Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women.

BACKGROUND: Safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preventing HIV infection. METHODS: We conducted a randomized, double-blind, double-dummy, noninferiority trial to compare long-acting injectable cabotegravir (CAB-LA, an integrase strand-transfer inhibitor [INSTI]) at a dose of 600 mg, given intramuscularly every 8 weeks, with daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for the prevention of HIV infection in at-risk cisgender men who have sex with men (MSM) and in at-risk transgender women who have sex with men. Participants were randomly assigned (1:1) to receive one of the two regimens and were followed for 153 weeks. HIV testing and safety evaluations were performed. The primary end point was incident HIV infection. RESULTS: The intention-to-treat population included 4566 participants who underwent randomization; 570 (12.5%) identified as transgender women, and the median age was 26 years (interquartile range, 22 to 32). The trial was stopped early for efficacy on review of the results of the first preplanned interim end-point analysis. Among 1698 participants from the United States, 845 (49.8%) identified as Black. Incident HIV infection occurred in 52 participants: 13 in the cabotegravir group (incidence, 0.41 per 100 person-years) and 39 in the TDF-FTC group (incidence, 1.22 per 100 person-years) (hazard ratio, 0.34; 95% confidence interval, 0.18 to 0.62). The effect was consistent across prespecified subgroups. Injection-site reactions were reported in 81.4% of the participants in the cabotegravir group and in 31.3% of those in the TDF-FTC group. In the participants in whom HIV infection was diagnosed after exposure to CAB-LA, INSTI resistance and delays in the detection of HIV infection were noted. No safety concerns were identified. CONCLUSIONS: CAB-LA was superior to daily oral TDF-FTC in preventing HIV infection among MSM and transgender women. Strategies are needed to prevent INSTI resistance in cases of CAB-LA PrEP failure. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 083 ClinicalTrials.gov number, NCT02720094.).

A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia.

BACKGROUND: Convalescent plasma is frequently administered to patients with Covid-19 and has been reported, largely on the basis of observational data, to improve clinical outcomes. Minimal data are available from adequately powered randomized, controlled trials. METHODS: We randomly assigned hospitalized adult patients with severe Covid-19 pneumonia in a 2:1 ratio to receive convalescent plasma or placebo. The primary outcome was the patient's clinical status 30 days after the intervention, as measured on a six-point ordinal scale ranging from total recovery to death. RESULTS: A total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. The median time from the onset of symptoms to enrollment in the trial was 8 days (interquartile range, 5 to 10), and hypoxemia was the most frequent severity criterion for enrollment. The infused convalescent plasma had a median titer of 1:3200 of total SARS-CoV-2 antibodies (interquartile range, 1:800 to 1:3200). No patients were lost to follow-up. At day 30 day, no significant difference was noted between the convalescent plasma group and the placebo group in the distribution of clinical outcomes according to the ordinal scale (odds ratio, 0.83; 95% confidence interval [CI], 0.52 to 1.35; P = 0.46). Overall mortality was 10.96% in the convalescent plasma group and 11.43% in the placebo group, for a risk difference of -0.46 percentage points (95% CI, -7.8 to 6.8). Total SARS-CoV-2 antibody titers tended to be higher in the convalescent plasma group at day 2 after the intervention. Adverse events and serious adverse events were similar in the two groups. CONCLUSIONS: No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo. (PlasmAr ClinicalTrials.gov number, NCT04383535.).

Telemedicine in HIV health care during the COVID-19 pandemic: An implementation research study in Buenos Aires, Argentina.

BACKGROUND: From October 2020 to October 2022, we conducted an implementation study to offer telemedicine (TM) across four HIV units of general public hospitals in Buenos Aires. The intervention used TM to provide a continuum of care to patients with HIV. METHODS AND SETTING: We used the RE-AIM framework to evaluate the strategy. The study started during a COVID-19 outbreak with strict lockdown policies and continued until return to normal practices. Implementation facilitation served as the core implementation strategy. RESULTS: We reached 4118 patients (58% of eligible individuals), and the main perceived benefits were the ability to avoid exposure to infectious diseases and reduced travel time and cost. After a median of 515 days of follow-up, 95.7% of participants with HIV were receiving antiretroviral therapy, and 87.8% were virally suppressed, with a median CD4+ count of 648 cells/µL. In total, 36.6% reported clinical events, and 20.4% presented with COVID-19 infection. The proportion of physicians adopting TM was 69.37%. After enrolment, 2406 of 5640 (43%) follow-up visits were conducted via TM. By the end of the study, 26.29% of appointments offered in the four centres were through TM, whereas 73.71% were in-person appointments. CONCLUSION: It was feasible to implement TM in the four centres in the public health sector in Buenos Aires, Argentina. It was acceptable for both patients and healthcare workers, and effectively reached a large proportion of the population served in these clinics. Both healthcare workers and patients consider it a model of care that will continue to be offered in the future.

Deep-sequencing of viral genomes from a large and diverse cohort of treatment-naive HIV-infected persons shows associations between intrahost genetic diversity and viral load.

BACKGROUND: Infection with human immunodeficiency virus type 1 (HIV) typically results from transmission of a small and genetically uniform viral population. Following transmission, the virus population becomes more diverse because of recombination and acquired mutations through genetic drift and selection. Viral intrahost genetic diversity remains a major obstacle to the cure of HIV; however, the association between intrahost diversity and disease progression markers has not been investigated in large and diverse cohorts for which the majority of the genome has been deep-sequenced. Viral load (VL) is a key progression marker and understanding of its relationship to viral intrahost genetic diversity could help design future strategies for HIV monitoring and treatment. METHODS: We analysed deep-sequenced viral genomes from 2,650 treatment-naive HIV-infected persons to measure the intrahost genetic diversity of 2,447 genomic codon positions as calculated by Shannon entropy. We tested for associations between VL and amino acid (AA) entropy accounting for sex, age, race, duration of infection, and HIV population structure. RESULTS: We confirmed that the intrahost genetic diversity is highest in the env gene. Furthermore, we showed that mean Shannon entropy is significantly associated with VL, especially in infections of >24 months duration. We identified 16 significant associations between VL (p-value<2.0x10-5) and Shannon entropy at AA positions which in our association analysis explained 13% of the variance in VL. Finally, equivalent analysis based on variation in HIV consensus sequences explained only 2% of VL variance. CONCLUSIONS: Our results elucidate that viral intrahost genetic diversity is associated with VL and could be used as a better disease progression marker than HIV consensus sequence variants, especially in infections of longer duration. We emphasize that viral intrahost diversity should be considered when studying viral genomes and infection outcomes. TRIAL REGISTRATION: Samples included in this study were derived from participants who consented in the clinical trial, START (NCT00867048) (23), run by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT). All the participant sites are listed here: http://www.insight-trials.org/start/my_phpscript/participating.php?by=site.

Effect of Oral Oseltamivir on Virological Outcomes in Low-risk Adults With Influenza: A Randomized Clinical Trial.

BACKGROUND: Duration of viral shedding is a determinant of infectivity and transmissibility, but few data exist about oseltamivir's ability to alter viral shedding. METHODS: From January 2012 through October 2017, a randomized, double-blinded multicenter clinical trial was conducted in adults aged 18-64 years at 42 sites in Thailand, the United States, and Argentina. Participants with influenza A or B and without risk factors for complications of influenza were screened for the study. Eligible participants were randomized to receive oseltamivir 75 mg or placebo twice daily for 5 days. The primary endpoint was the percentage of participants with virus detectable by polymerase chain reaction in nasopharyngeal swab at day 3. RESULTS: Of 716 adults screened for the study, 558 were randomized, and 501 were confirmed to have influenza. Forty-six participants in the pilot study were excluded, and 449 of the 455 participants in the population for the primary analysis had day 3 viral shedding results. Ninety-nine (45.0%) of 220 participants in the oseltamivir arm had virus detected at day 3 compared with 131 (57.2%) of 229 participants in the placebo arm (absolute difference of -12.2% [-21.4%, -3.0%], P =; .010). The median time to alleviation of symptoms was 79.0 hours for the oseltamivir arm and 84.0 hours for the placebo arm (P =; .34) in those with confirmed influenza infection. CONCLUSIONS: Oseltamivir decreased viral shedding in this low-risk population. However, in the population enrolled in this study, it did not significantly decrease the time to resolution of clinical symptoms. CLINICAL TRIALS REGISTRATION: NCT01314911.

Association Between Single-Nucleotide Polymorphisms in HLA Alleles and Human Immunodeficiency Virus Type 1 Viral Load in Demographically Diverse, Antiretroviral Therapy-Naive Participants From the Strategic Timing of AntiRetroviral Treatment Trial.

The impact of variation in host genetics on replication of human immunodeficiency virus type 1 (HIV-1) in demographically diverse populations remains uncertain. In the current study, we performed a genome-wide screen for associations of single-nucleotide polymorphisms (SNPs) to viral load (VL) in antiretroviral therapy-naive participants (n = 2440) with varying demographics from the Strategic Timing of AntiRetroviral Treatment (START) trial. Associations were assessed using genotypic data generated by a customized SNP array, imputed HLA alleles, and multiple linear regression. Genome-wide significant associations between SNPs and VL were observed in the major histocompatibility complex class I region (MHC I), with effect sizes ranging between 0.14 and 0.39 log10 VL (copies/mL). Supporting the SNP findings, we identified several HLA alleles significantly associated with VL, extending prior observations that the (MHC I) is a major host determinant of HIV-1 control with shared genetic variants across diverse populations and underscoring the limitations of genome-wide association studies as being merely a screening tool.

Using Clinical Research Networks to Assess Severity of an Emerging Influenza Pandemic.

Background: Early clinical severity assessments during the 2009 influenza A H1N1 pandemic (pH1N1) overestimated clinical severity due to selection bias and other factors. We retrospectively investigated how to use data from the International Network for Strategic Initiatives in Global HIV Trials, a global clinical influenza research network, to make more accurate case fatality ratio (CFR) estimates early in a future pandemic, an essential part of pandemic response. Methods: We estimated the CFR of medically attended influenza (CFRMA) as the product of probability of hospitalization given confirmed outpatient influenza and the probability of death given hospitalization with confirmed influenza for the pandemic (2009-2011) and post-pandemic (2012-2015) periods. We used literature survey results on health-seeking behavior to convert that estimate to CFR among all infected persons (CFRAR). Results: During the pandemic period, 5.0% (3.1%-6.9%) of 561 pH1N1-positive outpatients were hospitalized. Of 282 pH1N1-positive inpatients, 8.5% (5.7%-12.6%) died. CFRMA for pH1N1 was 0.4% (0.2%-0.6%) in the pandemic period 2009-2011 but declined 5-fold in young adults during the post-pandemic period compared to the level of seasonal influenza in the post-pandemic period 2012-2015. CFR for influenza-negative patients did not change over time. We estimated the 2009 pandemic CFRAR to be 0.025%, 16-fold lower than CFRMA. Conclusions: Data from a clinical research network yielded accurate pandemic severity estimates, including increased severity among younger people. Going forward, clinical research networks with a global presence and standardized protocols would substantially aid rapid assessment of clinical severity. Clinical Trials Registration: NCT01056354 and NCT01056185

Differences in response to antiretroviral therapy in HIV-positive patients being treated for tuberculosis in Eastern Europe, Western Europe and Latin America.

BACKGROUND: Efavirenz-based antiretroviral therapy (ART) regimens are preferred for treatment of adult HIV-positive patients co-infected with tuberculosis (HIV/TB). Few studies have compared outcomes among HIV/TB patients treated with efavirenz or non-efavirenz containing regimens. METHODS: HIV-positive patients aged ≥16 years with a diagnosis of tuberculosis recruited to the TB:HIV study between Jan 1, 2011, and Dec 31, 2013 in 19 countries in Eastern Europe (EE), Western Europe (WE), and Latin America (LA) who received ART concomitantly with TB treatment were included. Patients either received efavirenz-containing ART starting between 15 days prior to, during, or within 90 days after starting tuberculosis treatment, (efavirenz group), or other ART regimens (non-efavirenz group). Patients who started ART more than 90 days after initiation of TB treatment, or who experienced ART interruption of more than 15 days during TB treatment were excluded. We describe rates and factors associated with death, virological suppression, and loss to follow up at 12 months using univariate, multivariate Cox, and marginal structural models to compare the two groups of patients. RESULTS: Of 965 patients (647 receiving efavirenz-containing ART, and 318 a non-efavirenz regimen) 50% were from EE, 28% from WE, and 22% from LA. Among those not receiving efavirenz-containing ART, regimens mainly contained a ritonavir-boosted protease inhibitor (57%), or raltegravir (22%). At 12 months 1.4% of patients in WE had died, compared to 20% in EE: rates of virological suppression ranged from 21% in EE to 61% in WE. After adjusting for potential confounders, rates of death (adjusted Hazard Ratio; aHR, 95%CI: 1.13, 0.72-1.78), virological suppression (aHR, 95%CI: 0.97, 0.76-1.22), and loss to follow up (aHR, 95%CI: 1.17, 0.81-1.67), were similar in patients treated with efavirenz and non-efavirenz containing ART regimens. CONCLUSION: In this large, prospective cohort, the response to ART varied significantly across geographical regions, whereas the ART regimen (efavirenz or non-efavirenz containing) did not impact on the proportion of patients who were virologically-suppressed, lost to follow up or dead at 12 months.

Persistent disparities in antiretroviral treatment (ART) coverage and virological suppression across Europe, 2004 to 2015.

BACKGROUND: Direct comparisons between countries in core HIV care parameters are often hampered by differences in data collection. AIM: Within the EuroSIDA study, we compared levels of antiretroviral treatment (ART) coverage and virological suppression (HIV RNA < 500 copies/mL) across Europe and explored temporal trends. METHODS: In three cross-sectional analyses in 2004-05, 2009-10 and 2014-15, we assessed country-specific percentages of ART coverage and virological suppression among those on ART. Temporal changes were analysed using logistic regression. RESULTS: Overall, the percentage of people on ART increased from 2004-05 (67.8%) to 2014-15 (78.2%), as did the percentage among those on ART who were virologically suppressed (75.2% in 2004-05, 87.7% in 2014-15). However, the rate of improvement over time varied significantly between regions (p < 0.01). In 2014-15, six of 34 countries had both ART coverage and virological suppression of above 90% among those on ART. The pattern varied substantially across clinics within countries, with ART coverage ranging from 61.9% to 97.0% and virological suppression from 32.2% to 100%. Compared with Western Europe (as defined in this study), patients in other regions were less likely to be virologically suppressed in 2014-15, with the lowest odds of suppression (adjusted odds ratio = 0.16; 95% confidence interval (CI): 0.13-0.21) in Eastern Europe. CONCLUSIONS: Despite overall improvements over a decade, we found persistent disparities in country-specific estimates of ART coverage and virological suppression. Underlying reasons for this variation warrant further analysis to identify a best practice and benchmark HIV care across EuroSIDA.

Antiretroviral therapy and arterial elasticity in HIV-infected patients.

Cardiovascular risk is increased in HIV-infected patients and has become a leading cause of morbi-mortality in this population. The purpose of this study is to compare HIV-infected patients on antiretroviral therapy (ART) and ART-naïve HIV-infected patients regarding arterial elasticity. From September 2010 to September 2015, 105 HIV-infected subjects were enrolled, 41 ART-naïve and 64 on ART with stable viral suppression. Elasticity of large and small arteries (LAE and SAE) was assessed by analysis of radial pulse waveforms using a calibrated device. A single set of measurements was performed. Multivariate linear regression models were constructed to estimate independent correlates of arterial elasticity. On-ART and ART-naïve patients were similar with respect to gender, age, body mass index, Framingham cardiovascular risk score, smoking habits, and CD4+ counts. Median time on treatment was 60 months and 79% of patients were on regimens based on non-nucleoside reverse-transcriptase inhibitors. No significant differences in LAE and SAE assessments were found between groups. However, time on ART and cholesterol levels were independently associated with LAE impairment. No association between arterial elasticity and CD4+ counts was found. We conclude that cumulative exposure to ART may play a role on LAE impairment and deserves further investigation.

Maraviroc, as a Switch Option, in HIV-1-infected Individuals With Stable, Well-controlled HIV Replication and R5-tropic Virus on Their First Nucleoside/Nucleotide Reverse Transcriptase Inhibitor Plus Ritonavir-boosted Protease Inhibitor Regimen: Week 48 Results of the Randomized, Multicenter MARCH Study.

BACKGROUND: Alternative combination antiretroviral therapies in virologically suppressed human immunodeficiency virus (HIV)-infected patients experiencing side effects and/or at ongoing risk of important comorbidities from current therapy are needed. Maraviroc (MVC), a chemokine receptor 5 antagonist, is a potential alternative component of therapy in those with R5-tropic virus. METHODS: The Maraviroc Switch Study is a randomized, multicenter, 96-week, open-label switch study in HIV type 1-infected adults with R5-tropic virus, virologically suppressed on a ritonavir-boosted protease inhibitor (PI/r) plus double nucleoside/nucleotide reverse transcriptase inhibitor (2 N(t)RTI) backbone. Participants were randomized 1:2:2 to current combination antiretroviral therapy (control), or replacing the protease inhibitor (MVC + 2 N(t)RTI arm) or the nucleoside reverse transcriptase inhibitor backbone (MVC + PI/r arm) with twice-daily MVC. The primary endpoint was the difference (switch minus control) in proportion with plasma viral load (VL) <200 copies/mL at 48 weeks. The switch arms were judged noninferior if the lower limit of the 95% confidence interval (CI) for the difference in the primary endpoint was < -12% in the intention-to-treat (ITT) population. RESULTS: The ITT population comprised 395 participants (control, n = 82; MVC + 2 N(t)RTI, n = 156; MVC + PI/r, n = 157). Baseline characteristics were well matched. At week 48, noninferior rates of virological suppression were observed in those switching away from a PI/r (93.6% [95% CI, -9.0% to 2.2%] and 91.7% [95% CI, -9.6% to 3.8%] with VL <200 and <50 copies/mL, respectively) compared to the control arm (97.6% and 95.1% with VL <200 and <50 copies/mL, respectively). In contrast, MVC + PI/r did not meet noninferiority bounds and was significantly inferior (84.1% [95% CI, -19.8% to -5.8%] and 77.7% [95% CI, -24.9% to -8.4%] with VL <200 and <50 copies/mL, respectively) to the control arm in the ITT analysis. CONCLUSIONS: These data support MVC as a switch option for ritonavir-boosted PIs when partnered with a 2-N(t)RTI backbone, but not as part of N(t)RTI-sparing regimens comprising MVC with PI/r. CLINICAL TRIALS REGISTRATION: NCT01384682.

Late diagnosis of HIV infection in asymptomatic patients.

Recent findings from the START Trial provided evidence that early initiation of antiretroviral treatment should be implemented as the global standard of care. However, a large proportion of patients are still being diagnosed in late stages. Our objective was to evaluate the temporal trend in the CD4+ cell count at diagnosis during a 13 year period and the factors associated with late HIV diagnosis in asymptomatic individuals tested in the Centre for Prevention, Counselling and Diagnosis of our hospital. It was a retrospective study including all asymptomatic patients with new diagnosis of HIV infection. Very late presenters (VLP) were defined as those with CD4+ counts < 200 and late presenters (LP) with CD4+ < 350 cell/mm3. We also evaluated the proportion of patients diagnosed with CD4+ cell counts below 500 cell/mm3. Between January 2002 and December 2014, 20 263 patients were tested for HIV, 1104 with a positive result of whom 995 asymptomatic individuals were included. Overall, median CD4+ count was 372 cells/mm3 and HIV-RNA 31 145 copies/ml. There was no evidence that the CD4+ count at diagnosis progressively increased over time, nor that the proportion of VLP and LP decreased. In a multivariate model older age, heterosexual transmission and intravenous drug use remained as independent factors associated with LP. In conclusion, late diagnosis of HIV infection remains prevalent among asymptomatic patients, highlighting the need to continue implementing strategies towards early diagnosis.

Repeat pregnancy in women with HIV infection in Latin America and the Caribbean.

Intended and unintended pregnancies occur frequently among human immunodeficiency virus (HIV)-infected women. We evaluated the occurrence of repeat pregnancy and characteristics associated with this outcome among HIV-infected women in Latin America and the Caribbean who were participating in the National Institute of Child Health and Human Development (NICHD) International Site Development Initiative (NISDI). Of the 1342 HIV-infected pregnant women enrolled in NISDI, 124 (9.2%) had one or more repeat pregnancies on study. Median time between the index delivery and date of conception of the subsequent pregnancy was 1.4 years (range 0.1-5.7). Younger age (odds ratio [OR] = 1.07, 95% confidence interval [CI]: 1.04-1.11 per one year decrease in age), hospitalization during the index pregnancy or up to six months post-partum [OR = 2.0, 95% CI: 1.2-3.4], and poor index pregnancy outcome (stillbirth or spontaneous/therapeutic abortion; OR = 3.4, 95% CI: 1.4-8.4) were associated with increased occurrence of repeat pregnancy in multivariable analysis. Among women with repeat pregnancies, the proportion receiving antiretroviral treatment (vs. prophylaxis) increased from 39.4% at the time of the index pregnancy to 81.8% at the time of the repeat pregnancy (p < 0.001). These results can help identify women most likely to benefit from reproductive counseling in order to assist with healthy pregnancy planning and prevention of unintended pregnancies.

Short- and long-term mortality and causes of death in HIV/tuberculosis patients in Europe.

Mortality of HIV/tuberculosis (TB) patients in Eastern Europe is high. Little is known about their causes of death. This study aimed to assess and compare mortality rates and cause of death in HIV/TB patients across Eastern Europe and Western Europe and Argentina (WEA) in an international cohort study. Mortality rates and causes of death were analysed by time from TB diagnosis (<3 months, 3-12 months or >12 months) in 1078 consecutive HIV/TB patients. Factors associated with TB-related death were examined in multivariate Poisson regression analysis. 347 patients died during 2625 person-years of follow-up. Mortality in Eastern Europe was three- to ninefold higher than in WEA. TB was the main cause of death in Eastern Europe in 80%, 66% and 61% of patients who died <3 months, 3-12 months or >12 months after TB diagnosis, compared to 50%, 0% and 15% in the same time periods in WEA (p<0.0001). In multivariate analysis, follow-up in WEA (incidence rate ratio (IRR) 0.12, 95% CI 0.04-0.35), standard TB-treatment (IRR 0.45, 95% CI 0.20-0.99) and antiretroviral therapy (IRR 0.32, 95% CI 0.14-0.77) were associated with reduced risk of TB-related death. Persistently higher mortality rates were observed in HIV/TB patients in Eastern Europe, and TB was the dominant cause of death at any time during follow-up. This has important implications for HIV/TB programmes aiming to optimise the management of HIV/TB patients and limit TB-associated mortality in this region.

Sequence analysis of in vivo defective interfering-like RNA of influenza A H1N1 pandemic virus.

Influenza virus defective interfering (DI) particles are naturally occurring noninfectious virions typically generated during in vitro serial passages in cell culture of the virus at a high multiplicity of infection. DI particles are recognized for the role they play in inhibiting viral replication and for the impact they have on the production of infectious virions. To date, influenza virus DI particles have been reported primarily as a phenomenon of cell culture and in experimentally infected embryonated chicken eggs. They have also been isolated from a respiratory infection of chickens. Using a sequencing approach, we characterize several subgenomic viral RNAs from human nasopharyngeal specimens infected with the influenza A(H1N1)pdm09 virus. The distribution of these in vivo-derived DI-like RNAs was similar to that of in vitro DIs, with the majority of the defective RNAs generated from the PB2 (segment 1) of the polymerase complex, followed by PB1 and PA. The lengths of the in vivo-derived DI-like segments also are similar to those of known in vitro DIs, and the in vivo-derived DI-like segments share internal deletions of the same segments. The presence of identical DI-like RNAs in patients linked by direct contact is compatible with transmission between them. The functional role of DI-like RNAs in natural infections remains to be established.

Quantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features.

In the ENSEMBLE randomized, placebo-controlled phase 3 trial (NCT04505722), estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe-critical COVID-19. SARS-CoV-2 Spike sequences were determined from 484 vaccine and 1,067 placebo recipients who acquired COVID-19. In this set of prespecified analyses, we show that in Latin America, VE was significantly lower against Lambda vs. Reference and against Lambda vs. non-Lambda [family-wise error rate (FWER) p < 0.05]. VE differed by residue match vs. mismatch to the vaccine-insert at 16 amino acid positions (4 FWER p < 0.05; 12 q-value ≤ 0.20); significantly decreased with physicochemical-weighted Hamming distance to the vaccine-strain sequence for Spike, receptor-binding domain, N-terminal domain, and S1 (FWER p < 0.001); differed (FWER ≤ 0.05) by distance to the vaccine strain measured by 9 antibody-epitope escape scores and 4 NTD neutralization-impacting features; and decreased (p = 0.011) with neutralization resistance level to vaccinee sera. VE against severe-critical COVID-19 was stable across most sequence features but lower against the most distant viruses.

Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons.

BACKGROUND: Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. METHODS: In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. RESULTS: A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9 × 10(-4)). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05-2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06-1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16-1.96), diabetes (OR = 1.66; 95% CI, 1.10-2.49), ≥ 1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06-1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17-2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. CONCLUSIONS: In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.

Does hepatitis C viremia or genotype predict the risk of mortality in individuals co-infected with HIV?

BACKGROUND & AIMS: The influence of HCV-RNA levels and genotype on HCV disease progression is not well studied. The prognostic value of these markers was investigated in HIV/HCV co-infected individuals from the EuroSIDA cohort. METHODS: EuroSIDA is a prospective cohort of 18,295 HIV-1 infected patients in 105 centres across Europe, Israel, and Argentina. All subjects with known HCV antibody (HCVAb) status (n=13,025) were enrolled in the present study. RESULTS: 4044 (31.0%) patients had detectable HCVAb. After adjustment, HCVAb+ patients had an increased incidence of liver-related death (LRD) compared to HCVAb- individuals (IRR 8.90; 95% CI 5.60-14.14, p<0.0001). Information on HCV-RNA was available for 2709 (67.0%) HCVAb+ patients and 2010 (74.2%) were HCV-RNA+. Of 1907 patients with measured HCV genotype, 1008 (52.9%), 62 (3.3%), 567 (29.7%), and 270 (14.2%) were infected with genotype 1, 2, 3 and 4, respectively. Patients with detectable HCV-RNA had similar incidence of non-LRD, but higher incidence of LRD compared to HCVAb+ aviremic patients (adjusted IRR 1.18; 95% CI 0.93-1.50, p=0.17) and (adjusted IRR 2.11; 95% CI 1.30-3.42, p=0.0025), respectively. In patients with HCV viremia, HCV-RNA levels and HCV genotype did not influence the risk of non-LRD or LRD. CONCLUSIONS: HCV seropositive HIV patients had a 9-fold increased risk of LRD compared to patients who were HCV seronegative. Risk of death from any cause or LRD was not influenced by level of HCV viremia or HCV genotype.

Quantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features.

It is of interest to pinpoint SARS-CoV-2 sequence features defining vaccine resistance. In the ENSEMBLE randomized, placebo-controlled phase 3 trial, estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe-critical COVID-19. SARS-CoV-2 Spike sequences were measured from 484 vaccine and 1,067 placebo recipients who acquired COVID-19 during the trial. In Latin America, where Spike diversity was greatest, VE was significantly lower against Lambda than against Reference and against all non-Lambda variants [family-wise error rate (FWER) p < 0.05]. VE also differed by residue match vs. mismatch to the vaccine-strain residue at 16 amino acid positions (4 FWER p < 0.05; 12 q-value ≤ 0.20). VE significantly decreased with physicochemical-weighted Hamming distance to the vaccine-strain sequence for Spike, receptor-binding domain, N-terminal domain, and S1 (FWER p < 0.001); differed (FWER ≤ 0.05) by distance to the vaccine strain measured by 9 different antibody-epitope escape scores and by 4 NTD neutralization-impacting features; and decreased (p = 0.011) with neutralization resistance level to vaccine recipient sera. VE against severe-critical COVID-19 was stable across most sequence features but lower against viruses with greatest distances. These results help map antigenic specificity of in vivo vaccine protection.

Long-Term Benefits from Early Antiretroviral Therapy Initiation in HIV Infection.

BACKGROUND: For people with HIV and CD4+ counts >500 cells/mm3, early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4+ counts are <350 cells/mm3. Whether excess risk of AIDS and SNA persists once ART is initiated for those who defer treatment is uncertain. METHODS: The Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4+ counts .500 cells/mm3 to immediate treatment initiation after random assignment (n = 2325) or deferred treatment (n= 2359). In 2015, a 57% lower risk of the primary end point (AIDS, SNA, or death) for the immediate group was reported, and the deferred group was offered ART. This article reports the follow-up that continued to December 31, 2021. Cox proportional-hazards models were used to compare hazard ratios for the primary end point from randomization through December 31, 2015, versus January 1, 2016, through December 31, 2021. RESULTS: Through December 31, 2015, approximately 7 months after the cutoff date from the previous report, the median CD4+ count was 648 and 460 cells/mm3 in the immediate and deferred groups, respectively, at treatment initiation. The percentage of follow-up time spent taking ART was 95% and 36% for the immediate and deferred groups, respectively, and the time-averaged CD4+ difference was 199 cells/mm3. After January 1, 2016, the percentage of follow-up time on treatment was 97.2% and 94.1% for the immediate and deferred groups, respectively, and the CD4+ count difference was 155 cells/mm3. After January 1, 2016, a total of 89 immediate and 113 deferred group participants experienced a primary end point (hazard ratio of 0.79 [95% confidence interval, 0.60 to 1.04] versus hazard ratio of 0.47 [95% confidence interval, 0.34 to 0.65; P<0.001]) before 2016 (P=0.02 for hazard ratio difference). CONCLUSIONS: Among adults with CD4+ counts >500 cells/mm3, excess risk of AIDS and SNA associated with delaying treatment initiation was diminished after ART initiation, but persistent excess risk remained. (Funded by the National Institute of Allergy and Infectious Diseases and others.).