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Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection.

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK, Purpose A lower daily pill burden may improve adherence to antiretroviral treatment (ART) and improve outcomes. The goal of this study was to assess differences in adherence rates based on [...]

Background: The effect of nonthymidine nucleoside reverse-transcriptase inhibitors (NRTIs) on fat mitochondrial DNA (mtDNA) content and function is unclear.Methods: A5202 randomized antiretroviral therapy-naive human immunodeficiency virus-infected subjects to abacavir-lamivudine (ABC/3TC) versus tenofovir DF-emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir-ritonavir (ATV/r). A5224s, substudy of A5202, enrolled 269 subjects with fat measurements by dual-energy x-ray absorptiometry and computed tomography. A subset of subjects underwent fat biopsies at baseline and week 96 for mtDNA content (real-time polymerase chain reaction) and oxidative phosphorylation nicotinamide adenine dinucleotide (reduced) dehydrogenase (complex I) and cytochrome c oxidase (complex IV) activity levels (immunoassays). Intent-to-treat analyses were performed using analysis of variance and paired t tests.Results: Fifty-six subjects (87% male; median age, 39 years) were included; their median body mass index, CD4 cell count, and fat mtDNA level were 26 kg/m(2), 227 cells/μL, and 1197 copies/cell, respectively. Fat mtDNA content decreased within the ABC/3TC and TDF/FTC groups (combining EFV and ATV/r arms; median change, -341 [interquartile range, -848 to 190; P = .03] and -400 [-661 to -221; P < .001] copies/cell, respectively), but these changes did not differ significantly between the 2 groups (P = .57). Complex I and IV activity decreased significantly in the TDF/FTC group (median change, -12.45 [interquartile range, -24.70 to 2.90; P = .003] and -8.25 [-13.90 to -1.30; P < .001], optical density × 10(3)/µg, respectively) but not the ABC/3TC group. Differences between the ABC/3TC and TDF/FTC groups were significant for complex I (P = .03).Conclusions: ABC/3TC and TDF/FTC significantly and similarly decreased fat mtDNA content, but only TDF/FTC decreased complex I and complex IV activity levels.Clinical Trials Registration: NCT00118898. [ABSTRACT FROM AUTHOR]

Background: The integrase inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) in a single tablet given once daily. We compared the efficacy and safety of EVG/COBI/FTC/TDF with standard of care-co-formulated efavirenz (EFV)/FTC/TDF-as initial treatment for HIV infection.Methods: In this phase 3 trial, treatment-naive patients from outpatient clinics in North America were randomly assigned by computer-generated allocation sequence with a block size of four in a 1:1 ratio to receive EVG/COBI/FTC/TDF or EFV/FTC/TDF, once daily, plus matching placebo. Patients and study staff involved in giving study treatment, assessing outcomes, and collecting and analysing data were masked to treatment allocation. Eligibility criteria included screening HIV RNA concentration of 5000 copies per mL or more, and susceptibility to efavirenz, emtricitabine, and tenofovir. The primary endpoint was HIV RNA concentration of fewer than 50 copies per mL at week 48. The study is registered with ClinicalTrials.gov, number NCT01095796.Findings: 700 patients were randomly assigned and treated (348 with EVG/COBI/FTC/TDF, 352 with EFV/FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to EFV/FTC/TDF; 305/348 (87·6%) versus 296/352 (84·1%) of patients had HIV RNA concentrations of fewer than 50 copies per mL at week 48 (difference 3·6%, 95% CI -1·6% to 8·8%). Proportions of patients discontinuing drugs for adverse events did not differ substantially (13/348 in the EVG/COBI/FTC/TDF group vs 18/352 in the EFV/FTC/TDF group). Nausea was more common with EVG/COBI/FTC/TDF than with EFV/FTC/TDF (72/348 vs 48/352) and dizziness (23/348 vs 86/352), abnormal dreams (53/348 vs 95/352), insomnia (30/348 vs 49/352), and rash (22/348 vs 43/352) were less common. Serum creatinine concentration increased more by week 48 in the EVG/COBI/FTC/TDF group than in the EFV/FTC/TDF group (median 13 μmol/L, IQR 5 to 20 vs 1 μmol/L, -6 to 8; p<0·001).Interpretation: If regulatory approval is given, EVG/COBI/FTC/TDF would be the only single-tablet, once-daily, integrase-inhibitor-based regimen for initial treatment of HIV infection.Funding: Gilead Sciences. [ABSTRACT FROM AUTHOR]

Background: AIDS Clinical Trials Group A5202 compared blinded abacavir/lamivudine (ABC/3TC) to tenofovir DF/emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in human immunodeficiency virus (HIV)-infected treatment-naive patients, stratified by screening HIV RNA (< or ≥ 10(5) copies/mL). Due to higher virologic failure with ABC/3TC in the high HIV RNA stratum, blinded treatment was stopped in this group, but study follow-up continued for all patients.Methods: Primary endpoints were times to virologic failure, regimen modification, and safety event.Results: In the low HIV RNA stratum, time to virologic failure was similar for ABC/3TC vs TDF/FTC with ATV/r (hazard ratio [HR] 1.25, 95% confidence interval [CI] 0.76, 2.05) or EFV (HR 1.23, 95% CI 0.77, 1.96), with significantly shorter times to regimen modification for ABC/3TC with EFV or ATV/r and to safety events with EFV. Prior to stopping blinded treatment in the high stratum, higher virologic failure rates were seen with ABC/3TC with EFV (HR 2.46, 95% CI 1.20, 5.05) or ATV/r (HR 2.22, 95% CI 1.19, 4.14).Conclusions: In the low HIV RNA stratum, times to virologic failure for ABC/3TC or TDF/FTC were not different with EFV or ATV/r. In the high stratum, virologic failure rate was significantly higher for ABC/3TC than for TDF/FTC when given with either EFV or ATV/r. [ABSTRACT FROM AUTHOR]

Background: The use of fixed-dose combination nucleoside reverse-transcriptase inhibitors (NRTIs) with a nonnucleoside reverse-transcriptase inhibitor or a ritonavir-boosted protease inhibitor is recommended as initial therapy in patients with human immunodeficiency virus type 1 (HIV-1) infection, but which NRTI combination has greater efficacy and safety is not known.Methods: In a randomized, blinded equivalence study involving 1858 eligible patients, we compared four once-daily antiretroviral regimens as initial therapy for HIV-1 infection: abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine plus efavirenz or ritonavir-boosted atazanavir. The primary efficacy end point was the time from randomization to virologic failure (defined as a confirmed HIV-1 RNA level > or = 1000 copies per milliliter at or after 16 weeks and before 24 weeks, or > or = 200 copies per milliliter at or after 24 weeks).Results: A scheduled interim review by an independent data and safety monitoring board showed significant differences in virologic efficacy, according to the NRTI combination, among patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more. At a median follow-up of 60 weeks, among the 797 patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the time to virologic failure was significantly shorter in the abacavir-lamivudine group than in the tenofovir DF-emtricitabine group (hazard ratio, 2.33; 95% confidence interval, 1.46 to 3.72; P<0.001), with 57 virologic failures (14%) in the abacavir-lamivudine group versus 26 (7%) in the tenofovir DF-emtricitabine group. The time to the first adverse event was also shorter in the abacavir-lamivudine group (P<0.001). There was no significant difference between the study groups in the change from the baseline CD4 cell count at week 48.Conclusions: In patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the times to virologic failure and the first adverse event were both significantly shorter in patients randomly assigned to abacavir-lamivudine than in those assigned to tenofovir DF-emtricitabine. (ClinicalTrials.gov number, NCT00118898.) [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess the association between the initiation of anti-tumor necrosis factor alpha (anti-TNFalpha) therapy and the risk of serious bacterial infections in routine care. METHODS: This was a cohort study of patients with rheumatoid arthritis (RA) in whom specific disease-modifying antirheumatic drugs (DMARDs) were initiated. Patients were Medicare beneficiaries ages 65 years and older (mean age 76.5 years) who were concurrently enrolled in the Pharmaceutical Assistance Contract for the Elderly provided by the state of Pennsylvania. A total of 15,597 RA patients in whom a DMARD was initiated between January 1, 1995 and December 31, 2003 were identified using linked data on all prescription drug dispensings, physician services, and hospitalizations. Initiation of anti-TNFalpha therapy, cytotoxic agents other than methotrexate (MTX), noncytotoxic agents, and glucocorticoids was compared with initiation of MTX. The main outcome measure was serious bacterial infections that required hospitalization. RESULTS: The incidence of serious bacterial infections was, on average, 2.2 per 100 patient-years in this population (95% confidence interval [95% CI] 2.0-2.4). Glucocorticoid use doubled the rate of serious bacterial infections as compared with MTX use, independent of previous DMARD use (rate ratio [RR] 2.1 [95% CI 1.5-3.1]), with a clear dose-response relationship for dosages >5 mg/day (for /=20 mg/day, RR 5.48 [P for trend < 0.0001]). Adjusted models showed no increase in the rate of serious infections among initiators of anti-TNFalpha therapy (RR 1.0 [95% CI 0.6-1.7]) or other DMARDs as compared with initiators of MTX. CONCLUSION: In a large cohort of patients with RA, we found no increase in serious bacterial infections among users of anti-TNFalpha therapy compared with users of MTX. Glucocorticoid use was associated with a dose-dependent increase in such infections. [ABSTRACT FROM AUTHOR]

Objective: We sought to project the lifetime cost of medical care for human immunodefiency virus (HIV)-infected adults using current antiretroviral therapy (ART) standards.Methods: Medical visits and hospitalizations for any reason were from the HIV Research Network, a consortium of high-volume HIV primary care sites. HIV treatment drug regimen efficacies were from clinical guidelines and published sources; data on other drugs used were not available. In a computer simulation model, we projected HIV medical care costs in 2004 U.S. dollars.Results: From the time of entering HIV care, per person projected life expectancy is 24.2 years, discounted lifetime cost is Dollars 385,200, and undiscounted cost is Dollars 618,900 for adults who initiate ART with CD4 cell count < 350/microL. Seventy-three percent of the cost is antiretroviral medications, 13% inpatient care, 9% outpatient care, and 5% other HIV-related medications and laboratory costs. For patients who initiate ART with CD4 cell count < 200/microL, projected life expectancy is 22.5 years, discounted lifetime cost is Dollars 354,100 and undiscounted cost is Dollars 567,000. Results are sensitive to drug manufacturers' discounts, ART efficacy, and use of enfuvirtide for salvage. If costs are discounted to the time of infection, the discounted lifetime cost is Dollars 303,100.Conclusions: Effective ART regimens have substantially improved survival and have increased the lifetime cost of HIV-related medical care in the U.S. [ABSTRACT FROM AUTHOR]

Background: Patients with HIV infection who are treated with antiretroviral agents often lose subcutaneous fat and have metabolic abnormalities, including insulin resistance and reduced adiponectin levels, which may be related to disrupted subcutaneous adipogenesis and altered peroxisome proliferator-activated receptor-gamma signaling.Objective: To investigate the effects of rosiglitazone (4 mg/d), a peroxisome proliferator-activated receptor-gamma agonist, in HIV-infected men and women with hyperinsulinemia and lipoatrophy.Design: A randomized, double-blind, placebo-controlled, 3-month study.Setting: University hospital.Patients: 28 HIV-infected men and women with hyperinsulinemia and lipoatrophy.Measurements: Insulin sensitivity measured by euglycemic hyperinsulinemic clamp testing; subcutaneous leg fat area measured by computed tomography; adiponectin, free fatty acid, and lipid levels; and safety variables.Results: Rosiglitazone, when compared with placebo, improved insulin sensitivity (mean [+/-SD] change, 1.5 +/- 2.1 mg of glucose/kg of lean body mass per minute vs. -0.4 +/- 1.6 mg/kg per minute; P = 0.02), increased adiponectin levels (mean [+/-SD], 2.2 +/- 2.2 micro g/mL vs. 0.1 +/- 1.1 microg/mL; P = 0.006), and reduced free fatty acid levels (mean [+/-SD], -0.09 +/- 0.1 mmol/L vs. 0.01 +/- 0.1 mmol/L; P = 0.02). Mean percentage (+/-SD) of body fat (1.38% +/- 3.03% vs. -0.83% +/- 2.76%; P = 0.03) and subcutaneous leg fat area (2.3 +/- 8.4 cm2 vs. -0.9 +/- 1.9 cm2; P = 0.02) increased significantly with rosiglitazone compared with placebo. Mean total cholesterol levels (+/-SD) also increased with rosiglitazone compared with placebo (0.6 +/- 1.0 mmol/L [25 +/- 37 mg/dL] vs. -0.4 +/- 0.6 mmol/L [-15 +/- 25 mg/dL]; P = 0.007).Limitations: The study was relatively small and of short duration.Conclusions: The authors demonstrated positive effects of rosiglitazone on lipoatrophy; insulin sensitivity; and metabolic indices, including adiponectin levels, in HIV-infected patients with lipoatrophy and insulin resistance. Peroxisome proliferator-activated receptor-gamma agonists may correct the metabolic abnormalities associated with disrupted adipogenesis in this population. Further studies must determine the clinical utility of such agents in HIV-infected patients. [ABSTRACT FROM AUTHOR]

Older patients with HIV disease are still a rarity for many physicians, but statistics suggest that you'll be seeing them in your practice sooner rather than later. Will you recognize them and be able to handle their special needs? [ABSTRACT FROM AUTHOR]

Background: COVID-19 remains a major public health concern, with continued resurgences of cases and substantial risk of mortality for hospitalized patients. Remdesivir has become standard-of-care for hospitalized COVID-19 patients. Given the continued evolution of the disease, clinical management relies on evidence from the current endemic period., Methods: Using the PINC AI Healthcare database, effectiveness of remdesivir was evaluated among adults hospitalized with a primary diagnosis of COVID-19 between December 2021 and February 2024. Three cohorts were analysed: adults, elderly (≥65 years), and those with documented COVID-19 pneumonia. Analyses were stratified by oxygen requirements. Patients receiving remdesivir were matched to those not receiving remdesivir using propensity score matching. Cox proportional hazards models were used to examine in-hospital mortality., Results: 169,965 adults hospitalized for COVID-19 were included, of which 94,129 (55.4%) initiated remdesivir in the first two days of hospitalization. Remdesivir was associated with a significantly lower mortality rate as compared to no remdesivir among patients with no supplemental oxygen charges (NSOc) (aHR [95% CI]: 14-day, 0.75 [0.69-0.82]; 28-day, 0.77 [0.72-0.83]) and among those with supplemental oxygen charges (SOc): 14-day, 0.76 [0.72-0.81]; 28-day, 0.79 [0.74-0.83]) (p<0.0001, for all). Similar findings were observed for elderly patients and those hospitalized with COVID-19 pneumonia., Conclusions: This evidence builds on learnings from randomized controlled trials from the pandemic era to inform clinical practices. Remdesivir was associated with significant reduction in mortality for hospitalized patients including the elderly and those with COVID-19 pneumonia., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Patients with immunocompromising conditions are at an increased risk for coronavirus disease 2019 (COVID-19)-related hospitalizations and mortality. Randomized clinical trials provide limited enrollment, if any, to inform outcomes of such patients treated with remdesivir., Methods: Using the US PINC AI Healthcare Database, we identified adult patients with immunocompromising conditions, hospitalized for COVID-19 between December 2021 and February 2024. Primary outcome was all-cause inpatient mortality examined in propensity score (PS) matched patients in remdesivir versus non-remdesivir groups. Subgroup analyses were performed for patients with cancer, hematologic malignancies, and solid organ/hematopoietic stem cell transplant recipients., Results: Of 28,966 patients included in the study, 16,730 (58%) received remdesivir during first two days of hospitalization. After PS matching, 8,822 patients in remdesivir and 8,822 patients in non-remdesivir group were analyzed. Remdesivir was associated with a significantly lower mortality among patients with no supplemental oxygen (aHR [95% CI]: 14-day, 0.73 [0.62-0.86]; 28-day, 0.79 [0.68-0.91]) and among those with supplemental oxygen (14-day, 0.75 [0.67-0.85]; 28-day, 0.78 [0.70-0.86]). Remdesivir was also associated with lower mortality in subgroups of patients with cancer, hematological malignancies (including leukemia, lymphoma, and multiple myeloma), and solid organ/hematopoietic stem cell transplantation., Conclusions: In this large cohort of patients with immunocompromising conditions hospitalized for COVID-19, remdesivir was associated with significant improvement in survival, including patients with varied underlying immunocompromising conditions. The integration of current real-world evidence into clinical guideline recommendations can inform clinical communities to optimize treatment decisions in the evolving COVID-19 era, extending beyond the conclusion of the public health emergency declaration., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Competing Interests: Potential conflicts of interest. The author: No reported conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

Body weight is influenced by an interplay of individual and environmental factors. In people with human immunodeficiency virus (HIV), weight is also influenced by disease status with loss accompanying disease progression that is reversed with effective antiretroviral therapy. Weight changes in comparative antiretroviral therapy trials differ by regimen, with greater gains observed with the integrase strand transfer inhibitors dolutegravir and bictegravir, particularly when coadministered with tenofovir alafenamide fumarate, compared with regimens that include agents such as tenofovir disoproxil fumarate that attenuate weight gain. We review weight changes in major randomized trials of preexposure prophylaxis and initial and switch HIV therapy, highlighting the challenges to assessing the role of antiretroviral therapy in weight change. This examination forms the basis for a model that questions assumptions regarding an association between integrase strand transfer inhibitors and tenofovir alafenamide fumarate and excessive weight gain and calls for more careful consideration of these data when making HIV treatment decisions., Competing Interests: Potential conflicts of interest . D. A. W. has received honoraria for consultancy from Gilead Sciences, ViiV Healthcare, Janssen Pharmaceuticals, Merck & Co, Theratechnologies, and EMD Serono. His institution has received grant funding to support his research from Gilead Sciences, ViiV Healthcare, and Merck & Co. J. R. K. has served as a consultant to Gilead, Merck, Theratechnologies, and Janssen Pharmaceuticals and has received research support from Gilead Sciences and Merck. P. E. S. has served as a scientific advisory board member/consultant for Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Merck & Co, and Janssen Pharmaceuticals, He has received research support from Gilead Sciences, and GlaxoSmithKline/ViiV Healthcare. G. A. M. has received consultant fees from Janssen Pharmaceuticals, Gilead Sciences, ViiV Healthcare, Merck, and Theratechnologies. D. R. K. is a consultant to and received honoraria from AbbVie, Gilead Sciences, GlaxoSmithKline, Janssen, Pharmaceuticals, Merck & Co, Roche, and ViiV Healthcare. He has received research support from Gilead Sciences, ViiV Healthcare, Merck & Co, and Roche and has provided expert testimony on behalf of Gilead Sciences and Janssen. G. M. has served as an advisor to Novartis and Ipsen Pharmaceuticals and a speaker for Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme UK, and ViiV Healthcare. L. K. is a scientific and/or medical consultant to Altimmune, Boehringer Ingelheim, Gilead Sciences, Glyscend, Intellihealth, Johnson & Johnson, Eli Lilly, Novo Nordisk, Pfizer, Sidekick Health, twenty30.health, and Xeno Biosciences. J. v. W. is employed by ViiV Healthcare. R. E. C. is employed by Merck & Co. C. C. is employed by Gilead Sciences. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Safety data from randomized trials of antiretrovirals in pregnancy are scarce. We evaluated maternal bone and renal data from the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 2010 trial, which compared the safety and efficacy of 3 antiretroviral therapy regimens started in pregnancy: dolutegravir + emtricitabine/tenofovir alafenamide (DTG + FTC/TAF), dolutegravir + emtricitabine/tenofovir disoproxil fumarate (DTG + FTC/TDF), and efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF)., Methods: A subset of participants underwent dual-energy X-ray absorptiometry scans at postpartum week 50 only. Maternal bone mineral density (BMD) Z-scores were compared between arms. Maternal creatinine was measured at enrolment and periodically through week 50 postpartum, and by-arm differences in average weekly change in estimated creatinine clearance were compared., Results: Six hundred forty-three participants were randomized to DTG + FTC/TAF (N = 217) or DTG + FTC/TDF (N = 215) or EFV/FTC/TDF (N = 211). Median age = 27 years (IQR 23, 32), median CD4 count = 466 cells/mm3 (IQR 308, 624); 564 (88%) women enrolled in Africa and 479 (74%) breastfed. Week 50 postpartum dual-energy X-ray absorptiometry results from 154 women were included in the analysis. Hip and spine BMD was on average higher in women in the DTG + FTC/TAF and lower in the DTG + FTC/TDF and EFV/FTC/TDF arms, but no significant differences in BMD Z-scores were observed between treatment groups. The weekly rate of change in estimated creatinine clearance differed among treatment groups during the antepartum period, but not over the full study follow-up., Conclusions: Markers of bone and renal toxicity did not differ significantly through week 50 postpartum among women randomized to start DTG + FTC/TAF or DTG + FTC/TDF or EFV/FTC/TDF in pregnancy., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Treatment guidelines were developed early in the pandemic when much about COVID-19 was unknown. Given the evolution of SARS-CoV-2, real-world data can provide clinicians with updated information. The objective of this analysis was to assess mortality risk in patients hospitalized for COVID-19 during the Omicron period receiving remdesivir+dexamethasone versus dexamethasone alone., Methods: A large, multicenter US hospital database was used to identify hospitalized adult patients, with a primary discharge diagnosis of COVID-19 also flagged as "present on admission" treated with remdesivir+dexamethasone or dexamethasone alone from December 2021 to April 2023. Patients were matched 1:1 using propensity score matching and stratified by baseline oxygen requirements. Cox proportional hazards model was used to assess time to 14- and 28-day in-hospital all-cause mortality., Results: A total of 33 037 patients were matched, with most patients ≥65 years old (72%), White (78%), and non-Hispanic (84%). Remdesivir+dexamethasone was associated with lower mortality risk versus dexamethasone alone across all baseline oxygen requirements at 14 days (no supplemental oxygen charges: adjusted hazard ratio [95% CI]: 0.79 [0.72-0.87], low flow oxygen: 0.70 [0.64-0.77], high flow oxygen/non-invasive ventilation: 0.69 [0.62-0.76], invasive mechanical ventilation/extracorporeal membrane oxygen (IMV/ECMO): 0.78 [0.64-0.94]), with similar results at 28 days., Conclusions: Remdesivir+dexamethasone was associated with a significant reduction in 14- and 28-day mortality compared to dexamethasone alone in patients hospitalized for COVID-19 across all levels of baseline respiratory support, including IMV/ECMO. However, the use of remdesivir+dexamethasone still has low clinical practice uptake. In addition, these data suggest a need to update the existing guidelines., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

What Is This Summary About?: This is a plain-language summary of an article that reported on two studies of the medication bictegravir/emtricitabine/tenofovir alafenamide (shortened to B/F/TAF). B/F/TAF is a single pill containing three different drugs used to treat human immunodeficiency virus (known as HIV). The drugs work together to lower the levels of HIV (called viral load) in the body and make the virus undetectable in the blood. Researchers measured whether B/F/TAF was safe and effective when taken over 5 years in over 400 people in 10 countries who had never taken HIV medication before., What Were the Results?: After 5 years, almost all (99%) of the people who took B/F/TAF had an undetectable viral load. This does not mean that they were cured, but that the levels of HIV were so low that the tests used by researchers could not detect the virus in the blood. CD4 is a type of immune system cell. HIV causes CD4 cell numbers to decrease. On average, the number of CD4 cells increased by more than 300 cells per microliter (cells/μL) of blood over 5 years. This means that the immune system was improving. HIV is able to change its genes to escape the effects of the drugs. This is known as HIV resistance to treatment. Nine people had a viral load high enough to suggest that the drugs might not be working, but no resistance to B/F/TAF was seen. Some people (less than one in three) experienced medical problems thought to be linked to B/F/TAF treatment, known as side effects. The most common side effects were headache, diarrhea, nausea, tiredness (fatigue), dizziness, and difficulty falling or staying asleep (insomnia). On average, people's body weight increased by 3 kg in the first year of taking B/F/TAF. This might be because their general health improved after starting HIV treatment. Weight gained after that time was similar to the level of weight gain expected in the general population. Very few people (less than 1 in 100) stopped taking B/F/TAF because of side effects thought to have been caused by B/F/TAF., What Do the Results Mean?: B/F/TAF was effective at treating HIV in people who had never taken HIV medication before. Most (70%) people were still taking B/F/TAF after 5 years. Clinical Trial Registration: NCT02607930 (Study 1489); NCT02607956 (Study 1490) (ClinicalTrials.gov).

Objective: Tenofovir alafenamide (TAF)-based antiretroviral therapy (ART) regimens have been associated with adverse changes in lipid and glucose profiles compared with tenofovir disoproxil fumarate (TDF)-based ART, but data in pregnancy is limited. We evaluated metabolic markers in pregnant women with HIV after starting TAF- vs TDF-based ART., Methods: We analyzed data within the IMPAACT 2010/VESTED trial, which demonstrated better pregnancy outcomes in pregnant women randomized to initiate TAF/Emtricitabine/Dolutegravir (TAF/FTC+DTG; n=217) or TDF/FTC+DTG (n=215). We measured non-fasting plasma concentrations of glucose, total-cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), lipoprotein (a), and triglycerides from samples collected eight weeks after enrollment. We employed linear regression models to estimate by-arm mean differences., Results: 219 participants enrolled in the DTG arms in Zimbabwe and Uganda: 109 in the TAF/FTC+DTG and 110 in the TDF/FTC+DTG arms. At study entry, mean gestational age was 22.6 weeks, median HIV-1 RNA was 711 copies/mL, and mean age was 25.8 years. By eight weeks, mean total cholesterol was 12 mg/dL higher in women randomized to TAF/FTC+DTG versus TDF/FTC+DTG (95% CI 3.8, 21.1). Pregnant women in the TAF/FTC+DTG arm had higher mean LDL-C (7.1 mg/dL, 95% CI 0.2, 14.0), triglycerides (12.3 mg/dL, 95% CI 1.8, 22.7), lipoprotein (a) (7.3 mg/dL, 95% CI 1.1, 13.6), and lower mean HDL-C (2.8 mg/dL, 95% CI 0.1, 5.6) compared to the TDF/FTC+DTG arm., Conclusion: Pregnant women randomized to start TAF/FTC+DTG had higher lipids than those randomized to TDF/FTC+DTG within eight weeks of ART initiation. However, lipid levels were within normal reference ranges., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: There is limited evidence of association of nirmatrelvir-ritonavir (NMV-r) and incidence of postacute sequelae of SARS-CoV-2 infection (PASC) in patients with pre-existing cardiovascular disease (CVD)., Objectives: The objective of this study was to assess the association of NMV-r in nonhospitalized, vaccinated patients with pre-existing CVD and occurrence of PASC., Methods: We conducted a retrospective cohort study utilizing the TriNetX research network, including vaccinated patients with pre-existing CVD who developed COVID-19 between December 2021 and December 2022. Two cohorts were created based on NMV-r administration within 5 days of diagnosis: NMV-r and non-NMV-r cohort. The main outcome was presence of PASC, assessed between 30 to 90 days and 90 to 180 days after index COVID-19 infection. After propensity score matching, both cohorts were compared using t-test and chi-square test for continuous and categorical variables, respectively., Results: A total of 26,953 patients remained in each cohort after propensity score matching. Broadly defined PASC occurred in 6,925 patients (26%) in the NMV-r cohort vs 8,150 patients (30.6%) in the non-NMV-r cohort (OR: 0.80; 95% CI: 0.76-0.82; P  < 0.001) from 30 to 90 days and in 6,692 patients (25.1%) as compared to 8,910 patients (33.5%) (OR: 0.25, 95% CI: 0.23-0.29; P  < 0.001) from 90 to 180 days. Similarly, narrowly defined PASC occurred in 5,335 patients (20%) in the NMV-r cohort vs 6,271 patients (23.6%) in the non-NMV-r cohort between 30 and 90 days (OR: 0.81, 95% CI: 0.78-0.84, P  < 0.001) and in 5,121 patients (19.2%) as compared to 6,964 patients (26.1%) (OR: 0.67, 95% CI: 0.64-0.70, P  < 0.001) between 90 and 180 days., Conclusions: NMV-r in nonhospitalized vaccinated patients with pre-existing CVD with COVID-19 was associated with a reduction in PASC and health care utilization., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.PERSPECTIVESCOMPETENCY IN MEDICAL KNOWLEDGE: In a retrospective analysis, there is a significant risk reduction in PASC burden in high-risk patients with pre-existing CVD receiving NMV-r for the treatment of acute COVID-19 suggesting an association between treatment with NMV-r and a reduced incidence of the symptoms commonly reported with PASC. TRANSLATIONAL OUTLOOK: Prospective studies in the form of randomized controlled trials are urgently needed to understand the potential effect of antiviral therapy on the incidence of PASC., (© 2024 The Authors.)

Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

Background: HIV infection and abacavir-containing antiretroviral regimens are associated with vascular endothelial dysfunction and increased cardiovascular risk. Positron emission tomography (PET)-derived myocardial blood flow reserve (MBFR), the ratio of vasodilator stress to rest myocardial blood flow, is a well-validated measure of coronary microvascular health and marker of cardiovascular risk. Our objective was to compare MBFR among people with HIV (PWH) with matched non-HIV controls and to assess whether switching from dolutegravir/lamivudine/abacavir to the non-abacavir regimen bictegravir/emtricitabine/tenofovir alafenamide (TAF) would improve MBFR., Methods and Results: Thirty-seven PWH were 1:2 matched on cardiovascular risk factors to 75 people without HIV, and MBFR corrected for differences in resting hemodynamics was compared in a cross-sectional design. PWH were majority men (68%) with a mean age of 56 years. Mean stress myocardial blood flow (1.83 mL/min per g [95% CI, 1.68-1.98] versus 2.40 mL/min per g [95% CI, 2.25-2.54]; P <0.001) and MBFR (2.18 [95% CI, 1.96-2.40] versus 2.68 [95% CI, 2.47-2.89]; P =0.002) was significantly lower in PWH than in people without HIV. In a single-arm, multicenter trial, a subset of 25 PWH who were virologically suppressed on dolutegravir/lamivudine/abacavir underwent positron emission tomography myocardial perfusion imaging at baseline and after switching to bictegravir/emtricitabine/TAF. MBFR was unchanged after switching to bictegravir/emtricitabine/TAF for a mean of 27 weeks (MBFR, 2.34 to 2.29; P =0.61), except in PWH with impaired MBFR at baseline (<2.00; N=6) in whom MBFR increased from 1.58 to 2.02 ( P =0.02)., Conclusions: PWH had reduced coronary microvascular function compared with controls without HIV. Coronary microvascular function did not improve after switching from dolutegravir/lamivudine/abacavir to bictegravir/emtricitabine/TAF., Registration: URL: https://www.clinicaltrials.gov; unique identifier: NCT03656783.

Background: The effects of nirmatrelvir/ritonavir (NMV/r [Paxlovid]) on coronavirus disease 2019 (COVID-19) outcomes in younger vaccinated adults are unclear. The objective of this study was to assess if NMV/r use in vaccinated adults aged ≤50 years is associated with improved outcomes and to identify beneficial and nonbeneficial subgroups., Methods: In this cohort study, we generated 2 propensity-matched cohorts of 2547 patients from an 86 119-person cohort assembled from the TriNetX database. Patients in 1 cohort received NMV/r, and patients in the matched control cohort did not. The main outcome was composite of all-cause emergency department visits, hospitalization, and mortality., Results: The composite outcome was detected in 4.9% of the NMV/r cohort and 7.0% of the non-NMV/r cohort (odds ratio, 0.683 [95% confidence interval, .540-.864]; P = .001), indicating a 30% relative risk reduction. The number needed to treat (NNT) for the primary outcome was 47. Subgroup analyses found significant associations for patients with cancer (NNT = 45), cardiovascular disease (NNT = 30), and both conditions (NNT = 16). No benefit was found for patients with only chronic lower respiratory disorders (asthma/chronic obstructive pulmonary disease [COPD]) or without serious comorbidities. Thirty-two percent of NMV/r prescriptions in the overall database were for 18- to 50-year-olds., Conclusions: NMV/r use in vaccinated adults aged 18-50 years, especially with serious comorbidities, was associated with reduced all-cause hospital visits, hospitalization, and mortality in the first 30 days of COVID-19 illness. However, NMV/r in patients without significant comorbidities or with only asthma/COPD had no association of benefit. Therefore, identifying high-risk patients should be a priority and overprescription should be avoided., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Skeletal muscle quality and mass are important for maintaining physical function during advancing age. We leveraged baseline data from Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) to evaluate whether paraspinal muscle density and muscle area are associated with cardiac or physical function outcomes in people with HIV (PWH)., Methods: REPRIEVE is a double-blind randomized trial evaluating the effect of pitavastatin for primary prevention of major adverse cardiovascular events in PWH. This cross-sectional analysis focuses on participants who underwent coronary computed tomography at baseline. Lower thoracic paraspinal muscle density (Hounsfield units [HU]) and area (cm 2 ) were assessed on noncontrast computed tomography., Results: Of 805 PWH, 708 had paraspinal muscle measurements. The median age was 51 years and 17% were natal female patients. The median muscle density was 41 HU (male) and 30 HU (female); area 13.2 cm 2 /m (male) and 9.9 cm 2 /m (female). In adjusted analyses, greater density (less fat) was associated with a lower prevalence of any coronary artery plaque, coronary artery calcium score >0, and high plaque burden ( P = 0.06); area was not associated with plaque measures. Among 139 patients with physical function measures, greater area (but not density) was associated with better performance on a short physical performance battery and grip strength., Conclusions: Among PWH, greater paraspinal muscle density was associated with a lower prevalence of coronary artery disease while greater area was associated with better physical performance. Whether changes in density or area are associated with changes in CAD or physical performance will be evaluated through longitudinal analyses in REPRIEVE., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In a demonstration project, long-acting, injectable cabotegravir-rilpivirine (CAB-RPV) achieved viral suppression in a high proportion of people with HIV (PWH) who were virologically nonsuppressed with adherence barriers. We projected the long-term impact of CAB-RPV for nonsuppressed PWH experiencing adherence barriers., Methods: Using the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) model, we compared 3 strategies: (1) standard of care oral integrase inhibitor-based ART ( INSTI ); (2) INSTI-based ART with supportive social services ("wraparound services" [WS]) ( INSTI/WS ); and (3) CAB-RPV with WS ( CAB-RPV/WS ). Model outcomes included viral suppression (%) and engagement in care (%) at 3 years, and life expectancy (life-years [LYs]). Base case cohort characteristics included mean age of 47y (standard deviation [SD], 10y), 90% male at birth, and baseline mean CD4 count 150/µL (SD, 75/µL). Viral suppression at 3 months was 13% ( INSTI ), 28% ( INSTI/WS ), and 60% ( CAB-RPV/WS ). Mean loss to follow-up was 28/100 person-years (PY) (SD, 2/100 PY) without WS and 16/100 PY (SD, 1/100 PY) with WS., Results: Projected viral suppression at 3 years would vary widely: 16% ( INSTI ), 38% ( INSTI/WS ), and 44% ( CAB-RPV/WS ). Life expectancy would be 7.4 LY ( INSTI ), 9.0 LY ( INSTI/WS ), and 9.4 LY ( CAB-RPV/WS ). Projected benefits over oral ART would be greater for PWH initiating CAB-RPV/WS at lower CD4 counts. Across plausible key parameter ranges, CAB-RPV/WS would improve viral suppression and life expectancy compared with oral INSTI strategies., Conclusions: These model-based results support that long-acting injectable CAB-RPV with extensive support services for nonsuppressed PWH experiencing adherence barriers is likely to increase viral suppression and improve survival. A prospective study to provide further evidence is needed., Competing Interests: Potential conflicts of interest. T. W. has served as an ad hoc consultant to Merck and has received grant support (paid to Weill Cornell) from Merck. J. E. is a consultant to Merck, ViiV Healthcare, and Gilead Sciences; his institution receives research support for studies on which he is an investigator. P. E. S. is a consultant to Merck, ViiV Healthcare, and Gilead Sciences; his institution receives research support from Gilead and ViiV Healthcare for studies on which he is an investigator. E. P. H. reports serving as a member of the US Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Drugs taken during pregnancy can affect maternal and child health outcomes, but few studies have compared the safety and virological efficacy of different antiretroviral therapy (ART) regimens. We report the primary safety outcomes from enrolment up to 50 weeks post partum and a secondary virological efficacy outcome at 50 weeks post partum of three commonly used ART regimens for HIV-1., Methods: In this multicentre, open-label, randomised, controlled, phase 3 trial, we enrolled pregnant women aged 18 years or older with confirmed HIV-1 infection at 14-28 weeks of gestation. Women were enrolled at 22 clinical research sites in nine countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, and Zimbabwe). Participants were randomly assigned (1:1:1) to one of three oral regimens: dolutegravir, emtricitabine, and tenofovir alafenamide; dolutegravir, emtricitabine, and tenofovir disoproxil fumarate; or efavirenz, emtricitabine, and tenofovir disoproxil fumarate. Up to 14 days of antepartum ART before enrolment was permitted. Women with known multiple gestation, fetal anomalies, acute significant illness, transaminases more than 2·5 times the upper limit of normal, or estimated creatinine clearance of less than 60 mL/min were excluded. Primary safety analyses were pairwise comparisons between ART regimens of the proportion of maternal and infant adverse events of grade 3 or higher up to 50 weeks post partum. Secondary efficacy analyses at 50 weeks post partum included a comparison of the proportion of women with plasma HIV-1 RNA of less than 200 copies per mL in the combined dolutegravir-containing groups versus the efavirenz-containing group. Analyses were done in the intention-to-treat population, which included all randomly assigned participants with available data. This trial was registered with ClinicalTrials.gov, NCT03048422., Findings: Between Jan 19, 2018, and Feb 8, 2019, we randomly assigned 643 pregnant women to the dolutegravir, emtricitabine, and tenofovir alafenamide group (n=217), the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (n=215), and the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (n=211). At enrolment, median gestational age was 21·9 weeks (IQR 18·3-25·3), median CD4 count was 466 cells per μL (308-624), and median HIV-1 RNA was 903 copies per mL (152-5183). 607 (94%) women and 566 (92%) of 617 liveborn infants completed the study. Up to the week 50 post-partum visit, the estimated probability of experiencing an adverse event of grade 3 or higher was 25% in the dolutegravir, emtricitabine, and tenofovir alafenamide group; 31% in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group; and 28% in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (no significant difference between groups). Among infants, the estimated probability of experiencing at least one adverse event of grade 3 or higher by postnatal week 50 was 28% overall, with small and non-statistically significant differences between groups. By postnatal week 50, 14 infants whose mothers were in the efavirenz-containing group (7%) died, compared with six in the combined dolutegravir groups (1%). 573 (89%) women had HIV-1 RNA data available at 50 weeks post partum: 366 (96%) in the dolutegravir-containing groups and 186 (96%) in the efavirenz-containing group had HIV-1 RNA less than 200 copies per mL, with no significant difference between groups., Interpretation: Safety and efficacy data during pregnancy and up to 50 weeks post partum support the current recommendation of dolutegravir-based ART (particularly in combination with emtricitabine and tenofovir alafenamide) rather than efavirenz, emtricitabine, and tenofovir disoproxil fumarate, when started in pregnancy., Funding: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health., Competing Interests: Declaration of interests JvW is an employee of ViiV Healthcare and JFR is an employee of Gilead Sciences. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The language we use in our scientific communications can either empower or stigmatize the people we study and care for. Clinical Infectious Diseases is committed to prioritizing the use of inclusive, nonstigmatizing language in published manuscripts. We hereby call upon submitting authors, reviewers, and editors to do the same., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is a single-tablet regimen recommended for HIV-1 treatment. The safety and efficacy of B/F/TAF as initial therapy was established in two Phase 3 studies: 1489 (vs dolutegravir [DTG]/abacavir/lamivudine) and 1490 (vs DTG + F/TAF). After 144 weeks of randomized follow-up, an open-label extension evaluated B/F/TAF to 240 weeks., Methods: Of 634 participants randomized to B/F/TAF, 519 completed the double-blinded treatment, and 506/634 (80%) chose the 96-week open-label B/F/TAF extension, which was completed by 444/506 (88%) participants. Efficacy was based on the secondary outcome of the proportion of participants with HIV-1 RNA <50 copies/mL at Week 240 by missing = excluded and missing = failure methods. All 634 participants who were randomized to B/F/TAF and received at least one dose of B/F/TAF were included in efficacy and safety analyses. (Study 1489: ClinicalTrials.govNCT02607930; EudraCT 2015-004024-54. Study 1490: ClinicalTrials.govNCT02607956; EudraCT 2015-003988-10)., Findings: Of those with available virologic data, 98.6% (95% CI [97.0%-99.5%], 426/432) maintained HIV-1 RNA <50 copies/mL at Week 240 (missing = excluded); when missing virologic data were considered as failure, 67.2% (95% CI [63.4%-70.8%], 426/634) maintained HIV-1 RNA <50 copies/mL. Mean (SD) change in CD4+ count from baseline was +338 (236.2) cells/μL. No treatment-emergent resistance to B/F/TAF was detected. Adverse events led to drug discontinuation in 1.6% (n = 10/634) of participants (n = 5 with events considered drug-related). No discontinuations were due to renal adverse events. Median (IQR) total cholesterol increased 21 (1,42) mg/dL from baseline; the change in total cholesterol:HDL was 0.1 (-0.5,0.6) . Median (IQR) weight change from baseline was +6.1 kg (2.0, 11.7) at Week 240. In Study 1489, hip and spine bone mineral density mean percent changes from baseline were ≤0.6%., Interpretation: Through 5 years of follow-up, B/F/TAF maintained high rates of virologic suppression with no treatment-emergent resistance and rare drug discontinuations due to adverse events. These results demonstrate the durability and safety of B/F/TAF in people with HIV., Funding: Gilead Sciences., Competing Interests: Paul Sax has received grants or contracts support from Gilead Sciences and ViiV Healthcare; consulting fees from Gilead Sciences, ViiV Healthcare, Janssen Pharmaceuticals, and Merck; and has served on board(s) for Merck. José R. Arribas has received grants or contracts and support for travel from ViiV Healthcare and Gilead Sciences, consulting fees from ViiV Healthcare, Gilead Sciences, MSD, Janssen Pharmaceuticals, and Aelix, and speaking honoraria from ViiV Healthcare, Gilead Sciences, and MSD; Chloe Orkin has received grants or contracts from Gilead Sciences, MSD, GSK, Janssen Pharmaceuticals, ViiV Healthcare, and AstraZeneca, speaking honoraria from Gilead Sciences, MSD, GSK, Janssen Pharmaceuticals, and ViiV Healthcare, and travel support from ViiV Healthcare and has served as president of the Medical Womens Federation and a governing council member for the International AIDS Society; Adriano Lazzarin and Yazdan Yazdanpanah have declared no interests; Anton Pozniak has received grant support from Gilead Sciences, Janssen Pharmaceuticals, ViiV Healthcare, and Merck, consulting fees from ViiV Healthcare, Merck, and Gilead Sciences, speaking honoraria from Gilead Sciences, Janssen Pharmaceuticals, ViiV Healthcare, and Merck, and travel support from Gilead Sciences and has served on boards for MRC Penta Studies, BHIV A Guidelines, and EACS Guidelines. Edwin DeJesus has participated in clinical trials for Gilead Sciences, ViiV Healthcare, Merck, AbbVie, and TheraTechnologies/Taimed. Franco Maggiolo has received consulting fees from ViiV Healthcare, Gilead Sciences, MSD, and Janssen Pharmaceuticals. Hans-Jürgen Stellbrink has received grants or contracts support, consulting fees, and speaking honoraria from Gilead Sciences, ViiV Healthcare, Janssen-Cilag, and MSD Sharp & Dohme; travel support from Gilead Sciences; has served on boards for Gilead Sciences, ViiV Healthcare, and MSD Sharp & Dohme; and has received non-financial support for either equipment, materials, drugs, medical writing, gifts, or other services from Gilead Sciences. Rima Acosta, Hailin Huang, Jason T. Hindman, Hal Martin, and Jared M. Baeten are current or former employees of Gilead Sciences and hold stock in the company. David Wohl has received support for the present manuscript from Gilead Sciences, grants or contracts support from Gilead Sciences, ViiV Healthcare, and Merck; and consulting fees and speaking honoraria from Gilead Sciences, ViiV Healthcare, Janssen Pharmaceuticals, and Merck., (© 2023 The Authors.)

Background: Treatment of coronavirus disease 2019 (COVID-19) with nirmatrelvir plus ritonavir (NMV-r) in high-risk nonhospitalized unvaccinated patients reduced the risk of progression to severe disease. However, the potential benefits of NMV-r among vaccinated patients are unclear., Methods: We conducted a comparative retrospective cohort study using the TriNetX research network. Patients ≥18 years of age who were vaccinated and subsequently developed COVID-19 between 1 December 2021 and 18 April 2022 were included. Cohorts were developed based on the use of NMV-r within 5 days of diagnosis. The primary composite outcome was all-cause emergency room (ER) visit, hospitalization, or death at a 30-day follow-up. Secondary outcomes included individual components of primary outcomes, multisystem symptoms, COVID-19-associated complications, and diagnostic test utilization., Results: After propensity score matching, 1130 patients remained in each cohort. A primary composite outcome of all-cause ER visits, hospitalization, or death in 30 days occurred in 89 (7.87%) patients in the NMV-r cohort compared with 163 (14.4%) patients in the non-NMV-r cohort (odds ratio: .5; 95% confidence interval: .39-.67; P < .005) consistent with 45% relative risk reduction. A significant reduction in multisystem symptom burden and subsequent complications, such as lower respiratory tract infection, cardiac arrhythmia, and diagnostic radiology testing, were noted in NMV-r-treated patients. There was no apparent increase in serious complications between days 10 and 30., Conclusions: Treatment with NMV-r in nonhospitalized vaccinated patients with COVID-19 was associated with a reduced likelihood of ER visits, hospitalization, or death. Complications and overall resource utilization were also decreased., Competing Interests: Potential conflicts of interest. G. M. A. reports payment for expert testimony (10 000/year) and is the immediate Past-President of the American College of Physicians. R. M. W. reports that he is a member of the Lucian Leape Institute of the Institute for Healthcare Improvement (no compensation except for travel expenses); receives a yearly stipend for serving on the Board of Directors of The Doctors Company; serves on the Board of Directors of Second Wave Delivery Solution (for which he receives stock options) and the scientific advisory boards for Teladoc, a large telemedicine provider (ended 2021), Amino.com, Curai Health, and EarlySense (stock options); consults with Commure (stipend and stock options), Forward (stock options), and Notable (stock options); received honoraria as a speaker at conferences for many (>150) healthcare organizations, medical societies, hospitals (vast majority are nonprofit; for-profit entities since 2017 include Nuance, GE, Health Catalyst, AvaCare, Siemens, and Voalte); has given more than 200 talks (a few to for-profit entities including Nuance, GE, Health Catalyst, Siemens, AvaCare, and the Governance Institute) for which he has received honoraria; and holds the Benioff Endowed Chair in Hospital Medicine from Marc and Lynne Benioff and the Holly Smith Distinguished Professorship in Science and Medicine at the University of California San Francisco (UCSF). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Recent advances in treatment and prevention of HIV warrant updated recommendations to guide optimal practice., Objective: Based on a critical evaluation of new data, to provide clinicians with recommendations on use of antiretroviral drugs for the treatment and prevention of HIV, laboratory monitoring, care of people aging with HIV, substance use disorder and HIV, and new challenges in people with HIV, including COVID-19 and monkeypox virus infection., Evidence Review: A panel of volunteer expert physician scientists were appointed to update the 2020 consensus recommendations. Relevant evidence in the literature (PubMed and Embase searches, which initially yielded 7891 unique citations, of which 834 were considered relevant) and studies presented at peer-reviewed scientific conferences between January 2020 and October 2022 were considered., Findings: Initiation of antiretroviral therapy (ART) is recommended as soon as possible after diagnosis of HIV. Barriers to care should be addressed, including ensuring access to ART and adherence support. Integrase strand transfer inhibitor-containing regimens remain the mainstay of initial therapy. For people who have achieved viral suppression with a daily oral regimen, long-acting injectable therapy with cabotegravir plus rilpivirine given as infrequently as every 2 months is now an option. Weight gain and metabolic complications have been linked to certain antiretroviral medications; novel strategies to ameliorate these complications are needed. Management of comorbidities throughout the life span is increasingly important, because people with HIV are living longer and confronting the health challenges of aging. In addition, management of substance use disorder in people with HIV requires an evidence-based, integrated approach. Options for preexposure prophylaxis include oral medications (tenofovir disoproxil fumarate or tenofovir alafenamide plus emtricitabine) and, for the first time, a long-acting injectable agent, cabotegravir. Recent global health emergencies, like the SARS-CoV-2 pandemic and monkeypox virus outbreak, continue to have a major effect on people with HIV and the delivery of services. To address these and other challenges, an equity-based approach is essential., Conclusions and Relevance: Advances in treatment and prevention of HIV continue to improve outcomes, but challenges and opportunities remain.

Combination therapy with three antiretroviral agents has been integral to successful HIV-1 treatment since 1996. Although the efficacy, adverse effects, and toxicities of contemporary three-drug regimens have improved, even the newest therapies have potential adverse effects. The use of two-drug regimens is one way to reduce lifetime exposure to antiretroviral drugs while maintaining the benefits of viral suppression. Multiple large, randomised trials have shown the virological non-inferiority of certain two-drug regimens versus three-drug comparators, including adverse effect differences that reflect known profiles of the antiretroviral drugs in the respective regimens. Two-drug combinations are now recommended in treatment guidelines and include the first long-acting antiretroviral regimen for the treatment of HIV-1. Recommended two-drug regimens differ in their risks for, and factors associated with, virological failure and emergent resistance. The tolerability, safety, metabolic profiles, and drug interactions of two-drug regimens also vary by the constituent drugs. No current two-drug regimen is recommended for people with chronic hepatitis B virus as none include tenofovir. Two-drug regimens have increased options for individualised care., Competing Interests: Declaration of interests SGK has served on advisory boards for Gilead, ViiV, and Theratechnologies. JRA has received advisory fees, speaker fees, and grant support from ViiV, Janssen, Gilead, Merck, Aelix, and Thera. PC has worked on advisory boards at ViiV and Merck and received research and speaker funds from ViiV, CanSino, and Janssen and has received honoraria as a data safety and monitoring board member for Moderna. CO has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead, ViiV, Janssen, GlaxoSmithKline, AstraZeneca, and Merck. ESD has received research support from and is a consultant for Gilead, Merck, GlaxoSmithKline, and ViiV. PES receives research support from Gilead, GlaxoSmithKline, and ViiV. He serves as a scientific advisory board member and consultant for Gilead, GlaxoSmithKline, ViiV, Merck, and Janssen; and has editorial positions with UpToDate, Medscape, New England Journal of Medicine Journal Watch, and Open Forum Infectious Diseases. BOT has served as a consultant and received honoraria from GlaxoSmithKline, ViiV, Gilead, Merck, and Johnson & Johnson. KMG received a training grant from the Agency For Health Care Research and Quality (T32HS026122)., (Copyright © 2022 Elsevier Ltd. All rights reserved.)