Pre-pandemic Metabolic Correlates of COVID-19 Severity and Long COVID Incidence in People Living with HIV.

Host metabolic dysregulation, especially in tryptophan metabolism, is intricately linked to COVID-19 severity and its post-acute sequelae (Long COVID). People living with HIV (PLWH) experience similar metabolic dysregulation and face an increased risk of developing Long COVID. However, whether pre-existing HIV-associated metabolic dysregulations contribute in predisposing PLWH to severe COVID-19 outcomes remains underexplored. Analyzing pre-pandemic samples from PLWH with documented post-infection outcomes, we found specific metabolic alterations, including increased tryptophan catabolism, predicting an elevated risk of severe COVID-19 and the incidence of Long COVID. These alterations warrant further investigation for their potential prognostic and mechanistic significance in determining COVID-19 complications.

Multi-drug resistant Pseudomonas aeruginosa: a 2019-2020 single center retrospective case control study.

Multi-drug resistance in the post COVID-19 world is a growing concern. The objective of this study was to describe temporal trends and explore independent risk factors for the isolation of multi-drug resistant (MDR) P. aeruginosa. Methods: This was a retrospective case-control study of patients with P. aeruginosa isolates recovered from January 2019 to December 2020. MDR P. aeruginosa was defined as non-susceptibility to at least one agent in three or more anti-pseudomonal antimicrobial categories. Results: In total, 258 unique isolates were identified. Prolonged hospitalization (P<0.001), prior antibiotic use (P<0.001), and respiratory sources (P<0.001) were strongly associated with the presence of MDR P. aeruginosa. From 2019 to 2020, there was a decrease in the total number of P. aeruginosa isolates but a significant increase in the proportion of MDR P. aeruginosa isolates (P=0.015). Conclusions: Over a period that coincided with the COVID-19 pandemic, there was an increased proportion of MDR P. aeruginosa isolates from hospitalized patients. Improved identification of patients at risk for MDR P. aeruginosa could facilitate appropriate empiric antibiotic decisions like dual anti-pseudomonal therapy. The features of the COVID-19 outbreak that had a severe impact on patient care and that may have affected drug resistance in other respiratory pathogens should be explored.

Health Insurance and Initiation of Direct-Acting Antivirals for Hepatitis C in US Women With Human Immunodeficiency Virus.

BACKGROUND: Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) is well tolerated, cost-effective, and yields high sustained virologic response rates, yet it has remained financially inaccessible to many patients. METHODS: Participants of the Women's Interagency HIV Study (an observational US cohort) with human immunodeficiency virus (HIV) and HCV (RNA+) reporting no prior hepatitis C treatment were followed for DAA initiation (2015-2019). We estimated risk ratios (RRs) of the relationship between time-varying health insurance status and DAA initiation, adjusting for confounders with stabilized inverse probability weights. We also estimated weighted cumulative incidences of DAA initiation by health insurance status. RESULTS: A total of 139 women (74% Black) were included; at baseline, the median age was 55 years and 86% were insured. Most had annual household incomes ≤$18 000 (85%); advanced liver fibrosis (21%), alcohol use (45%), and recreational drug use (35%) were common. Across 439 subsequent semiannual visits, 88 women (63%) reported DAA initiation. Compared with no health insurance, health insurance increased the likelihood of reporting DAA initiation at a given visit (RR, 4.94; 95% confidence limit [CL], 1.92 to 12.8). At 2 years, the weighted cumulative incidence of DAA initiation was higher among the insured (51.2%; 95% CL, 43.3% to 60.6%) than the uninsured (3.5%; 95% CL, 0.8% to 14.6%). CONCLUSIONS: Accounting for clinical, behavioral, and sociodemographic factors over time, health insurance had a substantial positive effect on DAA initiation. Interventions to increase insurance coverage should be prioritized to increase HCV curative therapy uptake for persons with HIV.

Human Immunodeficiency Virus Status, Tenofovir Exposure, and the Risk of Poor Coronavirus Disease 19 Outcomes: Real-World Analysis From 6 United States Cohorts Before Vaccine Rollout.

BACKGROUND: People with human immunodeficiency virus (HIV) (PWH) may be at increased risk for severe coronavirus disease 2019 (COVID-19) outcomes. We examined HIV status and COVID-19 severity, and whether tenofovir, used by PWH for HIV treatment and people without HIV (PWoH) for HIV prevention, was associated with protection. METHODS: Within 6 cohorts of PWH and PWoH in the United States, we compared the 90-day risk of any hospitalization, COVID-19 hospitalization, and mechanical ventilation or death by HIV status and by prior exposure to tenofovir, among those with severe acute respiratory syndrome coronavirus 2 infection between 1 March and 30 November 2020. Adjusted risk ratios (aRRs) were estimated by targeted maximum likelihood estimation, with adjustment for demographics, cohort, smoking, body mass index, Charlson comorbidity index, calendar period of first infection, and CD4 cell counts and HIV RNA levels (in PWH only). RESULTS: Among PWH (n = 1785), 15% were hospitalized for COVID-19 and 5% received mechanical ventilation or died, compared with 6% and 2%, respectively, for PWoH (n = 189 351). Outcome prevalence was lower for PWH and PWoH with prior tenofovir use. In adjusted analyses, PWH were at increased risk compared with PWoH for any hospitalization (aRR, 1.31 [95% confidence interval, 1.20-1.44]), COVID-19 hospitalizations (1.29 [1.15-1.45]), and mechanical ventilation or death (1.51 [1.19-1.92]). Prior tenofovir use was associated with reduced hospitalizations among PWH (aRR, 0.85 [95% confidence interval, .73-.99]) and PWoH (0.71 [.62-.81]). CONCLUSIONS: Before COVID-19 vaccine availability, PWH were at greater risk for severe outcomes than PWoH. Tenofovir was associated with a significant reduction in clinical events for both PWH and PWoH.

Factors associated with syphilis seroprevalence in women with and at-risk for HIV infection in the Women's Interagency HIV Study (1994-2015).

OBJECTIVE: Syphilis rates among women in the USA more than doubled between 2014 and 2018. We sought to identify correlates of syphilis among women enrolled in the Women's Interagency HIV Study (WIHS) to inform targeted interventions. METHODS: The retrospective cross-sectional analysis of secondary data included women with HIV or at-risk of HIV who enrolled in the multisite US WIHS cohort between 1994 and 2015. Syphilis screening was performed at baseline. Infection was defined serologically by a positive rapid plasma reagin test with confirmatory treponemal antibodies. Sociodemographic and behavioural characteristics stratified by baseline syphilis status were compared for women enrolled during early (1994-2002) and recent (2011-2015) years. Multivariable binomial modelling with backward selection (p>0.2 for removal) was used to model correlates of syphilis. RESULTS: The study included 3692 women in the early cohort and 1182 women in the recent cohort. Syphilis prevalence at enrolment was 7.5% and 3.7% in each cohort, respectively (p<0.01). In adjusted models for the early cohort, factors associated with syphilis included age, black race, low income, hepatitis C seropositivity, drug use, HIV infection and >100 lifetime sex partners (all p<0.05). In the recent cohort, age (adjusted prevalence OR (aPOR) 0.2, 95% CI 0.1 to 0.6 for 30-39 years; aPOR 0.5, 95% CI 0.2 to 1.0 for 40-49 years vs ≥50 years), hepatitis C seropositivity (aPOR 2.1, 95% CI 1.0 to 4.1) and problem alcohol use (aPOR 2.2, 95% CI 1.1 to 4.4) were associated with infection. CONCLUSIONS: Syphilis screening is critical for women with HIV and at-risk of HIV. Targeted prevention efforts should focus on women with hepatitis C and problem alcohol use.

T-Cell Immune Dysregulation and Mortality in Women With Human Immunodeficiency Virus.

SUMMARY: In women with HIV, higher activation and exhaustion of CD4+ T cells were associated with risk of non-HIV-related mortality during a median of 13.3 years of follow-up, independent of baseline demographic, behavioral, HIV-related, and cardiometabolic factors and longitudinal HIV disease progression. BACKGROUND: Dysregulation of adaptive immunity is a hallmark of human immunodeficiency virus (HIV) infection that persists on antiretroviral therapy (ART). Few long-term prospective studies have related adaptive immunity impairments to mortality in HIV, particularly in women. METHODS: Among 606 women with HIV in the Women's Interagency HIV Study, peripheral blood mononuclear cells collected from 2002 to 2005 underwent multiparameter flow cytometry. Underlying cause of death was ascertained from the National Death Index up to 2018. We examined associations of CD4+ and CD8+ T-cell activation (%CD38+HLA-DR+), senescence (%CD57+CD28-), exhaustion (%PD-1+), and nonactivation/normal function (%CD57-CD28+) with natural-cause, HIV-related, and non-HIV-related mortality. RESULTS: At baseline, median participant age was 41, and 67% were on ART. Among 100 deaths during a median of 13.3 years follow-up, 90 were natural-cause (53 non-HIV-related, 37 HIV-related). Higher activation and exhaustion of CD4+ T cells were associated with risk of natural-cause and non-HIV-related mortality, adjusting for age, demographic, behavioral, HIV-related, and cardiometabolic factors at baseline. Additional adjustment for time-varying viral load and CD4+ T-cell count did not attenuate these associations. CD8+ T-cell markers were not associated with any outcomes adjusting for baseline factors. CONCLUSIONS: Persistent CD4+ T-cell activation and exhaustion may contribute to excess long-term mortality risk in women with HIV, independent of HIV disease progression.

HLA B53 is associated with a poor outcome in black COVID-19 patients.

A disproportionate incidence of death has occurred in African Americans (Blacks) in the United States due to COVID-19. The reason for this disparity is likely to be multi-factorial and may involve genetic predisposition. The association of human leukocyte antigens (HLA) with severe COVID-19 was examined in a hospitalized population (89% Black, n = 36) and compared to HLA typed non-hospitalized individuals (20% Black, n = 40) who had recovered from mild disease. For additional comparison, HLA typing data was available from kidney transplant recipients and deceased donors. Hospitalized patients were followed for 45 days after admission to our medical center with death as the primary end-point. One HLA allele, B53, appeared to be more prevalent in the hospitalized COVID-19 patients (percent of positive subjects, 30.5) compared to national data in US Black populations (percent of positive subjects, 24.5). The percent B53 positive in non-hospitalized COVID-19 patients was 2.6, significantly less than the percent positive in the hospitalized COVID-19 patients (p = 0.001, Fisher's exact test) and less than the 8 percent positive listed in national data bases for US Caucasian populations. Significantly greater deaths (73 percent) were observed in HLA B53 positive hospitalized COVID-19 patients compared to hospitalized COVID-19 patients who were B53 negative (40 percent). Multi-variate analysis indicated that HLA B53 positive Black hospitalized COVID-19 patients were at a 7.4 fold greater risk of death than Black COVID-19 patients who were B53 negative. Consideration for accelerated vaccination and treatment should be given to HLA B53 positive Black COVID19 patients.

A genomic variant of ALPK2 is associated with increased liver fibrosis risk in HIV/HCV coinfected women.

HIV coinfection is associated with more rapid liver fibrosis progression in hepatitis C (HCV) infection. Recently, much work has been done to improve outcomes of liver disease and to identify targets for pharmacological intervention in coinfected patients. In this study, we analyzed clinical data of 1,858 participants from the Women's Interagency HIV Study (WIHS) to characterize risk factors associated with changes in the APRI and FIB-4 surrogate measurements for advanced fibrosis. We assessed 887 non-synonymous single nucleotide variants (nsSNV) in a subset of 661 coinfected participants for genetic associations with changes in liver fibrosis risk. The variants utilized produced amino acid substitutions that either altered an N-linked glycosylation (NxS/T) sequon or mapped to a gene related to glycosylation processes. Seven variants were associated with an increased likelihood of liver fibrosis. The most common variant, ALPK2 rs3809973, was associated with liver fibrosis in HIV/HCV coinfected patients; individuals homozygous for the rare C allele displayed elevated APRI (0.61, 95% CI, 0.334 to 0.875) and FIB-4 (0.74, 95% CI, 0.336 to 1.144) relative to those coinfected women without the variant. Although warranting replication, ALPK2 rs3809973 may show utility to detect individuals at increased risk for liver disease progression.

Decreases in markers of monocyte/macrophage activation after hepatitis C eradication in HIV/hepatitis C virus coinfected women.

OBJECTIVE: Eradication of hepatitis C virus (HCV) in HIV disease decreases liver and non-liver-related morbidity and mortality. Elevated markers of monocyte/macrophage activation (soluble CD163 and sCD14) are associated with excess non-AIDS morbidity and mortality in HIV. We examined the effect of HCV eradication on these markers in relation to change in hepatic fibrosis. DESIGN: A nested substudy within a longitudinal observational cohort. METHODS: We studied 126 HIV/HCV-coinfected women successfully treated for HCV, with undetectable HCV RNA at least 12 weeks after therapy completion. sCD163 and sCD14 were measured in serum collected before and after HCV eradication. Results were correlated with changes in markers of hepatic fibrosis. RESULTS: Mean age of participants was 56.3 years, mean CD4+ cell count was 615, and 72% had suppressed HIV RNA. After treatment, sCD163 and sCD14 levels significantly decreased from pre-treatment levels in unadjusted analyses. After adjusting for age, race, hepatic fibrosis status, baseline HCV RNA, CD4 count and HIV RNA status, cigarette smoking, and alcohol use, the decreases in sCD163 and sCD14 remained significant. Decrease in pre-treatment to post-treatment sCD163 were significantly positively correlated with changes in FIB-4 (r = 0.250, P = 0.005) and APRI (r = 0.262, P = 0.003); similarly decrease in sCD14 was significantly positively correlated with changes in FIB-4 (r = 0.333, P = 0.0001) and APRI (r = 0.457, P < 0.0001). CONCLUSION: HCV eradication is associated with significant reductions in monocyte/macrophage activation markers that correlate with reductions in markers of hepatic fibrosis. These findings support broad access to and early initiation of HCV treatment in order to decrease immune activation and improve health in HIV-infected persons.

Administration of high titer convalescent anti-SARS-CoV-2 plasma: From donor selection to monitoring recipient outcomes.

Early in the SARS-CoV-2 pandemic, convalescent plasma (CP) therapy was proposed as a treatment for severely ill patients. We conducted a CP treatment protocol under the Mayo Clinic Extended Access Program at University Hospital Brooklyn (UHB). Potential donors were screened with a lateral flow assay (LFA) for IgM and IgG antibodies against the SARS-CoV-2 S1 receptor-binding domain (RBD). Volunteers that were LFA positive were tested with an ELISA to measure IgG titers against the RBD. Subjects with titers of at least 1:1024 were selected to donate. Most donors with positive LFA had acceptable titers and were eligible to donate. Out of 171 volunteers, only 65 tested positive in the LFA (38.0%), and 55 (32.2%) had titers of at least 1:1024. Before our donation program started, 31 CP units were procured from the New York Blood Center (NYBC). Among the 31 CP units that were obtained from the NYBC, 25 units (80.6%) were positive in the LFA but only 12 units (38.7%) had titers of at least 1:1024. CP was administered to 28 hospitalized COVID-19 patients. Patients who received low titer CP, high titer CP and patients who did not receive CP were followed for 45 days after presentation. Severe adverse events were not associated with CP transfusion. Death was a less frequent outcome for patients that received high titer CP (>1:1024) 38.6% mortality, than patients that received low titer CP (≤1:1024) 77.8% mortality.

Clinical Performance of the BD CTGCTV2 Assay for the BD MAX System for Detection of Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis Infections.

BACKGROUND: Diagnostic options to combat the increasing rates of sexually transmitted infections recorded throughout the world increasingly include multiplex assays. Here we describe the estimated sensitivity and specificity of a triplex molecular assay that simultaneously detects Chlamydia trachomatis (CT), Neisseria gonorrhoeae (or gonococci [GC]), and Trichomonas vaginalis (TV). METHODS: Participants (2547 women and 1159 men) were recruited from 12 clinics in the United States. BD CTGCTV2 for BD MAX System assay (CTGCTV2) results were obtained from vaginal and endocervical swabs, endocervical samples in cytology medium, and female and male urine. Results were compared with infection standards that were sample type and pathogen dependent. RESULTS: Female specimen sensitivity estimates ranged from 92.7% to 98.4%, 92.9% to 100%, and 86.6% to 100% for CT, GC and TV, respectively. Male urine sensitivity estimates were 96.7%, 99.2%, and 97.9% for CT, GC, and TV, respectively. Specificity estimates were >98.7% for all sample types. CONCLUSIONS: BD CTGCTV2 performed well using a variety of sample types. As a true triplex assay, performed using a benchtop instrument, BD CTGCTV2 may be useful in settings where no testing is currently performed and in settings, such as reference laboratories, where testing turnaround time may be several days. Use of this assay at local laboratories may result in greater access to testing and a shorter time to result, which are important steps for improving our ability to combat sexually transmitted infections.

An Unusual Presentation of Prostatic Abscess due to Actinomyces turicensis and Peptostreptococcus.

Actinomyces is a rare cause of prostatic abscess. Most reported cases of abdominal and pelvic actinomycosis are a consequence of invasive procedures or abdominal infections. In this report, we present a previously healthy 53-year-old man with inguinal pain, fever and dysuria who was found to have a prostate abscess, secondary to Actinomyces turicensis and Peptostreptococcus, which was removed via transurethral resection of the prostate. This case was complicated by Peptostreptococcus bacteremia and a facial abscess. The patient was treated with antibiotics and ultimately made a full recovery.

Weight Gain Associated With Integrase Stand Transfer Inhibitor Use in Women.

BACKGROUND: Integrase strand-transfer inhibitor (INSTI)-based antiretroviral therapy (ART) is recommended for human immunodeficiency virus (HIV) management. Although studies have suggested associations between INSTIs and weight gain, women living with HIV (WLHIV) have been underrepresented in research. We evaluated the effect of switching or adding INSTIs among WLHIV. METHODS: Women enrolled in the Women's Interagency HIV Study (WIHS) from 2006-2017 who switched to or added an INSTI to ART (SWAD group) were compared to women on non-INSTI ART (STAY group). Body weight, body mass index (BMI), percentage body fat (PBF), and waist, hip, arm, and thigh circumferences were measured 6-12 months before and 6-18 months after the INSTI switch/add in SWAD participants, with comparable measurement time points in STAY participants. Linear regression models compared changes over time by SWAD/STAY group, adjusted for age, race, WIHS site, education, income, smoking status, and baseline ART regimen. RESULTS: We followed 1118 women (234 SWAD and 884 STAY) for a mean of 2.0 years (+/- 0.1 standard deviation [SD]; mean age 48.8 years, SD +/- 8.8); 61% were Black. On average, compared to the STAY group, the SWAD group experienced mean greater increases of 2.1 kg in body weight, 0.8 kg/m2 in BMI, 1.4% in PBF, and 2.0, 1.9, 0.6, and 1.0 cm in waist, hip, arm, and thigh circumference, respectively (all P values < .05). No differences in magnitudes of these changes were observed by INSTI type. CONCLUSIONS: In WLHIV, a switch to INSTI was associated with significant increases in body weight, body circumferences, and fat percentages, compared to non-INSTI ART. The metabolic and other health effects of these changes deserve further investigation.

Loss of Preexisting Immunological Memory Among Human Immunodeficiency Virus-Infected Women Despite Immune Reconstitution With Antiretroviral Therapy.

BACKGROUND: It is unclear whether human immunodeficiency virus (HIV) infection results in permanent loss of T-cell memory or if it affects preexisting antibodies to childhood vaccinations or infections. METHODS: We conducted a matched cohort study involving 50 pairs of HIV-infected and HIV-uninfected women. Total memory T-cell responses were measured after anti-CD3 or vaccinia virus (VV) stimulation to measure T cells elicited after childhood smallpox vaccination. VV-specific antibodies were measured by means of enzyme-linked immunosorbent assay (ELISA). RESULTS: There was no difference between HIV-infected and HIV-uninfected study participants in terms of CD4+ T-cell responses after anti-CD3 stimulation (P = .19) although HIV-infected participants had significantly higher CD8+ T-cell responses (P = .03). In contrast, there was a significant loss in VV-specific CD4+ T-cell memory among HIV-infected participants (P = .04) whereas antiviral CD8+ T-cell memory remained intact (P > .99). VV-specific antibodies were maintained indefinitely among HIV-uninfected participants (half-life, infinity; 95% confidence interval, 309 years to infinity) but declined rapidly among HIV-infected participants (half-life; 39 years; 24-108 years; P = .001). CONCLUSIONS: Despite antiretroviral therapy-associated improvement in CD4+ T-cell counts (nadir, <200/µL; >350/µL after antiretroviral therapy), antigen-specific CD4+ T-cell memory to vaccinations or infections that occurred before HIV infection did not recover after immune reconstitution, and a previously unrealized decline in preexisting antibody responses was observed.

Association between Use of Methadone, Other Central Nervous System Depressants, and QTc Interval-Prolonging Medications and Risk of Mortality in a Large Cohort of Women Living with or at Risk for Human Immunodeficiency Virus Infection.

STUDY OBJECTIVE: To evaluate the association between use of methadone, other central nervous system (CNS) depressants, and QTc interval-prolonging medications and risk of mortality among human immunodeficiency virus (HIV)-infected and at-risk HIV-uninfected women. DESIGN: Multicenter, prospective, observational cohort study (Women's Interagency HIV Study [WIHS]). PARTICIPANTS: A total of 4150 women enrolled in the WIHS study between 1994 and 2014 who were infected (3119 women) or not infected (1031 women) with HIV. MEASUREMENTS AND MAIN RESULTS: Data on medication utilization were collected from all study participants via interviewer-administered surveys at 6-month intervals (1994-2014). Mortality was confirmed by National Death Index data. With age defining the time scale for the analysis, Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause mortality in HIV-infected and -uninfected women and non-acquired immunodeficiency syndrome (AIDS) deaths in HIV-infected women. A total of 1046 deaths were identified, of which 429 were considered non-AIDS deaths. Use of benzodiazepines, CNS depressants (excluding methadone), and number of medications with conditional QTc interval-prolonging effects were each associated with all-cause mortality in multivariate models of HIV-infected women: hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.01-1.60, p=0.037; HR 1.61, 95% CI 1.35-1.92, p<0.0001; and HR 1.15 per drug, 95% CI 1.00-1.33, p=0.047, respectively. Other explanatory variables for all-cause mortality in this model included HIV viral load, CD4+  cell count, renal function, hemoglobin and albumin levels, HIV treatment era, employment status, existence of depressive symptoms, ever use of injection drugs, and tobacco smoking. Of interest, use of CNS depressants (excluding methadone) was also associated with non-AIDS deaths (HR 1.49, 95% CI 1.49-2.2, p<0.0001). Although use of benzodiazepines and conditional QT interval-prolonging medications were associated with increased risk of non-AIDS mortality (HR 1.32 and 1.25, respectively), the effect was not statistically significant (p>0.05). CONCLUSION: In this cohort of HIV-infected and at-risk HIV-uninfected women, use of benzodiazepines, CNS depressants, and conditional QTc interval-prolonging medications were associated with a higher risk of mortality independent of methadone and other well-recognized mortality risk factors. Care must be taken to assess risk when prescribing these medications in this underserved and at-risk patient population.

A Fungal Immunotherapeutic Vaccine (NDV-3A) for Treatment of Recurrent Vulvovaginal Candidiasis-A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Recurrent vulvovaginal candidiasis (RVVC) is a problematic form of mucosal Candida infection, characterized by repeated episodes per year. Candida albicans is the most common cause of RVVC. Currently, there are no immunotherapeutic treatments for RVVC. Methods: This exploratory randomized, double-blind, placebo-controlled trial evaluated an immunotherapeutic vaccine (NDV-3A) containing a recombinant C. albicans adhesin/invasin protein for prevention of RVVC. Results: The study in 188 women with RVVC (n = 178 evaluable) showed that 1 intramuscular dose of NDV-3A was safe and generated rapid and robust B- and T-cell immune responses. Post hoc exploratory analyses revealed a statistically significant increase in the percentage of symptom-free patients at 12 months after vaccination (42% vaccinated vs 22% placebo; P = .03) and a doubling in median time to first symptomatic episode (210 days vaccinated vs 105 days placebo) for the subset of patients aged <40 years (n = 137). The analysis of evaluable patients, which combined patients aged <40 years (77%) and ≥40 years (23%), trended toward a positive impact of NDV-3A versus placebo (P = .099). Conclusions: In this unprecedented study of the effectiveness of a fungal vaccine in humans, NDV-3A administered to women with RVVC was safe and highly immunogenic and reduced the frequency of symptomatic episodes of vulvovaginal candidiasis for up to 12 months in women aged <40 years. These results support further development of NDV-3A vaccine and provide guidance for meaningful clinical endpoints for immunotherapeutic management of RVVC. Clinical Trials Registration: NCT01926028.

Artificial Differences in Clostridium difficile Infection Rates Associated with Disparity in Testing.

In 2015, Clostridium difficile testing rates among 30 US community, multispecialty, and cancer hospitals were 14.0, 16.3, and 33.9/1,000 patient-days, respectively. Pooled hospital onset rates were 0.56, 0.84, and 1.57/1,000 patient-days, respectively. Higher testing rates may artificially inflate reported rates of C. difficile infection. C. difficile surveillance should consider testing frequency.

Chronic hepatitis C virus infection and subsequent HIV viral load among women with HIV initiating antiretroviral therapy.

OBJECTIVES: One in four persons living with HIV is coinfected with hepatitis C virus (HCV). Biological and behavioral mechanisms may increase HIV viral load among coinfected persons. Therefore, we estimated the longitudinal effect of chronic HCV on HIV suppression after ART initiation among women with HIV (WWH). DESIGN: HIV RNA was measured every 6 months among 441 WWH in the Women's Interagency HIV Study who initiated ART from 2000 to 2015. METHODS: Log-binomial regression models were used to compare the proportion of study visits with detectable HIV RNA between women with and without chronic HCV. Robust sandwich variance estimators accounted for within-person correlation induced by repeated HIV RNA measurements during follow-up. We controlled for confounding and selection bias (because of loss to follow-up and death) using inverse probability-of-exposure-and-censoring weights. RESULTS: One hundred and fourteen women (25%) had chronic HCV before ART initiation. Overall, the proportion of visits with detectable HIV RNA was similar among women with and without chronic HCV [relative risk (RR) 1.19 (95% CI 0.72, 1.95)]. Six months after ART initiation, the proportion of visits with detectable HIV RNA among women with chronic HCV was 1.88 (95% CI 1.41-2.51) times that among women without HCV, at 2 years, the ratio was 1.60 (95% CI 1.17-2.19), and by 6 years there was no difference (1.03; 95% CI 0.60-1.79). CONCLUSION: Chronic HCV may negatively impact early HIV viral response to ART. These findings reaffirm the need to test persons with HIV for HCV infection, and increase engagement in HIV care and access to HCV treatment among persons with HIV/HCV coinfection.

Moderate Alcohol Use Is Not Associated With Fibrosis Progression in Human Immunodeficiency Virus/Hepatitis C Virus-Coinfected Women: A Prospective Cohort Study.

BACKGROUND: Heavy alcohol use can lead to progressive liver damage, especially in individuals with chronic hepatitis C (HCV); however, the impact of nonheavy use is not clear. We studied long-term effects of modest alcohol use on fibrosis progression in a large cohort of women coinfected with human immunodeficiency virus (HIV)/HCV. METHODS: Alcohol intake was ascertained every 6 months and use categorized as abstinent, light (1-3 drinks/week), moderate (4-7 drinks/week), heavy (>7 drinks/week), and very heavy (>14 drinks/week). Fibrosis progression was defined as the change in Fibrosis-4 Index for Liver Fibrosis (FIB-4) units per year using random-intercept, random-slope mixed modeling. RESULTS: Among 686 HIV/HCV-coinfected women, 46.0% reported no alcohol use; 26.8% reported light use, 7.1% moderate use, and 19.7% heavy use (6.7% had 8-14 drinks/week and 13.0% had >14 drinks/week) at cohort entry. Median FIB-4 at entry was similar between groups. On multivariable analysis, compared to abstainers, light and moderate alcohol use was not associated with fibrosis progression (0.004 [95% confidence interval {CI}, -.11 to .12] and 0.006 [95% CI, -.18 to .19] FIB-4 units/year, respectively). Very heavy drinking (>14 drinks/week) showed significant fibrosis acceleration (0.25 [95% CI, .01-.49] FIB-4 units/year) compared to abstaining, whereas drinking 8-14 drinks per week showed minimal acceleration of fibrosis progression (0.04 [95% CI, -.19 to .28] FIB-4 units/year). CONCLUSIONS: Light/moderate alcohol use was not substantially associated with accelerated fibrosis progression, whereas drinking >14 drinks per week showed increased rates of fibrosis progression. Women with HIV/HCV infection should be counseled against heavy alcohol consumption, but complete abstinence may not be required to prevent accelerated liver fibrosis progression.

Macrophage Activation and the Tumor Necrosis Factor Cascade in Hepatitis C Disease Progression Among HIV-Infected Women Participating in the Women's Interagency HIV Study.

BACKGROUND: HIV/hepatitis C-coinfected persons experience more rapid liver disease progression than hepatitis C virus (HCV) monoinfected persons, even in the setting of potent antiretroviral therapy. METHODS: We sought to articulate the role of macrophage activation and inflammation in liver disease progression by measuring serial soluble markers in HIV/HCV-coinfected women. We compared markers measured during retrospectively defined periods of rapid liver disease progression to periods where little or no liver disease progression occurred. Liver disease progression was defined by liver biopsy, liver-related death or the serum markers AST-to-platelet ratio index and FIB-4. Soluble CD14, sCD163, lipopolysaccharide (LPS), tumor necrosis factor (TNF) receptor II, interleukin-6, and chemokine ligand 2 (CCL 2) were measured at 3 time points over 5 years. RESULTS: One hundred six time intervals were included in the analysis: including 31 from liver disease progressors and 75 from nonprogressors. LPS, sCD14, interleukin-6, and CCL2 levels did not differ in slope or quantity over time between rapid liver disease progressors and nonprogressors. TNFRII and sCD163 were significantly higher in liver disease progressors at (P = 0.002 and <0.0001 respectively) and preceding (P = 0.01 and 0.003 respectively) the liver fibrosis outcome in unadjusted models, with similar values when adjusted for HIV RNA and CD4 count. CONCLUSIONS: In women with HIV/HCV coinfection, higher sCD163 levels, a marker of macrophage activation, and TNFRII levels, implying activation of the TNF-α system, were associated with liver disease progression. Our results provide an addition to the growing body of evidence regarding the relationship between macrophage activation, inflammation, and liver disease progression in HIV/HCV coinfection.