Zidovudine/Lamivudine for HIV-1 Infection Contributes to Limb Fat Loss

Lipoatrophy is known to be associated with stavudine as part of the treatment for HIV infection, but it is less clear if this serious side effect is also related to other nucleoside reverse transcriptase inhibitors like zidovudine. We aimed to determine whether zidovudine-sparing first-line antiretroviral therapy would lead to less lipoatrophy and other metabolic changes than zidovudine-containing therapy.Fifty antiretroviral therapy-naïve HIV-1 infected men with an indication to start antiretroviral therapy were included in a randomized single blinded clinical trial. Randomisation was between zidovudine-containing therapy (zidovudine/lamivudine+lopinavir/ritonavir) and zidovudine-sparing therapy (nevirapine+lopinavir/ritonavir). Main outcome measures were body composition assessed by computed tomography and dual-energy X-ray absorptiometry scan and lipid profile before and after 3, 12, 24 months of antiretroviral therapy. In the zidovudine/lamivudine+lopinavir/ritonavir group, from 3 months onward limb fat decreased progressively by 684+/-293 grams (estimated mean+/-standard error of the mean)(p = 0.02) up to 24 months whereas abdominal fat increased, but exclusively in the visceral compartment (+21.9+/-8.1 cm(2), p = 0.008)). In contrast, in the nevirapine+lopinavir/ritonavir group, a generalized increase in fat mass was observed. After 24 months no significant differences in high density lipoprotein and total/high density lipoprotein cholesterol ratio were found between both treatment groups, but total and low density lipoprotein cholesterol levels were higher in the nevirapine+lopinavir/ritonavir group (6.1+/-0.2 versus 5.3+/-0.2 and 3.6+/-0.1 versus 2.8+/-0.1 mmol/l respectively, p<0.05). Virologic response and safety were comparable in both groups.Zidovudine/lamivudine+lopinavir/ritonavir, but not nevirapine+lopinavir/ritonavir in antiretroviral therapy-naïve patients, is associated with lipoatrophy and greater relative intraabdominal lipohypertrophy, suggesting that zidovudine/lamivudine contributes to both these features of lipodystrophy. These findings support to no longer consider zidovudine/lamivudine as one of the preferred possible components of first-line antiretroviral therapy where alternative treatments are available.ClinicalTrials.gov NCT 00122226

Immunogenicity of an additional mRNA-1273 SARS-CoV-2 vaccination in people with HIV with hyporesponse after primary vaccination

Background:The COVIH study is a prospective coronavirus disease 2019 (COVID-19) vaccination study in 1154 people with HIV (PWH), of whom 14% showed reduced antibody levels after primary vaccination. We evaluated whether an additional vaccination boosts immune responses in these hyporesponders. Methods: The primary end point was the increase in antibodies 28 days after additional mRNA-1273 vaccination. Secondary end points included neutralizing antibodies, S-specific T-cell and B-cell responses, and reactogenicity. Results:Of the 66 participants, 40 previously received 2 doses ChAdOx1-S, 22 received 2 doses BNT162b2, and 4 received a single dose Ad26.COV2.S. The median age was 63 years (interquartile range [IQR], 60–66), 86% were male, and median CD4 + T-cell count was 650/μL (IQR, 423–941). The mean S1-specific antibody level increased from 35 binding antibody units (BAU)/ mL (95% confidence interval [CI], 24–46) to 4317 BAU/mL (95% CI, 3275–5360) (P &lt; .0001). Of all participants, 97% showed an adequate response and the 45 antibody-negative participants all seroconverted. A significant increase in the proportion of PWH with ancestral S-specific CD4 + T cells (P = .04) and S-specific B cells (P = .02) was observed. Conclusions:An additional mRNA-1273 vaccination induced a robust serological response in 97% of PWH with a hyporesponse after primary vaccination.</p

Prospective individual patient data meta-analysis of two randomized trials on convalescent plasma for COVID-19 outpatients

Data on convalescent plasma (CP) treatment in COVID-19 outpatients are scarce. We aimed to assess whether CP administered during the first week of symptoms reduced the disease progression or risk of hospitalization of outpatients. Two multicenter, double-blind randomized trials (NCT04621123, NCT04589949) were merged with data pooling starting when = 50 years and symptomatic for <= 7days were included. The intervention consisted of 200-300mL of CP with a predefined minimum level of antibodies. Primary endpoints were a 5-point disease severity scale and a composite of hospitalization or death by 28 days. Amongst the 797 patients included, 390 received CP and 392 placebo; they had a median age of 58 years, 1 comorbidity, 5 days symptoms and 93% had negative IgG antibody-test. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The odds ratio (OR) of CP for improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311); OR for hospitalization or death was 0.919 (CI 0.592-1.416). CP effect on hospital admission or death was largest in patients with <= 5 days of symptoms (OR 0.658, 95%CI 0.394-1.085). CP did not decrease the time to full symptom resolution

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Increase in Carotid Artery Intima-Media Thickness and Arterial Stiffness but Improvement in Several Markers of Endothelial Function after Initiation of Antiretroviral Therapy

Background. The risk of cardiovascular disease in human immunodeficiency virus (HIV)-infected patients is an increasing concern. We studied the changes in vascular properties after the initiation of combination antiretroviral therapy (cART) as well as the contribution of different drug classes. Methods. cART-naive men were randomized to receive either lopinavir/ritonavir (LPV/r) plus zidovudine/lamivudine (ZDV/3TC) (n = 19) or LPV/r plus nevirapine (NVP) (n = 18). Carotid artery intima-media thickness (C-IMT), arterial stiffness (distensibility coefficients [DCs] and compliance coefficients [CCs] of the carotid, femoral, and brachial arteries; carotid elastic modulus; and augmentation index), and markers of endothelial function (soluble vascular cell adhesion molecule [sVCAM]-1, intercellular adhesion molecule [sICAM]-1, plasma von Willebrand factor (vWF) antigen, and plasminogen activator inhibitor-1 antigen) and inflammation (high-sensitivity C-reactive protein) were measured before the initiation of cART and after 3, 12, and 24 months of cART. Results. C-IMT increased by 0.061 +/- 0.016mm (P <.001) in the ZDV/3TC/LPV/r arm and by 0.044 +/- 0.018 mm (P = .012) in the NVP/LPV/r arm ( data are estimated means +/- SEs). Femoral artery DC( -1.66 +/- 0.78 x 10(-3)/kPa [P = .035]) and CC (-0.11 +/- 0.053 mm(2)/kPa [P = .043]) decreased in the ZDV/3TC/LPV/r arm and femoral DC decreased in the NVP/LPV/r arm (-1.72 +/- 0.85 x 10(-3)/kPa [P = .046]), with no significant difference in C-IMT or arterial stiffness between arms. sVCAM-1, sICAM-1, and vWF levels decreased significantly in both groups. Conclusion. C-IMT and femoral artery stiffness increased after the initiation of cART, whereas several markers of endothelial function improved, regardless of the composition of cAR

Carotid Intima-Media Thickness and Arterial Stiffness in HIV-Infected Patients: The Role of HIV, Antiretroviral Therapy, and Lipodystrophy

Objectives: HIV-infected patients using combination antiretroviral therapy (ART) have an increased cardiovascular risk. We aimed to identify the effects of HIV ART, and lipodystrophy (LD) on carotid artery intima-media thickness (C-IMT), a surrogate measure of atherosclerosis, and arterial stiffness, a marker of cardiovascular risk. Design: Case-control study of 77 HIV infected men (55 exposed to ART, 22 ART naive, and 23 with LD) and 52 controls. Methods: C-IMT was measured ultrasonically, and arterial stiffness was estimated by distensibility (DC) and compliance (CC) coefficients of the carotid, femoral, and brachial arteries, by the carotid Young elastic modulus and pulse wave velocity. Results: After adjustment for cardiovascular risk factors, HIV-infected patients had a 0.067 mm (10.8%) greater C-IMT than controls, 13.6% and 29.5% lower DC, and 14.1% and 31%, lower CC of the carotid and femoral arteries, respectively, but similar Young elastic modulus and pulse wave velocity. Patients exposed to ART had similar C-IMT compared with ART-naive patients but 25.9% lower DC and 21.7% lower CC of the femoral artery. Arterial properties did not differ between patients with and without LD. Conclusions: HIV infection is independently associated with C-IMT and generally increased arterial stiffness. ART use is associated with increased stiffness of the femoral arter