor backbone combined with a protease inhibitor. This study was an observational study of pregnant patients living with HIV who received prenatal care and delivered after 20 weeks of gestation at an urban safety net hospital. All pregnant patients with HIV were referred to a centralized clinic for HIV counseling, medication management, and prenatal care. Antiretroviral therapy was continued or initiated according to protocols based on national guidance. Among patients on a dual-nucleoside reverse transcriptase inhibitor backbone combined with integrase strand transfer inhibitor vs protease inhibitor at delivery, we compared the demographics and HIV disease characteristics, including year of diagnosis, viral load, and antiretroviral therapy class. The outcome of interest was viral suppression at delivery, defined as a viral load of <50 copies/mL. From January 2011 to December 2021, 604 patients on dual-nucleoside reverse transcriptase inhibitor met the inclusion criteria, including 411 patients (68%) on protease inhibitor and 193 patients (32%) on integrase strand transfer inhibitor at delivery. Demographic distribution was similar, and prenatal care was initiated at 12 weeks of gestation. Among the integrase strand transfer inhibitor group, 101 (17%) were on antiretroviral therapy at initiation of prenatal care compared with 169 (28%) in the protease inhibitor group. At delivery, the frequency of viral load suppression was higher among those on an integrase strand transfer inhibitor (147/193 [76%]) than among those on a protease inhibitor (275/411 [67%]) (odds ratio, 1.59; 95% confidence interval, 1.08-2.33). Among those with a detectable virus, quantitative viral load was not different. During the study period, the use of a protease inhibitor decreased, whereas the use of an integrase strand transfer inhibitor increased. Among pregnant patients living with HIV, viral suppression was more common among those on a dual-nucleoside reverse transcriptase inhibitor backbone combined with integrase strand transfer inhibitor than among those on a dual-nucleoside reverse transcriptase inhibitor backbone protease inhibitor at delivery. Our results support the use of dual-nucleoside reverse transcriptase inhibitor with integrase strand transfer inhibitor as a first-line antiretroviral therapy regimen in pregnancy.

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.

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.

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.

Prevalence and factors associated with SARS-CoV-2 seropositivity in the Spanish HIV Research Network Cohort

ObjectivesWe aimed to assess the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and factors associated with seropositivity and asymptomatic coronavirus disease 2019 (COVID-19) among people with HIV (PWH). MethodsThis was a cross-sectional study carried out within the cohort of the Spanish HIV Research Network. Participants were consecutive PWH with plasma collected from 1st April to 30th September 2020. We determined SARS-CoV-2 antibodies (Abs) in plasma. Illness severity (NIH criteria) was assessed by a review of medical records and, if needed, participant interviews. Multivariable logistic regression analysis was used to identify predictors of seropositivity among the following variables: sex, age, country of birth, education level, comorbidities (hypertension, chronic heart disease, diabetes mellitus, non-AIDS-related cancer, chronic kidney disease, cirrhosis), route of HIV acquisition, prior AIDS, CD4+ cell count, HIV viral load, nucleoside/nucleotide reverse transcriptase inhibitor (N [t]RTI) backbone, type of third antiretroviral drug, and month of sample collection. ResultsOf 1076 PWH (88.0% males, median age 43 years, 97.7% on antiretroviral therapy, median CD4+ 688 cells/mm3, 91.4% undetectable HIV viral load), SARS-CoV-2 Abs were detected in 91 PWH, a seroprevalence of 8.5% (95%CI 6.9–10.3%). Forty-five infections (45.0%) were asymptomatic. Variables independently associated with SARS-CoV-2 seropositivity were birth in Latin American countries versus Spain (adjusted odds ratio (aOR) 2.30, 95%CI 1.41–3.76, p 0.001), and therapy with tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) versus tenofovir alafenamide (TAF)/FTC as the N(t)RTI backbone (aOR 0.49, 95%CI 0.26–0.94, p 0.031). ConclusionsMany SARS-CoV-2 infections among PWH were asymptomatic, and birth in Latin American countries increased the risk of SARS-CoV-2 seropositivity. Our analysis, adjusted by comorbidities and other variables, suggests that TDF/FTC may prevent SARS-CoV-2 infection among PWH.

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.

Antiretrovirals and Risk of COVID-19 Diagnosis and Hospitalization in HIV-Positive Persons.

Antiretrovirals and Risk of COVID-19 Diagnosis and Hospitalization in HIV-Positive Persons.

No overall change in the rate of weight gain after switching to an integrase-inhibitor in virologically suppressed adults with HIV.

Excessive weight gain has been reported with integrase strand transfer inhibitors (INSTIs). We evaluated weight changes in virologically suppressed adults with HIV who switched from non-INSTI regimens to raltegravir (RAL)-containing or dolutegravir (DTG)-containing antiretroviral therapy. Retrospective single-centre cohort. Adults who switched to RAL or DTG before or between January 2015 and October 2017 were identified. Virologically suppressed, treatment-experienced (≥2 years) individuals, at least 6 months on INSTI, with weight measurements 2 years or less pre and postswitch were included. Our analysis used a random effects model with linear slope pre and post-INSTI with adjustment for age, sex, ethnicity, preswitch-regimen (protease inhibitor vs. nonprotease inhibitor), and RAL vs. DTG use. A total of 378 individuals, 81.2% male, 70.1% white ethnicity, median age of 49 years, median of four weight measurements per participant, and median weight and BMI at switch of 76.6 kg and 25.3 kg/m, respectively, were included. Weight increased by an average of 0.63 kg/year (95% confidence interval 0.17-1.09) preswitch with no overall change in rate of weight gain postswitch [+0.05 kg/year (-0.61-0.71, P = 0.88)]. In our adjusted model, a transition from minimal weight change to weight gain postswitch was isolated to older individuals though this lacked statistical significance [e.g., +1.59 kg/year (-0.26-3.45) if aged 65 years]. Our findings did not differ by sex, ethnicity, preswitch regimen, or RAL vs. DTG. Similar results were seen for BMI and after adjusting for fixed nucleoside/nucleotide reverse transcriptase inhibitor backbone. We found no clear evidence of an overall increase in rate of weight gain following switch to INSTI in virologically suppressed individuals.

2509. Pooled Resistance Analyses of Darunavir (DRV) Once Daily (QD) Regimens and Formulations Across 10 Clinical Studies of Treatment-Naïve (TN) and Treatment-Experienced (TE) Patients with Human Immunodeficiency Virus (HIV)-1 Infection

BackgroundDRV has demonstrated high efficacy and barrier to resistance development across diverse populations, from TN to heavily TE patients. We evaluated resistance data from 10 clinical studies of different DRV 800 mg QD–based antiretroviral regimens and formulations.MethodsThe analysis included patients from 10 phase 2/3 studies (48–192 weeks in duration) of ritonavir- and cobicistat-boosted DRV 800 mg QD–based regimens in TN and virologically failing or suppressed TE patients with HIV-1 (table). Three were phase 3 studies of the DRV/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg single-tablet regimen (STR). Post-baseline resistance was evaluated in patients experiencing protocol-defined virologic failure (PDVF); definitions and criteria for resistance testing varied slightly among studies. Resistance-associated mutations (RAMs) were based on respective International Antiviral Society–USA mutation lists over time.ResultsOf the 3,635 patients evaluated, 250 met PDVF criteria and 205 had post-baseline genotypes/phenotypes. Overall, 4 (0.1%) patients developed (or had identified [switch studies]) ≥1 DRV and/or primary protease inhibitor (PI) RAM (table), and only 1 (< 0.1%, ODIN) patient lost DRV phenotypic susceptibility; this TE patient had prior VF with lopinavir. Among those who used a nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone (mostly emtricitabine [FTC] + tenofovir [TFV]), 12 (0.4%) patients had ≥1 NRTI RAM, including 10 with M184I/V associated with FTC resistance. No TFV RAMs were observed. Among patients receiving D/C/F/TAF (n = 1,949), none had post-baseline DRV, primary PI, or TFV RAMs; only 2 (0.1%) patients developed an FTC RAM.ConclusionAcross a large, diverse population using DRV 800 mg QD–based regimens and formulations, resistance development remains rare; 0.1% of patients had ≥1 DRV and/or primary PI RAM post-baseline. Among 3 trials of the D/C/F/TAF STR, no patients developed a DRV or primary PI RAM. After > 10 years of investigating DRV 800 mg QD–based regimens in clinical trials, loss of phenotypic susceptibility to DRV has never been observed in TN or TE virologically suppressed patients and was only once observed in a TE patient with prior VF on multiple antiretrovirals, including a PI. Disclosures All authors: No reported disclosures.

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.

Abacavir versus other nucleoside reverse transcriptase inhibitor (NRTI) backbone therapies for treatment of HIV infection

Abacavir versus other nucleoside reverse transcriptase inhibitor (NRTI) backbone therapies for treatment of HIV infection