Efficacy and safety of switching to dolutegravir/lamivudine in virologically suppressed people with HIV-1 aged ≥ 50 years: week 48 pooled results from the TANGO and SALSA studies.

BACKGROUND: As the population of people with HIV ages, concerns over managing age-related comorbidities, polypharmacy, immune recovery, and drug-drug interactions while maintaining viral suppression have arisen. We present pooled TANGO and SALSA efficacy and safety results dichotomized by age (< 50 and ≥ 50 years). METHODS: Week 48 data from the open-label phase 3 TANGO and SALSA trials evaluating switch to once-daily dolutegravir/lamivudine (DTG/3TC) fixed-dose combination vs continuing current antiretroviral regimen (CAR) were pooled. Proportions of participants with HIV-1 RNA ≥ 50 and < 50 copies/mL (Snapshot, intention-to-treat exposed) and safety were analyzed by age category. Adjusted mean change from baseline in CD4 + cell count was assessed using mixed-models repeated-measures analysis. RESULTS: Of 1234 participants, 80% of whom were male, 29% were aged ≥ 50 years. Among those aged ≥ 50 years, 1/177 (< 1%) DTG/3TC participant and 3/187 (2%) CAR participants had HIV-1 RNA ≥ 50 copies/mL at 48 weeks; proportions with HIV-1 RNA < 50 copies/mL were high in both treatment groups (≥ 92%), consistent with overall efficacy and similar to observations in participants aged < 50 years (≥ 93%). Regardless of age category, CD4 + cell count increased or was maintained from baseline with DTG/3TC. Change from baseline in CD4 + /CD8 + ratio was similar across age groups and between treatment groups. One CAR participant aged < 50 years had confirmed virologic withdrawal, but no resistance was detected. In the DTG/3TC group, incidence of adverse events (AEs) was similar across age groups. Proportions of AEs leading to withdrawal were low and comparable between age groups. Although drug-related AEs were generally low, across age groups, drug-related AEs were more frequent in participants who switched to DTG/3TC compared with those who continued CAR. While few serious AEs were observed in both treatment groups, more were reported in participants aged ≥ 50 years vs < 50 years. CONCLUSIONS: Among individuals with HIV-1, switching to DTG/3TC maintained high rates of virologic suppression and demonstrated a favorable safety profile, including in those aged ≥ 50 years despite higher prevalence of concomitant medication use and comorbidities. TRIAL REGISTRATION NUMBER: TANGO, NCT03446573 (February 27, 2018); SALSA, NCT04021290 (July 16, 2019).

Changes in Inflammatory and Atherogenesis Biomarkers With the 2-Drug Regimen Dolutegravir Plus Lamivudine in Antiretroviral Therapy-Experienced, Virologically Suppressed People With HIV-1: A Systematic Literature Review.

Background: The 2-drug regimen dolutegravir plus lamivudine has demonstrated long-term noninferior efficacy vs 3-/4-drug regimens (3/4DRs) in phase 3 trials. This systematic literature review summarizes clinical trial and real-world evidence evaluating impact of dolutegravir plus lamivudine on inflammatory and atherogenesis biomarkers in people with human immunodeficiency virus type 1 (PWH). Methods: Using Ovid MEDLINE, Embase, PubMed, and Cochrane library databases and conference proceedings, we searched for studies published from 1 January 2013 to 14 July 2021, reporting changes in inflammatory and atherogenesis biomarkers with dolutegravir plus lamivudine in antiretroviral therapy-experienced, virologically suppressed PWH aged ≥18 years. Results: Four records representing 2 randomized controlled trials (RCTs) and 6 records of real-world evidence met eligibility criteria. All real-world studies evaluated CD4+/CD8+ ratio, while only 1 assessed inflammatory biomarkers. Across both RCTs, no consistent pattern of change in biomarkers was observed between dolutegravir/lamivudine and 3/4DR comparators. There were significant changes in soluble CD14 favoring dolutegravir/lamivudine in TANGO at weeks 48 and 144 and SALSA at week 48, and in interleukin-6 favoring the control group in TANGO at weeks 48 and 144. In the real-world study evaluating inflammatory biomarkers, median soluble CD14 significantly decreased 48 weeks postswitch to dolutegravir plus lamivudine (P < .001), while other biomarkers remained stable. In all 6 real-world studies, increases in CD4+/CD8+ ratio were reported after switch to dolutegravir plus lamivudine (follow-up, 12-60 months). Conclusions: Results show that dolutegravir plus lamivudine has a comparable impact on inflammatory and atherogenesis biomarkers vs 3/4DRs, with no consistent pattern of change after switch in virologically suppressed PWH.

Final efficacy analysis, interim safety analysis, and immunogenicity of a single dose of recombinant novel coronavirus vaccine (adenovirus type 5 vector) in adults 18 years and older: an international, multicentre, randomised, double-blinded, placebo-controlled phase 3 trial.

BACKGROUND: The Ad5-nCoV vaccine is a single-dose adenovirus type 5 (Ad5) vectored vaccine expressing the SARS-CoV-2 spike protein that was well-tolerated and immunogenic in phase 1 and 2 studies. In this study, we report results on the final efficacy and interim safety analyses of the phase 3 trial. METHODS: This double-blind, randomised, international, placebo-controlled, endpoint-case driven, phase 3, clinical trial enrolled adults aged 18 years older at study centres in Argentina, Chile, Mexico, Pakistan, and Russia. Participants were eligible for the study if they had no unstable or severe underlying medical or psychiatric conditions; had no history of a laboratory-confirmed SARS-CoV-2 infection; were not pregnant or breastfeeding; and had no previous receipt of an adenovirus-vectored, coronavirus, or SARS-CoV-2 vaccine. After informed consent was obtained, 25 mL of whole blood was withdrawn from all eligible participants who were randomised in a 1:1 ratio to receive a single intramuscular dose of 0·5 mL placebo or a 0·5 mL dose of 5 × 1010 viral particle (vp)/mL Ad5-nCoV vaccine; study staff and participants were blinded to treatment allocation. All participants were contacted weekly by email, telephone, or text message to self-report any symptoms of COVID-19 illness, and laboratory testing for SARS-CoV-2 was done for all participants with any symptoms. The primary efficacy objective evaluated Ad5-nCoV in preventing symptomatic, PCR-confirmed COVID-19 infection occurring at least 28 days after vaccination in all participants who were at least 28 days postvaccination on Jan 15, 2021. The primary safety objective evaluated the incidence of any serious adverse events or medically attended adverse events postvaccination in all participants who received a study injection. This trial is closed for enrolment and is registered with ClinicalTrials.gov (NCT04526990). FINDINGS: Study enrolment began on Sept 22, 2020, in Pakistan, Nov 6, 2020, in Mexico, Dec 2, 2020, in Russia and Chile, and Dec 17, 2020, in Argentina; 150 endpoint cases were reached on Jan 15, 2021, triggering the final primary efficacy analysis. One dose of Ad5-nCoV showed a 57·5% (95% CI 39·7-70·0, p=0·0026) efficacy against symptomatic, PCR-confirmed, COVID-19 infection at 28 days or more postvaccination (21 250 participants; 45 days median duration of follow-up [IQR 36-58]). In the primary safety analysis undertaken at the time of the efficacy analysis (36 717 participants), there was no significant difference in the incidence of serious adverse events (14 [0·1%] of 18 363 Ad5-nCoV recipients and 10 [0·1%] of 18 354 placebo recipients, p=0·54) or medically attended adverse events (442 [2·4%] of 18 363 Ad5-nCoV recipients and 411 [2·2%] of 18 354 placebo recipients, p=0·30) between the Ad5-nCoV or placebo groups, or any serious adverse events considered related to the study product (none in both Ad5-nCoV and placebo recipients). In the extended safety cohort, 1004 (63·5%) of 1582 of Ad5-nCoV recipients and 729 (46·4%) of 1572 placebo recipients reported a solicited systemic adverse event (p<0·0001), of which headache was the most common (699 [44%] of Ad5-nCoV recipients and 481 [30·6%] of placebo recipients; p<0·0001). 971 (61·3%) of 1584 Ad5-nCoV recipients and 314 (20·0%) of 1573 placebo recipients reported an injection-site adverse event (p<0·0001), of which pain at the injection site was the most frequent; reported by 939 (59%) Ad5-nCoV recipients and 303 (19%) placebo recipients. INTERPRETATION: One dose of Ad5-nCoV is efficacious and safe in healthy adults aged 18 years and older. FUNDING: CanSino Biologics and the Beijing Institute of Biotechnology.

Consensus statement on the role of health systems in advancing the long-term well-being of people living with HIV.

Health systems have improved their abilities to identify, diagnose, treat and, increasingly, achieve viral suppression among people living with HIV (PLHIV). Despite these advances, a higher burden of multimorbidity and poorer health-related quality of life are reported by many PLHIV in comparison to people without HIV. Stigma and discrimination further exacerbate these poor outcomes. A global multidisciplinary group of HIV experts developed a consensus statement identifying key issues that health systems must address in order to move beyond the HIV field's longtime emphasis on viral suppression to instead deliver integrated, person-centered healthcare for PLHIV throughout their lives.

Liver cirrhosis in HIV/HCV-coinfected individuals is related to NK cell dysfunction and exhaustion, but not to an impaired NK cell modulation by CD4+ T-cells.

INTRODUCTION: HIV worsens HCV-related liver disease by accelerating fibrosis progression; however, progression rates are extremely variable among HIV/HCV-coinfected individuals. NK cells are associated with modulation of liver fibrosis and are profoundly altered during HCV and HIV infections. CD4+ T-cells modulate NK cell function, and are also affected by HIV infection. Here, we aim to characterize the association of hepatic fibrosis with both the phenotype and function of peripheral NK cells and their regulation by CD4+ T-cells, in HIV/HCV-coinfected individuals. METHODS: Thirty-four HIV/HCV-coinfected individuals with minimal (n = 16) and advanced (n = 18) fibrosis (METAVIR F0/F1 and F4 scores respectively) and 20 healthy volunteers were enrolled. PBMC were obtained from peripheral blood samples and NK and CD4+ T-cells were isolated and analysed. NK cell phenotype (CD25, CD69, Nkp46, NKG2D, PD-1), degranulation (CD107a) and IFN-γ and TNF-α production, as well as CD4+ T-cell activation (CD69, CD25 and CD38) were measured by flow cytometry. CD4+ T-cell conditioned medium (CM) derived from F0/F1 or F4 individuals was assessed for IL-2 levels by ELISA. Modulation of NK cell functionality by these CMs was also analysed. RESULTS: When comparing to NK cells from individuals with minimal fibrosis, degranulation and cytokine secretion by NK cells from subjects with F4 scores was significantly impaired, while PD-1 expression was augmented. On the one hand, neither the expression of activation markers nor IL-2 secretion was distinctly induced in CD4+ T-cells from subjects with F0/F1 or F4 METAVIR scores. Finally, NK cell degranulation and cytokine secretion were not differentially modulated by CD4+ T-cell CM, whether CD4+ T-cells derived from subjects with minimal or advanced fibrosis. CONCLUSIONS: Low levels of NK and CD4+ T-cells in HIV/HCV-coinfected individuals with advanced liver fibrosis have been previously described. Here, we show that advanced liver fibrosis in coinfected individuals is associated to a defective function of NK cells and an increased expression of the exhaustion/senescence marker PD-1. This NK signature could not be attributed to changes in the ability of CD4+ T-cells to modulate NK cell function.

Rates and reasons for early change of first HAART in HIV-1-infected patients in 7 sites throughout the Caribbean and Latin America.

BACKGROUND: HAART rollout in Latin America and the Caribbean has increased from approximately 210,000 in 2003 to 390,000 patients in 2007, covering 62% (51%-70%) of eligible patients, with considerable variation among countries. No multi-cohort study has examined rates of and reasons for change of initial HAART in this region. METHODOLOGY: Antiretroviral-naïve patients >or= 18 years who started HAART between 1996 and 2007 and had at least one follow-up visit from sites in Argentina, Brazil, Chile, Haiti, Honduras, Mexico and Peru were included. Time from HAART initiation to change (stopping or switching any antiretrovirals) was estimated using Kaplan-Meier techniques. Cox proportional hazards modeled the associations between change and demographics, initial regimen, baseline CD4 count, and clinical stage. PRINCIPAL FINDINGS: Of 5026 HIV-infected patients, 35% were female, median age at HAART initiation was 37 years (interquartile range [IQR], 31-44), and median CD4 count was 105 cells/uL (IQR, 38-200). Estimated probabilities of changing within 3 months and one year of HAART initiation were 16% (95% confidence interval (CI) 15-17%) and 28% (95% CI 27-29%), respectively. Efavirenz-based regimens and no clinical AIDS at HAART initiation were associated with lower risk of change (hazard ratio (HR) = 1.7 (95% CI 1.1-2.6) and 2.1 (95% CI 1.7-2.5) comparing neverapine-based regimens and other regimens to efavirenz, respectively; HR = 1.3 (95% CI 1.1-1.5) for clinical AIDS at HAART initiation). The primary reason for change among HAART initiators were adverse events (14%), death (5.7%) and failure (1.3%) with specific toxicities varying among sites. After change, most patients remained in first line regimens. CONCLUSIONS: Adverse events were the leading cause for changing initial HAART. Predictors for change due to any reason were AIDS at baseline and the use of a non-efavirenz containing regimen. Differences between participant sites were observed and require further investigation.

[HBV and HCV co-infections in HIV positive patients in the "HAART era": new challenges]. / Coinfecciones por HBV y HCV en pacientes hiv positivos en la "era HAART": nuevos desafios.

Co-infections with HIV and HCV/HBV are frequently found due to the similar routes of transmission (sexual, parenteral and vertical). Since the introduction of highly active antiretroviral therapy (HAART) there has been a notably decrease in patients morbidity and mortality, nevertheless with the prolonged survival, many of these patients are at risk of developing chronic complication, secondary to the infection of hepatotropic viruses. End stage liver disease is one of the main causes of morbid-mortality among HIV patients in developed countries. Nowadays there are new available therapies, diagnostic and follow up techniques for HBV and HCV, what provides a better control of both co-infections.

Coinfecciones por HBV y HCV en pacientes HIV positivos en la era HAART: nuevos desafíos / HBV and HCV co-infections in HIV positive patients in the HAART era: new challenges

Las coinfecciones con virus de la hepatitis C (HCV) y/o virus de la hepatitis B (HBV) en pacientes infectados por el virus de la inmunodeficiencia humana (HIV) son un hallazgo frecuente en virtud de las similares vías de transmisión que estos agentes presentan (sexual, parenteral y vertical). Desde el advenimiento del tratamiento antirretroviral de alta eficiencia (TARV) se evidenció una marcada disminución en la morbi-mortalidad de los pacientes; sin embargo, ante la prolongación de su sobrevida, las complicaciones crónicas debidas a las coinfecciones con estos virus hepatotropos han cobrado importancia, convirtiéndose la enfermedad hepática en una de las primeras causas de morbi-mortalidad de los pacientes HIV positivos en los países desarrollados. Se disponen en la actualidad de nuevas terapias y métodos de diagnóstico y seguimiento para HBV y HCV, lo cual permite un mejor control de ambas coinfecciones.

Co-infections with HIV and HCV/HBV are frequently found due to the similar routes of transmission (sexual, parenteral and vertical). Since the introduction of highly active antiretroviral therapy (HAART) there has been a notably decrease in patients morbidity and mortality, nevertheless with the prolonged survival, many of these patients are at risk of developing chronic complication, secondary to the infection of hepatotropic viruses. End stage liver disease is one of the main causes of morbid-mortality among HIV patients in developed countries. Nowadays there are new available therapies, diagnostic and follow up techniques for HBV and HCV, what provides a better control of both co-infections.

Maternal antiretroviral drugs during pregnancy and infant low birth weight and preterm birth.

OBJECTIVE: To determine the relationship between maternal antiretroviral regimens during pregnancy and adverse infant outcomes [low birth weight (LBW) and preterm birth]. The a priori hypothesis was that protease inhibitor (PI)-containing regimens are associated with an increased risk of LBW and preterm birth. DESIGN: Prospective cohort study of HIV-1-infected women and their infants (NISDI Perinatal Study). METHODS: Data were analysed from 681 women receiving at least one antiretroviral drug [in order of increasing complexity: one or two nucleoside reverse transcriptase inhibitors (1-2 NRTI), two NRTI plus one non-nucleoside reverse transcriptase inhibitor (NNRTI) (HAART/NNRTI), or two NRTI plus one PI (HAART/PI)] for at least 28 days during pregnancy, and who delivered live born, singleton infants with known birth weight and gestational age by 1 March 2005. Multivariable logistic regression modeling was used to assess the relationship of maternal ART with LBW and with preterm birth, adjusting for covariates. RESULTS: The incidence of LBW and preterm birth, respectively, was 9.6% and 7.4% (1-2 NRTI), 7.4% and 5.8% (HAART/NNRTI), and 16.7% and 10.6% (HAART/PI). There was no statistically significant increased risk of LBW [adjusted odds ratio (AOR), 1.5; 95% confidence interval (95% CI), 0.7-3.2] or preterm birth (AOR, 1.1; 95% CI, 0.5-2.8) among women who received HAART/PI compared with women receiving 1-2 NRTI. CONCLUSIONS: Among a population of HIV-1-infected women in Latin America and the Caribbean, maternal receipt of PI-containing ART regimens during pregnancy was not associated with a statistically significant increase in risk of LBW or preterm birth.

Atazanavir--a once-daily HIV protease inhibitor that does not cause dyslipidemia in newly treated patients: results from two randomized clinical trials.

Protease inhibitor (PI) treatment can result in dyslipidemia in a significant proportion of patients. Atazanavir (ATV) is a once-daily PI that has not been associated with clinically relevant increases in total cholesterol (TC), fasting low-density lipoprotein cholesterol (LDL-C), or fasting triglyceride (TG) concentrations. The objectives of this paper were to evaluate lipid profiles in untreated patients, and investigate the frequency and severity of dyslipidemia in the same individuals after treatment with ATV or nelfinavir (NFV) for 48 weeks. Two multinational, randomized, active-controlled, blinded trials compared the safety and efficacy of ATV and NFV in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) in antiretroviral (ARV)-naive patients. Serum lipid concentrations were analyzed in patients who had available measurements both at baseline and at week 48. Patients who had missing data at either time point were not included. Lipid levels remained within baseline ranges at week 48 with ATV treatment, whereas clinically relevant elevations in TC, fasting LDL-C, and fasting TG concentrations occurred with NFV treatment. Mean changes from pre-treatment baseline in fasting LDL-C ranged from -6 percent to +6 percent in the ATV-treatment groups, and from +27 percent to +31 percent in the NFV-treatment groups. After 48 weeks, there was a substantive increase in the proportion of NFV-treated patients who would be recommended for lipid-lowering treatment by National Cholesterol Education Program (NCEP) guidelines, whereas a lesser proportion of ATV-treated patients would be recommended for lipid-lowering treatment. Atazanavir does not lead to dyslipidemia in ARV-naive patients, and may limit the need for lipid-lowering strategies to reduce the risk of cardiovascular disease.