Scientific News

Introduction: Clostridioides difficile infections (CDI) are the most common cause of healthcare-associated infections in U.S. hospitals, with 15% to 30% of patients experiencing relapses. The objective of this randomized, double-blind trial was to evaluate the efficacy and tolerability of fecal transplantation administered in capsule form versus placebo in reducing relapses of diarrhea and CDI.

Methods: Between 2018 and 2022, patients in Veterans Affairs hospitals with a relapse of C. difficile infection (CDI) who responded to antibiotic treatment were randomized in a 1:1 ratio to receive fecal microbiota transplantation capsules or placebo. Randomization was stratified by the number of previous relapses (1 or ≥ 2). The primary endpoint was the occurrence of a clinical relapse at Day 56, defined as more than 3 loose stools over a period of 2 days or more, with or without confirmation of C. difficile, or death.

Results: The study was terminated for futility after analysis of the pre-specified endpoints. Among the 153 participants (76 receiving fecal transplantation and 77 receiving placebo), with a mean age of 66.5 years, the primary endpoint (relapse or death) occurred in 32.9% and 29.0%, respectively (difference 3%, 95% CI: -11.7 to 17.7%). Stratification by number of relapses did not reveal any significant differences. There was no clinically significant difference in the occurrence of adverse events.

Conclusion: Fecal transplantation did not reduce the rate of ICD recurrence or death at Day 56 compared with placebo.

Introduction: Candida spp. joint prosthesis infection is a serious complication of arthroplasty. We evaluated the trends in Candida spp. joint prosthesis infections.

Methods: A multinational, retrospective, observational study of patients with Candida spp. joint prosthesis infections diagnosed between 2010 and 2021. The follow-up period was 2 years.

Results: Among the 269 patients, the median age was 73 years; 46.5% were men, and 10.8% were immunocompromised. The sites of infection were primarily the hip (53%) and the knee (43.1%); 33.8% had a fistula. Surgical management consisted of drainage, retention of the prosthesis, and antibiotics (35.7%), single-stage prosthesis replacement (28.3%), or two-stage prosthesis replacement (29%). The Candida species identified were Candida albicans (55.8%), Candida parapsilosis (29.4%), Candida glabrata (7.8%), and Candida tropicalis (5.6%). In 51.3% of cases, a bacterial co-infection was present. Antifungal treatment consisted of azoles (75.8%) and echinocandins (30.9%), administered for a median duration of 92 days (IQR: 54.5–181.3). Cure was observed in 58% of cases. Treatment failure was associated with age > 70 years (OR: 1.81; 95% CI: 1.08–3.08) and the absence of prosthesis replacement (1.95; 1.16–3.29). The prognosis was more favorable in infections caused by C. parapsilosis (0.55; 0.31–0.96). Cure rates were significantly higher following one-stage or two-stage prosthesis replacement than in cases where the prosthesis was not replaced (67.1% and 69.2%, respectively, vs. 46.9%; p = 0.008 and 0.003).

Conclusion: The prognosis for Candida spp. joint prosthesis infections is poor, with a high failure rate that does not appear to be related to immunosuppression, the use of azoles, or the duration of treatment.

Introduction: HIV PrEP for women poses challenges related to implementation, adherence, and continuation.

Method: A phase 3, randomized, controlled, double-blind study among adolescent girls and young women in South Africa and Uganda. Participants were randomized in a 2:2:1 ratio to receive lenacapavir subcutaneously every 26 weeks, F/TAF orally daily, or F/TDF orally daily; all participants also received the alternative drug as a placebo. The efficacy of lenacapavir and F/TAF was assessed by comparing the incidence of HIV infection with the estimated incidence in the screened population, and evaluated relative to F/TDF.

Results: Among the 5,338 participants who were initially HIV-negative, 55 incident HIV infections were observed: 0 among 2,134 participants in the lenacapavir group (0 per 100 person-years; 95% CI: 0.00 to 0.19), 39 among 2,136 participants in the F/TAF group (2.02 per 100 person-years; 95% CI: 1.44 to 2.76), and 16 among 1,068 participants in the F/TDF group (1.69 per 100 person-years; 95% CI: 0.96 to 2.74). The incidence of HIV in the screened population (n = 8,094) was 2.41 per 100 person-years; 95% CI: 1.82 to 3.19). The incidence of HIV was significantly lower with lenacapavir compared with the incidence in the screened population (incidence rate ratio 0.00; 95% CI: 0.00 to 0.04; p < 0.001) and with that in the F/TDF group (0.00; 95% CI: 0.00 to 0.10; p < 0.001). The incidence with F/TAF did not differ from that of the screened population (0.84; 95% CI: 0.55 to 1.28; p = 0.21), Adherence to F/TAF and F/TDF was low. There were no tolerability issues. Injection-site reactions (ISRs) were more frequent with lenacapavir (68.8%) than with the combined placebo groups (34.9%); 4 participants in the lenacapavir group (0.2%) discontinued the study due to ISRs.

Conclusions: No participant receiving lenacapavir twice a year acquired HIV infection. The incidence of HIV was significantly lower with lenacapavir compared with that of the screened population and that of the F/TDF group.

Introduction: Pneumococcal infections cause significant morbidity and mortality in adults. V116 is an experimental 21-valent pneumococcal conjugate vaccine specifically designed to protect adults against the pneumococcal serotypes responsible for the majority of infections not covered by previous vaccines. This Phase 3 trial evaluated the efficacy, safety, and immunogenicity of V116 in adults aged 50 years or older who had previously been vaccinated against pneumococcus

Methods: A total of 717 adults were enrolled to receive a single dose of V116: Cohort 1 (n = 350) had previously received the non-conjugated Pneumo 23 vaccine and was randomized 2:1 to V116 or Prevenar 15 (PCV15); Cohort 2 (n = 261), previously vaccinated with PCV13, was randomized 2:1 to V116 or Pneumo 23; Cohort 3 (n = 106), previously vaccinated with Pneumo 23 + PCV 13, PCV 13 + Pneumo 23, PCV 15 + Pneumo 23, or PCV 15, received V116 in an open-label setting. Immunogenicity was assessed on Day 30 after vaccination by measuring the geometric mean titers (GMT) of opsonophagocytic activity specific to the vaccine serotypes and the geometric mean concentrations of IgG against all V116 serotypes. Tolerability was assessed by the proportion of participants experiencing an adverse event.

Results: V116 was immunogenic across all three cohorts against the 21 serotypes. Immune responses were comparable against serotypes common to PCV 15 (cohort 1) or Pneumo 23 (cohort 2), and were higher against serotypes unique to V116. The proportion of participants who experienced an adverse event was generally comparable across all three cohorts.

Conclusion: V116 is well tolerated, with a safety profile comparable to that of currently marketed pneumococcal vaccines, and induces IgG and functional responses against all vaccine serotypes, regardless of the previously administered pneumococcal vaccine.

Introduction: Men who have sex with men (MSM) are at increased risk for STIs, necessitating new prevention strategies. In this population, we evaluated whether post-exposure prophylaxis with doxycycline could reduce the incidence of Chlamydia and syphilis infections and whether the group B meningococcal vaccine could reduce the incidence of gonorrhea

Methods: A multicenter, open-label, randomized trial among MSM aged 18 years or older who were HIV-negative and had a history of STIs within the past 12 months, and who were participants in the PREVENIR study on HIV PrEP with TDF/FTC. Participants were randomized (2:1) to receive doxycycline (200 mg within 72 hours after unprotected sex, with a maximum of 3 doses of 200 mg per week) or no prophylaxis, and were also randomized (1:1) to receive the Group B meningococcal vaccine (1 IM injection at enrollment and a second at M2) or no vaccine. Follow-up visits took place every 3 months for at least 12 months, and up to 24 months. The primary endpoints were the occurrence, in a modified ITT analysis (at least 1 follow-up visit), of a first episode of Chlamydia and/or syphilis after enrollment in the doxycycline intervention group and of gonococcal infection beyond month 3 in the vaccine intervention group.

Results: Of the 556 participants enrolled, 545 were included in the modified ITT analysis for the doxycycline intervention and 544 for the vaccine intervention. The median follow-up was 14 months. There was no interaction between the two interventions regarding the outcome measure. The incidence of a first episode of chlamydia and/or syphilis was reduced by 83% with doxycycline (adjusted hazard ratio 0.17; 95% CI: 0.12–0.26, p < 0.0001). The incidence of a first episode of gonorrhea was reduced, though not significantly, with the vaccine (adjusted hazard ratio 0.78; 95% CI: 0.60– 1.01, p = 0.061). One serious adverse event (skin rash) occurred in the doxycycline group. In the doxycycline group, 6 participants discontinued prophylaxis due to gastrointestinal symptoms.

Conclusion: Post-exposure prophylaxis with doxycycline significantly reduced the incidence of Chlamydia and/or syphilis among MSM, but the vaccine was not effective in preventing gonorrhea.

Objective: To characterize the differences between HSV and VZV encephalitis and other infectious causes of encephalitis, and to evaluate the impact of the time to initiation of acyclovir, the administered dose, and the duration of treatment on clinical outcomes.

Method: Comparison within the prospective ENCEIF cohort of 132 cases of HSV encephalitis, 65 cases of VZV encephalitis, and 297 cases of encephalitis due to other infectious causes, with an assessment of the association between the time to initiation of acyclovir, the dose administered, and the duration of treatment on the course of the disease, using logistic regression analysis.

Results: Differences were found between HSV, VZV, and other causes of encephalitis regarding the presence of immunosuppression (10%, 23%, and 10%, respectively; p < 0.05) and seizures at admission (20%, 6%, and 14%, respectively; p < 0.05). At hospital discharge, an unfavorable outcome (Glasgow Sequelae Severity Scale ≤ 3) was observed in 31%, 18%, and 13% of cases, respectively (p < 0.05). The time to initiation of ACV was associated with clinical outcome in HSV encephalitis (ORa 3.61; 1.25 to 10.40) but not in VZV encephalitis. Higher doses of ACV did not alter the clinical outcome for either HSV or VZV.

Conclusion: HSV and VZV encephalitis have different clinical presentations and courses. The impact of early initiation of AV was significant for HSV but not for VZV, although this finding is limited by the smaller number of cases and fewer adverse outcomes in the latter situation.

Introduction: Weight gain following initiation of antiretroviral therapy is common. We evaluated the impact of changes in weight during the year following the initiation of antiretroviral therapy on the subsequent occurrence of cardiometabolic disease among ACTG participants.

Methods: We used linear regression models to assess the association between changes in weight and waist circumference between Day 0 and Week 48 and changes in metabolic parameters between Day 0 and Week 48 and between Week 48 and Week 96. We used Cox regression models to assess the association between changes in weight and waist circumference between Day 0 and Week 48 and the onset of diabetes, metabolic syndrome, or cardiometabolic and cardiovascular events after Week 48.

Results: Among the 2,624 participants included, 81% were men, and 60% were non-white. The mean weight gain between Day 0 and Week 48 was 3.6 ± 7.3 kg; 130 participants developed diabetes, 360 developed metabolic syndrome, 424 experienced a cardiometabolic event, and 28 experienced a cardiovascular event during 480 weeks of follow-up. In the adjusted models, total cholesterol increased by 0.63 mg/dL (95% CI: 0.38–0.89) and LDL cholesterol by 0.39 mg/dL (0.19–0.59) for every 1 kg increase in weight between Day 0 and Week 48. Individuals with weight gain of more than 10% (vs. −5% to +5%) had an increased risk of diabetes (hazard ratio 2.01, 95% CI 1.30–4.08), metabolic syndrome (2.24, 1.55–2.62), and cardiometabolic events (1.54, 1.22–1.95). Participants with weight loss of more than 5% had a lower risk of incident metabolic syndrome (0.67, 0.42–1.07). Similar trends were observed for changes in waist circumference.

Conclusion: Changes in weight and waist circumference 1 year after initiation of antiretroviral (ARV) therapy are associated with concurrent changes in metabolic parameters and subsequent risk of cardiometabolic disease.

Objective: To characterize plasma ARV concentrations in the intermittent maintenance treatment strategy (4 days/7) within the ANRS 170 QUATUOR trial.

Method: Patients were randomized to either continuous triple therapy 7 days a week or treatment taken on 4 consecutive days with a 3-day treatment-free period at the end of the week. Plasma concentrations were measured during the treatment period (Days 3–4) and on Day 3 (the last day) of the treatment- free period in the 4-days-a-week group, and before daily dosing in the 7-days-a-week group, up to Week 48.

Results: Median plasma concentrations during treatment were significantly lower in the 4-days-per-week group than in the 7-days-per-week group for rilpivirine (88 ng/mL, IQR: 64–112) versus 130 ng/mL, IQR: 82–160; p < 0.001) and for tenofovir (tenofovir disoproxil fumarate: 93 ng/mL (73–135) versus 117 ng/mL (83–160); p < 0.001; tenofovir alafenamide: 11 ng/mL (7–15) versus 14 ng/mL (11–18); p = 0.001). Median concentrations on Day 3 of the treatment interruption in the 4-day/week group were significantly lower (p < 0.001) at Week 48 for all ARVs except etravirine (p = 0.625) and atazanavir (p = 0.5), due to a very small number of patients for these two ARVs.

Conclusion: With 4-day-on/7-day-off intermittent treatment, plasma concentrations of ARVs during treatment were similar to those in the 7-day-on/7-day-off continuous treatment group. After a 3-day treatment interruption, plasma concentrations of ARVs were low.

Introduction: Nirmatrelvir –ritonavir has short-term efficacy against COVID-19; however, its effect on post-COVID-19 manifestations, particularly in hospitalized patients, remains understudied. This study evaluated the effect of nirmatrelvir –ritonavir on post-COVID-19 manifestations in hospitalized patients in Hong Kong.

Methods: A retrospective cohort study using data on hospital stays and vaccinations from hospitals in Hong Kong. The study included patients aged 18 years or older who tested positive for SARS-CoV-2 between March 2022 and October 2023 and were hospitalized for COVID-19. The treatment group consisted of patients who received nirmatrelvir –ritonavir within the first 5 days of symptom onset, excluding those who had received molnupiravir within the previous 21 days. The control group received neither nirmatrelvir –ritonavir nor molnupiravir. The outcomes were in-hospital death and 13 sequelae (heart failure, atrial fibrillation, coronary artery disease, phlebitis, chronic respiratory disease, ARDS, interstitial lung disease, seizures, anxiety, post- traumatic stress disorder, end-stage renal disease, acute kidney injury, and pancreatitis). These outcomes were assessed starting 21 days after a positive PCR test. Weighted standardized mortality ratios were applied to adjust for covariates, and a Cox regression model was used to assess the association between nirmatrelvir –ritonavir and patient outcomes.

Results: Of the 136,973 screened, 50,066 were included in the analysis (49.7% women): 15,242 received nirmatrelvir –ritonavir and 23,756 were in the control group; 11,057 did not meet the criteria for either the exposed or unexposed group. Patients were followed for a a median of 339 days. In the nirmatrelvir –ritonavir group, there was a significantly lower risk of acute post-infection events related to in-hospital death (hazard ratio 0.62, 95% CI: 0.57 to 0.68, p < 0.0001), congestive heart failure (HR 0.62), atrial fibrillation (HR = 0.63), coronary artery disease (HR = 0.71), chronic respiratory failure (HR = 0.68), ARDS (HR = 0.71), interstitial pneumonia (HR = 0.17), and end-stage renal disease (HR = 0.37). There was no difference between the nirmatrelvir-ritonavir group and the control group regarding phlebitis, seizures, anxiety, post-traumatic stress, acute kidney injury, and pancreatitis.

Conclusion: Nirmatrelvir-ritonavir reduces the risk of in-hospital death following acute infection as well as cardiovascular and respiratory complications in patients hospitalized for COVID-19. Further studies are needed to elucidate the mechanism underlying these findings and to define optimal strategies for preventing post-acute infection sequelae.

Introduction: NNRTs and TAF have been associated with weight gain in several clinical trials and observational cohorts. However, it remains unclear whether weight gain while taking NNRTs and TAF leads to a higher risk of adverse clinical events. We evaluated the relationship between body mass index and the risk of hypertension and dyslipidemia in HIV-positive patients receiving treatment with NIs, TAF, or both, compared with other antiretroviral combinations.

Method: RESPOND, a prospective, multicenter observational cohort study combining data from several international cohorts, has been enrolling patients since 2017 in 37 European countries and Australia. Inclusion criteria were age ≥ 18 years, treatment with or without NNRTs, no history of hypertension or dyslipidemia, and at least two post-enrollment measurements of BMI, lipids, and blood pressure. Participants without baseline CD4 counts or viral load data were excluded, as were those receiving concomitant medications associated with weight changes, including antipsychotics, mood stabilizers, corticosteroids, and insulin. Participants were followed until the onset of hypertension or dyslipidemia, their last visit, or December 31, 2021, whichever occurred first. The primary outcome measure was the incidence of hypertension and dyslipidemia, using a multivariate Poisson regression adjusted for follow-up-adjusted BMI to determine unadjusted and adjusted incidence rate ratios (IRRs). The IRRs for hypertension and dyslipidemia were calculated for NNRTs, TAF, or the combination of the two, with a test for interaction between the ARV regimen over time and actuarial BMI.

Results: Among the 35,941 RESPOND participants, 9,704 (75.5% men) were included in the analysis of hypertension and 5,231 (72.6% men) in the analysis of dyslipidemia. In the univariate model, hypertension was more common among individuals receiving an INI combined with TAF (OR 1.70, 95% CI: 1.54 to 1.88) or an INI without TAF (1.41, 1.30 to 1.53) than among those receiving treatment without an INI and without TAF. Adjustment for updated BMI and confounding factors reduced the risk among participants on INIs with or without TAF (ORs of 1.48, 1.31 to 1.68, and 1.25, 1.13 to 1.39, respectively). Dyslipidemia was more common among participants receiving TAF in combination with INI (TRI 1.24, 1.10 to 1.40) or TAF without INI (1.22, 1.03 to 1.44) than among those receiving treatment without INI or TAF. Adjustment for updated BMI and confounding factors reduced the risk among participants on INIs and TAF (OR 1.21, 1.07 to 1.37), whereas the risk became nonsignificant among those on TAF without INIs (1.15, 0.96 to 1.38).

Conclusion: Although residual confounding factors cannot be ruled out, INI treatment was associated with the onset of hypertension, and TAF treatment was associated with the onset of dyslipidemia, the latter being partially mediated by weight gain.

Introduction: A growing body of evidence suggests that symptoms associated with post-COVID-19 syndrome (long COVID) can affect multiple organs, but their association with viral persistence remains unclear. The objective of this study was to investigate the persistence of SARS-CoV-2 in various tissues following recovery from mild COVID-19, as well as its association with long COVID symptoms.

Methods: A single-center cross-sectional study in Beijing, conducted following the Omicron wave in December 2022. The study included individuals with mild COVID-19 confirmed by PCR who were scheduled to undergo esophagogastroscopy, surgery, chemotherapy, or hospitalization 1 month, 2 months, or 4 months after infection. Surgical specimens, EGD samples, and blood samples were collected approximately 1 month (18–33 days), 2 months (55–84 days), or 4 months (115–134 days) after infection. SARS-CoV-2 was detected by digital PCR and confirmed by detection of viral RNA via hybridization, immunofluorescence, or immunohistochemistry. A telephone follow-up was conducted 4 months after infection to assess the association between long COVID symptoms and the persistence of SARS-CoV-2.

Results: Between January 3 and April 28, 2023, 317 samples were collected from 225 patients (201 surgical samples, 59 FOGD, and 57 blood samples). Viral RNA was detected in 30% of samples at M1, 27% at M2, and 11% at M4, and was found in 10 different tissue types: liver, kidney, stomach, intestine, brain, blood vessel, lung, breast, skin, and thyroid. In addition, subgenomic RNA was detected in 43% of tissue samples (which were also positive for viral RNA). Two months post-infection, among 9 immunocompromised patients, viral RNA was detected in the plasma of 3 patients, in white blood cells in 1, and in PBMCs in 2; however, testing of blood compartments was negative in 10 immunocompetent patients. Among the 213 patients who completed the telephone questionnaire, 34% reported a symptom of long COVID, with fatigue being the most common symptom (21%). The detection of viral RNA was significantly associated with the onset of long COVID symptoms (odds ratio: 5.17; 95% CI: 2.64 to 10.13, p < 0.0001). Patients with the highest viral copy numbers had a higher risk of developing long COVID.

Conclusion: These results suggest that residual SARS-CoV-2 may persist in patients who have recovered from mild COVID-19 and that there is a significant association between viral persistence and the onset of long COVID symptoms. Further research is needed to verify the mechanistic link and identify potential therapeutic targets to improve long COVID.

Introduction: There are few real-world data on the efficacy of semaglutide for weight loss in people with HIV infection. We evaluated weight loss in a cohort of patients who initiated semaglutide treatment in the U.S.

Methods: An observational study within the CNICS cohort. We identified adults with HIV who initiated semaglutide between 2018 and 2022 and had at least two weight measurements. The primary outcome measure was individual weight change at 1 year. The secondary outcome measure was change in HbA1c. Both outcomes were estimated using a multivariate linear mixed-effects model.

Results: A total of 222 individuals were treated with semaglutide. The mean follow-up was 1.1 years. Approximately 75% of the patients were men, and at the start of treatment, the mean age was 53 years, the mean weight was 108 kg, the mean BMI was 35.5 kg/m², the mean HbA1c was 7.7%, and 77% had a known diagnosis of diabetes: 97% were on antiretroviral therapy (ART), and 89% had an undetectable viral load. In the multivariate model, semaglutide was associated with a mean weight loss of 6.47 kg at 1 year (95% CI: 5.18 to 7.67) and a 1-year reduction in HbA1c of 1.07% (95% CI: 0.50 to 1.64).

Conclusion: Semaglutide was associated with a significant reduction in weight and HbA1c among people living with HIV, comparable to the results of previous studies in the general population.

Introduction: People living with HIV who have been exposed to antiretrovirals for a long time may have limited or exhausted treatment options (LTO) due to resistance, comorbidities, or ARV-related toxicity. Predictors of LTO were investigated in the RESPOND cohort.

Method: Participants on ARV therapy for at least 5 years were considered to have LTO when they switched to a triple therapy other than 2 NRTIs plus a third agent: triple therapy with 2 third- line agents plus a third ARV, dual therapy with 2 third-line agents (other than RPV + DTG or RPV + CAB), or a regimen containing at least 3 NRTIs. Follow-up began no later than January 2012, upon enrollment in the cohort or 5 years after initiation of antiretroviral therapy. A Poisson regression model assessed OTL rates and clinical events (all-cause mortality, non-AIDS-related cancers, cardiovascular disease, and chronic kidney disease).

Results: Among 23,827 participants, 2,164 reached the OTL status (9.1%) after 130,061 person-years of follow-up, corresponding to an incidence of 1.66 per 100 person-years of follow-up (95% CI: 1.59 to 1.73). Predictors of OTL included a duration of HIV infection > 15 years (vs. 7.5–15 years; adjusted relative incidence of 1.32 [95% CI: 1.19 to 1.46]), the onset of kidney failure (1.84; 1.59 to 2.13), cardiovascular disease (1.64; 1.38 to 1.94), AIDS (1.18; 1.07 to 1.30), and a current CD4 count of 350/mm³ or less (vs. 351–500; 1.51; 1.32 to 1.74). The risk of OTL was lower among individuals followed between 2018 and 2021 (vs. 2015–2017; 0.52; 0.47 to 0.59), among those with a baseline viral load below 200 copies/mL (0.46; 0.40 to 0.53), and among individuals under 40 years of age. The occurrence of OTL was not associated with the occurrence of clinical events after adjusting for age and current CD4 count, except for renal failure (1.74; 1.48 to 2.05).

Conclusion: Despite the aging of the HIV population and the increase in comorbidities, we observed a decrease in OTL status between 2018 and 2021, likely due to the development of new antiretroviral (ARV) therapies. Reassuringly, OTL status was not associated with an increase in major clinical events, except for renal failure.

Importance: Cardiovascular disease is on the rise among people with HIV and is characterized by premature noncalcified coronary plaques. In the REPRIEVE randomized trial, pitavastatin reduced the occurrence of major cardiovascular events by 35% after a median follow-up of 5.1 years.

Objective: To investigate the effects of pitavastatin on noncalcified coronary artery plaques as assessed by coronary CT angiography and on inflammatory markers, as potential mechanisms for the prevention of major cardiovascular events.

Methods: This randomized, double-blind trial comparing pitavastatin 4 mg/day with placebo included HIV-positive patients on antiretroviral therapy (ART) with low or moderate 10-year cardiovascular risk. The data were analyzed. Coronary CT angiography and inflammatory markers were assessed at Day 0 and Month 24. The primary endpoint was the change in the volume of noncalcified coronary plaques and the progression of noncalcified plaques.

Results: Of the 804 participants enrolled, 774 underwent at least one coronary CT scan. Plaque changes were assessed in 611 participants who underwent 2 CT scans (84% men, mean age 51 years, median 10-year cardiovascular risk 4.5%; 302 received pitavastatin and 309 received placebo. The mean volume of noncalcified plaques decreased in the pitavastatin group compared with the placebo group (mean change: –1.7 ± 25.2 mm³ vs. 2.6 ± 27.1 mm³; difference adjusted for baseline data at Day 0: –4.3 mm³ (95% CI –8.6 to –0.1; p = 0.04; a 7% (1 to 12) greater reduction than in the placebo group). An even greater effect was observed in patients with plaques present at Day 0 (-8.8 mm³ (95% CI -17.9 to 0.4). The progression of noncalcified plaques was 33% lower in the pitavastatin group compared with the placebo group (relative risk 0.67; 95% CI 0.52 to 0.88; p = 0.003). Compared with the placebo group, LDL cholesterol decreased with pitavastatin (mean change –28.5 mg/dl; 95% CI –31.9 to –21.5) but not with placebo (–0.8; –3.8 to 2.2). In the pitavastatin group, there was a reduction at week 24 in oxidized LDL (-29%; –32 to –26 vs. –13%; –17 to –9; p < 0.001) and in phospholipase A2 (–7%; –11 to –4 vs. 14%; 10 to 18; p < 0.001)

Conclusion: In people with HIV infection and low or moderate cardiovascular risk, 24 months of pitavastatin reduced the volume and progression of noncalcified coronary plaques as well as markers of lipid oxidation and arterial inflammation. These changes may help explain the reduction in major cardiovascular events observed in the REPRIEVE trial.

Objective: We present the results from a large cohort of individuals treated at the time of primary HIV-1 infection and examine the impact of the time interval between HIV-1 acquisition and the initiation of antiretroviral (ARV) therapy on clinical outcomes. We also determine changes over time in the demographic characteristics of individuals with primary HIV-1 infection to inform prevention strategies.

Methods: Individuals meeting the criteria for primary HIV infection who initiated ARV therapy within 3 months of a confirmed diagnosis of HIV-1 infection were included between 2009 and 2020. Demographic data at Day 0 were compared between the 2009–2015 period (before PrEP and universal antiretroviral therapy) and the 2015–2020 period. We examined factors associated with immune reconstitution and the time to virologic suppression.

Results: 204 individuals were included — 144 between 2009 and 2015 and 90 between 2015 and 2020— with a median follow-up of 33 months. At the time of primary infection, the median age was 33 years (MSM 84%, women 4%, born in the United Kingdom 39% [47% in the first period, 29% between 2015 and 2020]). We found an association between earlier initiation of antiretroviral (ARV) therapy and improved immune recovery; each day of delay in initiating ARV therapy was associated with a lower probability of achieving a CD4 count > 900/mm³ (HR 0.99, 95% CI: 0.98–0.99) and a CD4/CD8 ratio > 1 (HR 0.98, 95% CI: 0.97–0.99).

Conclusion: Early initiation of antiretroviral therapy upon diagnosis of primary HIV infection is associated with better immune recovery, providing further support for immediate antiretroviral therapy in cases of primary HIV infection. MSM born outside the United Kingdom account for an increasingly large proportion of primary HIV infections, necessitating better-targeted prevention efforts for this group.

Introduction: HIV infection leads to chronic immune activation and inflammation that can persist and increase the risk of cancer in people with viral suppression on antiretroviral therapy. The prognostic role of a low CD4:CD8 ratio and high CD8 count on cancer risk remains unclear.

Methods: We investigated the association between the CD4:CD8 ratio and the risk of non-AIDS-related cancers, AIDS-related cancers, and the most common types of cancer in HIV-positive individuals receiving antiretroviral therapy (ART), with viral load, CD4, and CD8 measurements available at Day 0. We developed Cox risk models adjusted for known confounding factors associated with cancer risk and for cumulative exposure time to the CD4:CD8 ratio in order to account for changes in risk factors over time and avoid reverse causality.

Results: A CD4:CD8 ratio < 0.5 was, compared with a ratio > 1.0, independently associated with a higher risk of AIDS-related cancers and infection- related cancers over the following 12 months (hazard ratios of 2.61 [95% CI: 1.10–6.19] and 2.03 [1.24–3.33], respectively). A CD4 count < 350/mm³ was associated with a higher risk of AIDS-related and non-AIDS-related cancers, as well as cancers associated with infections, smoking, and obesity.

Conclusions: Among HIV-positive individuals receiving antiretroviral therapy (ART), a low CD4:CD8 ratio was associated — regardless of CD4 and CD8 counts — with a higher risk of AIDS-related or infection-related cancers. This information should alert clinicians to the importance of screening for and preventing non-AIDS-related cancers.

Introduction: We investigated the association between NAFLD with or without NASH and the incidence of type 2 diabetes, as well as the risk factors associated with the development of NAFLD or NASH.

Methods: A prospective study analyzing HIV-positive individuals aged 18 years or older, without excessive alcohol consumption or hepatic coinfection. NAFLD was defined as a value of 248 dB/m or higher on the controlled attenuation parameter; NASH with significant activity and fibrosis was defined as a FibroScan-AST score ≥ 0.67. A proportional hazards Cox model assessed the association between NAFLD with or without NASH and the incidence of type 2 diabetes.

Results: Among the 847 people living with HIV (43% women), the median age at enrollment was 45 years (IQR 38–51). NAFLD at enrollment was associated with a 2.8-fold higher risk of developing type 2 diabetes after adjusting for age, sex, family history of diabetes, duration of antiretroviral (ARV) therapy, smoking, statin use, exposure to d4T/ZDV, body mass index over time, hypertension, and dyslipidemia. The presence of both NAFLD and NASH at baseline was associated with a 3.1-fold higher risk of new-onset diabetes. In separate analyses, the presence of diabetes at enrollment did not predict progression to NAFLD or NASH, but the use of TAF was associated with a higher risk of developing NAFLD (hazard ratio 2.01, 95% CI: 1.02–4.02) or NASH (2.31, 1.12–5.11).

Conclusions: NAFLD, either alone or in combination with NASH, is strongly associated with the development of emerging type 2 diabetes. This underscores the need to systematically assess the risk of NAFLD/NASH in people living with HIV and to ensure appropriate management, as these liver conditions can contribute to metabolic complications, such as diabetes, and subsequently to cardiovascular disease.

Introduction: Fatty liver disease, including NAFLD, is common among people living with HIV. We report the prevalence of fatty liver disease at enrollment and cardiometabolic characteristics among participants in a REPRIEVE substudy.

Methods: REPRIEVE is an international, randomized, controlled trial of primary prevention of cardiovascular disease comparing pitavastatin with placebo in 7,769 people living with HIV aged 40 to 75 years who are on antiretroviral therapy (ART) and have low or moderate cardiovascular risk. A subgroup of participants underwent a non-contrast CT scan, with hepatic steatosis defined as a mean hepatic attenuation < 40 HU or a liver-to-spleen ratio < 1.0, and NAFLD defined as the presence of steatosis in the absence of alcoholism or viral hepatitis.

Results: Among the 687 individuals evaluated, the median age was 51 years, the median BMI was 27 kg/m², and the median CD4 count was 607/mm³; 17% were women, 36% were Black, 24% were Hispanic, and 98% had a viral load < 400 copies/mL. The prevalence of hepatic steatosis was 22% (149/687), and that of NAFLD was 21% (96/466). These prevalences were higher among men, older individuals, non-Black individuals, and those with higher BMI and waist circumference. Fatty liver and NAFLD were associated with a BMI > 30 kg/m², the presence of metabolic syndrome components, a higher atherosclerotic cardiovascular disease risk score, a higher HOMA-IR, higher levels of LpPLA-2 and CRPus, and lower levels of HDL cholesterol. Among HIV infection characteristics, only a history of AIDS was more common among individuals with steatosis/NAFLD. After adjusting for age, sex, and race, a BMI > 30 kg/m², a HOMA-IR > 2, and metabolic syndrome or its components were associated with the prevalence of NAFLD.

Conclusion: In this cohort of patients with well-controlled HIV infection and low to moderate cardiovascular risk, hepatic steatosis and NAFLD were common and associated with clinically significant metabolic and inflammatory abnormalities, but not with factors related to the current status of HIV infection or antiretroviral (ARV) therapy.

Introduction: The widespread use of the integrase inhibitor dolutegravir in first- and second-line antiretroviral therapy may facilitate the emergence of resistance. The DTG RESIST study pooled data from several HIV cohorts to assess the characteristics of DTG resistance mutations and identify risk factors for DTG resistance.

Methods: We included cohorts with data on DTG resistance from two collaborative groups (ART CC, IEDEA in South Africa, and UK CHIC). Cohorts from eight countries (Canada, France, Germany, Italy, the Netherlands, Switzerland, South Africa, and the United Kingdom) provided data on individuals who were viremic while on DTG treatment and had a resistance genotype. Individuals with an unknown DTG initiation date were excluded. Resistance levels were determined using the Stanford algorithm. We identified risk factors for DTG resistance using mixed-effects ordinal logistic regression models.

Results: We included 599 individuals with a resistance genotype following treatment failure on DTG between May 2013 and December 2021. The majority had HIV-1 subtype B (59%), and one-third (32%) had received first-generation NRTIs prior to DTG. DTG treatment was administered as a dual-drug regimen in 12% of cases and as monotherapy in 3% (n = 18). NNRTIs resistance mutations were detected in 86 (14%) individuals; 20 (3%) had more than one mutation. Most genotypes (94%) showed susceptibility to DTG, 7 (1%) showed possible low-level resistance, 6 (1%) showed low-level resistance, 17 (3%) showed intermediate-level resistance, and 6 (1%) showed high-level resistance. The risk of DTG resistance was higher with DTG monotherapy (adjusted odds ratio: 34.1, 95% CI: 9.93–117) and DTG/3TC dual therapy (OR: 9.21, 2.20–38.6) compared with triple therapy, and in cases of possible low-level or low-level resistance (OR: 5.23; 1.32–20.7) or intermediate- or high-level resistance (OR: 13.4; 4.55–39.7) to NRTIs.

Interpretation: Among individuals with viremia on DTG-based ARV therapy, mutation-based resistance to NRTIs and resistance to DTG were rare. Resistance to NRTIs significantly increases the risk of DTG resistance, which is a concern, particularly in resource-limited countries. Surveillance is important to prevent resistance at the individual and population levels and to ensure the long-term effectiveness of ARV treatments.

Introduction: Acute community-acquired pneumonia is associated with high morbidity and mortality. In this study, we evaluated the effect of corticosteroids on all-cause mortality in patients hospitalized for acute community-acquired pneumonia.

Methods: For this meta-analysis and meta-regression, we conducted a systematic search for trials conducted before March 2023 that evaluated corticosteroid therapy in patients hospitalized for acute community-acquired pneumonia. We included randomized, controlled trials that compared adjunctive corticosteroid therapy with standard of care alone in patients hospitalized for acute community-acquired pneumonia and reported all-cause mortality. We excluded retrospective and observational studies, as well as study protocols. The primary outcome measure was all-cause mortality at 30 days after admission. The safety analysis included the incidence of adverse events and corticosteroid-related adverse events.

Results: The literature review identified 35,713 citations, of which 15 studies involving 3,367 patients were eligible for the final analysis. All-cause mortality at 30 days was significantly lower in the corticosteroid group (104/1,690 = 6.15%) than in the control group (152/1,677 = 9.06%), yielding a relative risk of 0.67 (95% CI: 0.53 to 0.85, p = 0.001, I² = 0%). In 9 studies (2,549 patients) reporting safety, corticosteroid therapy was not associated with an increased risk of adverse events (RR = 0.90, 95% CI: 0.65 to 1.24, p = 0.5, I² = 88%)

Conclusion: Adjuvant corticosteroid therapy in patients hospitalized for acute community-acquired pneumonia is associated with a reduction in all-cause mortality at 30 days. The benefits of corticosteroid therapy are greater in patients with severe pneumonia.

Introduction: The risk of cardiovascular disease is increased in people infected with HIV, so data on primary prevention strategies in this population are needed.

Methods: In this phase 3 trial, we randomized 7,769 HIV-infected participants on antiretroviral therapy with low to moderate cardiovascular risk to receive pitavastatin (4 mg/day) or placebo. The primary endpoint was the occurrence of a major cardiovascular event, defined as cardiovascular death or death from an undetermined cause, myocardial infarction, hospitalization for unstable angina, stroke or transient ischemic attack, peripheral arterial ischemia, or revascularization procedure

Results: Participants had a median age of 50 years (IQR 45–55), a median CD4 count of 621/mm³ (IQR 448–827), and viral load was undetectable in 87.5% of participants with available data. The trial was stopped for efficacy after a median follow-up of 5.1 years (IQR 4.3 to 5.9). The incidence of major cardiovascular events was 4.81 per 1,000 person-years in the pitavastatin group and 7.32 per 1,000 person-years in the placebo group (hazard ratio 0.65; 95% CI: 0.48 to 0.90, p = 0.002). Muscle symptoms were reported in 91 participants (2.3%) in the pitavastatin group and 53 (1.4%) in the placebo group; diabetes developed in 206 participants (5.3%) and 155 (4.0%), respectively.

Conclusions: Participants with HIV infection treated with pitavastatin had a lower risk of major cardiovascular events than those who received placebo over a median follow-up of 5.1 years.

Introduction: Invasive infection with the Streptococcus bovis/Streptococcus equinus complex (cSB/SE) is associated with the presence of colorectal cancer. However, the link between intestinal and fecal colonization by cSB/SE or the antibody response to cSB/SE and colorectal cancer has not been thoroughly studied.

Methods: We searched PubMed, EMBASE, and Web of Science for case-control studies, as well as prospective and retrospective cohort studies reporting an association between cSB/SE bacteremia and colorectal cancer.

Results: We identified 22 studies (15 case-control studies and 7 cohort studies) that met our inclusion criteria. Among the cohort studies, compared with patients without bacteremia, patients with cSB/SE bacteremia had a higher risk of colorectal cancer (relative risk: 3.73; 95% CI: 2.75 to 5.01), but no increased risk of colorectal adenoma (RR: 5.00; 95% CI: 0.83 to 30.03). In case-control studies, patients with colorectal cancer had a higher risk than controls of fecal or intestinal colonization with cSB/SE (odds ratio: 2.27; 95% CI: 1.11 to 4.62) and of having anti-cSB/SE IgG antibodies (OR: 2.27; 95% CI: 1.06 to 4.86). Patients with colorectal adenoma were no more likely than controls to be colonized by cSB/SE (OR: 1.12; 95% CI: 0.55 to 2.25).

Conclusions: Aside from the well-established association between cSB/SE bacteremia and colorectal cancer, intestinal or fecal colonization and the antibody response to cSB/SE were higher in patients with colorectal cancer than in controls. Neither cSB/SE bacteremia nor colonization was associated with the presence of a colorectal adenoma.