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Objective: The primary objective of the study was to assess the immunogenicity of an HIV-1 Gag conserved element DNA vaccine (p24CE DNA) in people with HIV (PWH) receiving suppressive antiretroviral therapy (ART)., Design: AIDS Clinical Trials Group A5369 was a phase I/IIa, randomized, double-blind, placebo-controlled study of PWH receiving ART with plasma HIV-1 RNA less than 50 copies/ml, current CD4 + T-cell counts greater than 500 cells/μl, and nadir CD4 + T-cell counts greater than 350 cells/μl., Methods: The study enrolled 45 participants randomized 2 : 1 : 1 to receive p24CE DNA vaccine at weeks 0 and 4, followed by p24CE DNA admixed with full-length p55 Gag DNA vaccine at weeks 12 and 24 (arm A); full-length p55 Gag DNA vaccine at weeks 0, 4, 12, and 24 (arm B); or placebo at weeks 0, 4, 12, and 24 (arm C). The active and placebo vaccines were administered by intramuscular electroporation., Results: There was a modest, but significantly greater increase in the number of conserved elements recognized by CD4 + and/or CD8 + T cells in arm A compared with arm C ( P  = 0.014). The percentage of participants with an increased number of conserved elements recognized by T cells was also highest in arm A (8/18, 44.4%) vs. arm C (0/10, 0.0%) ( P  = 0.025). There were no significant differences between treatment groups in the change in magnitude of responses to total conserved elements., Conclusion: A DNA-delivered HIV-1 Gag conserved element vaccine boosted by a combination of this vaccine with a full-length p55 Gag DNA vaccine induced a new conserved element-directed cellular immune response in approximately half the treated PWH on ART., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To examine recent trends and differences in all-cause and cause-specific hospitalization rates by race, ethnicity, and gender among persons with HIV (PWH) in the United States and Canada., Design: HIV clinical cohort consortium., Methods: We followed PWH at least 18 years old in care 2005-2015 in six clinical cohorts. We used modified Clinical Classifications Software to categorize hospital discharge diagnoses. Incidence rate ratios (IRR) were estimated using Poisson regression with robust variances to compare racial and ethnic groups, stratified by gender, adjusted for cohort, calendar year, injection drug use history, and annually updated age, CD4+, and HIV viral load., Results: Among 27 085 patients (122 566 person-years), 80% were cisgender men, 1% transgender, 43% White, 33% Black, 17% Hispanic of any race, and 1% Indigenous. Unadjusted all-cause hospitalization rates were higher for Black [IRR 1.46, 95% confidence interval (CI) 1.32-1.61] and Indigenous (1.99, 1.44-2.74) versus White cisgender men, and for Indigenous versus White cisgender women (2.55, 1.68-3.89). Unadjusted AIDS-related hospitalization rates were also higher for Black, Hispanic, and Indigenous versus White cisgender men (all P < 0.05). Transgender patients had 1.50 times (1.05-2.14) and cisgender women 1.37 times (1.26-1.48) the unadjusted hospitalization rate of cisgender men. In adjusted analyses, among both cisgender men and women, Black patients had higher rates of cardiovascular and renal/genitourinary hospitalizations compared to Whites (all P < 0.05)., Conclusion: Black, Hispanic, Indigenous, women, and transgender PWH in the United States and Canada experienced substantially higher hospitalization rates than White patients and cisgender men, respectively. Disparities likely have several causes, including differences in virologic suppression and chronic conditions such as diabetes and renal disease., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Compared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) has been associated with improvement in markers of renal dysfunction in individual randomized trials; however, the comparative incidence of clinically significant renal events remains unclear., Design: We used a pooled data approach to increase the person-years of drug exposure analysed, maximizing our ability to detect differences in clinically significant outcomes., Methods: We pooled clinical renal safety data across 26 treatment-naive and antiretroviral switch studies to compare the incidence of proximal renal tubulopathy and discontinuation due to renal adverse events between participants taking TAF-containing regimens vs. those taking TDF-containing regimens. We performed secondary analyses from seven large randomized studies (two treatment-naive and five switch studies) to compare incidence of renal adverse events, treatment-emergent proteinuria, changes in serum creatinine, creatinine clearance, and urinary biomarkers (albumin, beta-2-microglobulin, and retinol binding protein-to-creatinine ratios)., Results: Our integrated analysis included 9322 adults and children with HIV (n = 6360 TAF, n = 2962 TDF) with exposure of 12 519 person-years to TAF and 5947 to TDF. There were no cases of proximal renal tubulopathy in participants receiving TAF vs. 10 cases in those receiving TDF (P < 0.001), and fewer individuals on TAF (3/6360) vs. TDF (14/2962) (P < 0.001) discontinued due to a renal adverse event. Participants initiating TAF-based vs. TDF-based regimens had more favourable changes in renal biomarkers through 96 weeks of therapy., Conclusion: These pooled data from 26 studies, with over 12 500 person-years of follow-up in children and adults, support the comparative renal safety of TAF over TDF.

Objective: Characterize virologic and immunologic outcomes of INSTI-based antiretroviral therapy (ART) in experienced patients with and without virologic failure., Design: Prospective clinical cohort., Methods: ART-experienced, INSTI-naive participants in the University of North Carolina Center for AIDS Research HIV Clinical Cohort (UCHCC) initiating an INSTI-containing regimen 2007-2016 were followed from INSTI initiation (baseline) to the earliest of: outcome of interest, loss to follow-up (LTFU, 1 year without clinical visit), or death. Outcomes of interest were virologic failure (first of two consecutive viral loads at least 200 copies/ml more than 2 weeks apart, or one viral load ≥200 before LTFU) and immune recovery (first CD4 ≥500 cells/μl). Patients with baseline viral load at least 50 copies/ml were given 24 weeks before meeting virologic failure criteria. Kaplan-Meier curves and Cox proportional hazards models compared INSTI regimens and patient characteristics., Results: Of 773 patients, 32% were women, 59% African-American, and 42% had a viral load at least 50 copies/ml at INSTI initiation. After 2 years, 5% of patients with baseline viral load less than 50 copies/ml experienced virologic failure, compared with 35% of patients with baseline viral load at least 50 copies/ml (P < 0.01). Among patients with baseline viral load less than 50 copies/ml, dolutegravir/NRTIs was associated with longer time to virologic failure [adjusted hazard ratio (aHR) 0.11, 95% confidence interval (CI) 0.01-0.80], whereas among patients with baseline viral load at least 50 copies/ml, raltegravir/NRTIs was associated with longer time to virologic failure (aHR 0.35, 95% CI 0.18-0.68), both compared with elvitegravir/NRTIs. After 5 years suppressed, irrespective of baseline viral load, 61% of patients experienced immune recovery., Conclusion: In this cohort, INSTI-containing regimens led to low virologic failure rates in patients switching ART while suppressed. Viremic patients initiating INSTIs were at high risk of virologic failure during follow-up.

Objectives: To compare efficacy, safety, tolerability, and patient-reported outcomes between two single-tablet regimens, rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) and efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF), in HIV-1-infected, treatment-naive adults., Design: This was a phase 3b, 96-week, randomized, open-label, international, noninferiority trial., Methods: A total of 799 participants were randomized (1 : 1) to receive RPV/FTC/TDF or EFV/FTC/TDF. The primary efficacy endpoint evaluated proportions of participants with HIV-1 RNA less than 50 copies/ml using the Snapshot algorithm. Additional assessments included CD4 cell counts, genotypic/phenotypic resistance, adverse events, patient-reported outcomes, and quality of life questionnaires., Results: At week 96, trial completion rates were 80.2% (316/394; RPV/FTC/TDF) and 74.0% (290/392; EFV/FTC/TDF). Overall, RPV/FTC/TDF was noninferior to EFV/FTC/TDF [HIV-1 RNA <50 copies/ml: 77.9 vs. 72.4%, respectively; difference -5.5; 95%CI (-0.6, 11.5); P = 0.076]. RPV/FTC/TDF was significantly more efficacious compared with EFV/FTC/TDF in participants with baseline HIV-1 RNA equal to or less than 100 000 copies/ml (78.8 vs. 71.2%; P = 0.046) and in those with CD4 cell count greater than 200 cells/μl (80.6 vs. 73.0%; P = 0.018). There was no significant between-group difference in the CD4 cell count increase (278 ± 189 vs. 259 ± 191 cells/μl; P = 0.17). Few participants developed resistance after week 48 (1.0% RPV/FTC/TDF; 0.3% EFV/FTC/TDF). Compared with EFV/FTC/TDF, RPV/FTC/TDF was associated with fewer adverse event-related discontinuations (3.0 vs. 11.0%; P<0.001), significantly fewer adverse events due to central nervous system issues and rash, greater improvements in patient-reported symptoms, and significant improvements in the SF-12v2 quality of life questionnaire mental health composite score (P = 0.014)., Conclusion: In treatment-naive, HIV-1-infected participants, 96-week RPV/FTC/TDF treatment demonstrated noninferior efficacy and better tolerability than EFV/FTC/TDF.

Background: Decreased bone mineral density (BMD) is prevalent in HIV-infected patients. Bisphosphonates are currently the mainstay of treatment for postmenopausal and male osteoporosis in HIV-uninfected individuals; however, their efficacy and safety in HIV-infected patients remains unclear., Methods: In this prospective, randomized, placebo-controlled multicenter trial, we studied the effectiveness of calcium and vitamin D supplementation with or without alendronate in improving BMD in HIV-infected subjects receiving stable antiretroviral therapy. Subjects with secondary causes of osteoporosis were excluded. The study was powered to detect differences of 3.5% between arms and to detect a moderate sex effect in percentage change in lumbar spine BMD. All dual-energy X-ray absorptiometry scans were analysed centrally, blinded by arm., Results: The 82 subjects enrolled were 71% men, 77% white, with a baseline median age of 48 years, CD4 cell count of 469 cells/mul, and lumbar spine t-score of less than 2.1; 91% had HIV-RNA levels less than 400 copies/ml, and 99% were taking antiretroviral drugs. Compared with calcium/vitamin D alone, alendronate plus calcium/vitamin D resulted in significant improvements in BMD at the lumbar spine, total hip, and trochanter, but not at the femoral neck, compared with baseline. There were trends towards significant increases in BMD values in the calcium/vitamin D group at the lumbar spine, total hip, and femoral neck. There were no apparent sex differences in the responses to therapy. Alendronate was well tolerated, without significant adverse events., Conclusion: Once-weekly alendronate is safe and effective in the treatment of decreased BMD in HIV-infected patients.

Background: HIV-1 triple-class antiretroviral drug resistance (TC-DR) may substantially limit therapeutic options and compromise clinical outcomes., Objective: To estimate TC-DR prevalence and incidence, and identify risk factors for TC-DR acquisition., Methods: We identified patients in the University of North Carolina HIV Cohort Study with TC-DR HIV-1 variants. Nucleos(t)ide reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), and major protease inhibitor (PI) mutations, were based on the International AIDS Society - USA guidelines. Prevalence was estimated with the exact binomial distribution, incidence with the exact Poisson distribution, and multivariable analyses were performed using logistic regression., Results: Of 1587 patients, half initiated therapy with HAART (N = 789), 20% (N = 320) with non-HAART combination therapy, and 30% (N = 478) with one NRTI. The median time on therapy was 5.7 years [interquartile range (IQR) 2.9, 8.6], the median number of previous antiretroviral agents was six (IQR 4, 8), and 47% (N = 752) were exposed to at least one NRTI, NNRTI and PI. Assuming patients without genotypes did not harbor TC-DR virus, the prevalence of TC-DR among all antiretroviral-experienced patients was 8% [95% confidence interval (CI) 6%, 9%]. The prevalence was 3% (95% CI 2%, 4%) and 12% (95% CI 10%, 15%) among patients treated initially with HAART and non-HAART, respectively. The number of antiretroviral agents received and initiating therapy with non-HAART or an unboosted PI, increased TC-DR risk in multivariable analyses., Conclusion: The majority of patients with TC-DR have extensive antiretroviral exposure, particularly to non-HAART regimens, whereas HAART initiators are at low risk of acquiring TC-DR during a median of 4 years of follow-up.

Objectives: To identify the predictors of cytomegalovirus reactivation in AIDS patients on highly active antiretroviral therapy (HAART)., Design: This prospective study enrolled cytomegalovirus-seropositive AIDS patients on or about to start HAART, who were not receiving anti-cytomegalovirus prophylaxis. Clinical and laboratory data were collected over 3.5 years at clinic visits, which coincided with the study visits., Methods: Blood was obtained at every study visit and was used for measurements of cytomegalovirus cell-mediated immunity (lymphocyte proliferation, IFN-gamma, IL-2, and IL-10 production), cytomegalovirus viral load, CD4 cell count, and HIV viral load. A logistic-normal model was used to analyse outcome data with repeated observations., Results: Twenty-six patients had 40 episodes of cytomegalovirus reactivation (positive cytomegalovirus viral load) during the study. Their immunological and virological parameters were compared with 26 randomly selected control individuals from the same cohort. The risk of cytomegalovirus reactivation significantly decreased with every 6-month increase in HAART duration [odds ratio (OR) 0.5; P = 0.02] and marginally increased with every log10 RNA copies/ml HIV viral load (OR 2; P = 0.07). CD4 cell counts, cytomegalovirus lymphocyte proliferation, IL-2, and IL-10 did not reach significance as predictors of cytomegalovirus reactivation. However, cytomegalovirus IFN-gamma production significantly decreased the risk of cytomegalovirus reactivation (OR 0.03; P = 0.04)., Conclusion: Cytomegalovirus-specific IFN-gamma has a unique value as an immunological predictor of cytomegalovirus reactivation, demonstrating the importance of cellular immune responses in the control of cytomegalovirus replication in HAART recipients.