Faculty Bibliography

Background. Paired with other active antiretrovirals (ARVs), fostemsavir (FTR) may offer heavily treatment-experienced (HTE) people with HIV (PWH) options for continuing effective treatment. Durability and effectiveness of FTR-containing regimens in routine clinical care in the United States were assessed. Methods. Electronic health record data from the OPERA cohort were used to identify adults initiating FTR-containing regimens between 2JUL2020 (FDA approval) and 1SEP2021. Eligible PWH were followed from first FTR prescription (baseline) until FTR discontinuation, death, loss to follow up, or study end (28FEB2022). Durability was assessed as frequency of FTR discontinuation. Virologic outcomes assessed at 6 and 12 months (+/-3 months) included suppression (viral load [VL] < 50 copies/mL), virologic failure (2 consecutive VL >=200 copies/mL or 1 VL >=200 copies/ mL + FTR discontinuation within 120 days after suppression), and viral blips (1 VL >=50 copies/mL preceded and followed by VLs < 50 copies/mL). Analyses were stratified by baseline viral load (bVL < 50 copies/mL; bVL >=50 copies/mL). Results. Overall, 86 PWH initiated FTR (bVL < 50: 30; bVL >=50: 55), with median follow up of 10.8 months (IQR: 6.8, 15.3). Compared to PWH with bVL >=50, those with bVL < 50 were older and more likely to be white and have lived longer with HIV (Table 1). Over follow up, 20% discontinued FTR (Table 2). Most (82%) FTR discontinuations were switches to alternative regimens; the remaining were ARV interruptions (no ARVs for > 45 days). Among PWH with bVL < 50, most maintained suppression (6 months: 74%; 12 months: 82%; Figure). Among PWH with bVL >=50 and with follow up VL during the period assessed, 33% were suppressed at 6 months, 36% were suppressed at 12 months, and 48% achieved suppression at any time over the entire follow up (Figure). In either group, <=5 PWH experienced virologic failure or blip, though the proportion of PWH with multiple follow up VLs was low. Conclusion. Despite a heterogenous population and diverse regimens, most HTE PWH remained on FTR at study end. Most PWH with bVL < 50 remained suppressed and half of PWH with bVL >=50 achieved suppression over the entire study period. Virologic failure and blips were infrequent, although follow up was limited in this early evaluation of real-world FTR use

Background. HIV-associated wasting (i.e., progressive, involuntary weight loss with both fat and lean tissue loss; HIVAW) is an under-appreciated AIDS-defining illness; the 2012-2018 period prevalence was reported as 18% in a recent claims study in the United States. We aimed to assess the association between incident HIVAW/ low weight and all-cause mortality in the era of modern combination antiretroviral therapy (ART). Methods. In the Observational Pharmaco-Epidemiology Research & Analysis (OPERA) cohort, PWH without (a) any prior HIVAW/low weight, (b) malignancy within 3 years, and (c) opportunistic infection within 1 year who were active in care between 2016 and 2020 were followed through death, loss to follow-up, or study end (31OCT2021). HIVAW/low weight included a wasting or low BMI/underweight diagnosis (ICD codes, title search) or BMI < 20 kg/m2. Hazard ratios (HR) and 95% confidence intervals (CI) for the association between time-dependent incident HIVAW/low weight (exposure) and all-cause mortality (outcome) were estimated with extended Cox regression models. The adjusted model included age at baseline, race, ethnicity, and time-dependent covariates (log10 viral load, Veterans Aging Cohort Study [VACS] Mortality Index score). Viral load and VACS score were included as surrogate markers for ART use and comorbidities, respectively. Linear and quadratic terms of continuous variables were included. Results. Of 67,119 PWH without prior HIVAW/low weight in OPERA, 62,314 (93%) PWH had non-missing covariate data and were included in the models; baseline characteristics did not differ between the full and model study populations (Table 1). Over a median follow-up of 45 months (interquartile range: 27, 65), there were 4,755 (8%) cases of incident HIVAW/low weight and 1,354 (2%) deaths. In the adjusted model, PWH who experienced incident HIVAW/low weight had a significantly increased risk of death over follow-up than those who did not experience HIVAW/low weight (HR: 1.96; 95% CI: 1.68, 2.27) (Table 2). Conclusion. In this analysis of 62,314 PWH in care, incident HIVAW/low weight was associated with twice the risk for all-cause mortality in the modern ART era. Particular attention needs to be paid to HIVAW/low weight among PWH to restore health and potentially reduce the risk of death

Introduction: The United States Preventive Services Taskforce lowered the recommended starting age for colorectal cancer (CRC) screening in average-risk adults from 50 to 45 years due to a rapid increase in young CRC incidence and overall favorable benefit-to-burden ratio in the US. This recommendation has not been widely adopted by other countries partially because the burden of young CRC in these countries is unclear compared to the United States Methods: The incidence rates of early-onset CRC in young adults (defined as the onset of CRC in individuals aged between 20 to 49 years) from 1990 to 2019 were collected from the Global Health Data Exchange (GHDx) results tool (available at https://vizhub.healthdata.org/gbd-results). Data from 204 countries and geographic areas were available. The socio-demographic index (SDI) was used to categorize countries and geographic areas by development (low, low-middle, middle, high-middle, and high).
Result(s): The global incidence rate of young CRC increased from 4.2/100,000 to 6.7/100,000 from 1990 to 2019, with an annual percentage change (APC) of 1.6%. The increase in CRC incidence rate was faster in young adults than in individuals aged 50-74 years (APC 0.6%). In the high HDI region, the CRC incidence rate decreased in adults aged 50-74 years old while it increased in adults 20-49 years old from 1995 to 2019 (Table). The increase in young CRC incidence rate was consistently observed in all five SDI regions and 185 out of 204 countries and territories (Figure a). Middle (120.8%), high-middle (98.5%), and lowmiddle (63.7%) SDI regions experienced the most rapid increase in young CRC incidence rate, while the high SDI region had the highest incidence rate by 2019 (11.5 per 100,000). By 2019, nine countries and territories (Taiwan, Monaco, Portugal, Andorra, Japan, China, Bulgaria, Hungary, and Slovakia) had higher young CRC incidence rates than the United States (Figure b); CRC screening for average-risk adults aged 45-49 years should be studied in these countries. A concerning 142 countries had a higher annual percentage increase of young CRC than the United States, which warrants further attention and investigation. (Table) (Figure a/b)
Conclusion(s): The global incidence, mortality, and DALYs of young CRC increased from 1990 to 2019. The increase in young CRC incidence was prevalent in most countries worldwide. Several countries were found to have higher incidence rates or faster increase in young CRC, which warrants further attention

Background/Purpose: Knee osteoarthritis (OA) is an inflammatory disease, with a probable role for IL-1b. Calcium and urate crystals may promote OA by activating the NLRP3 inflammasome to produce IL-1b. Colchicine is a well-tolerated anti-inflammatory agent that inhibits the inflammasome and suppresses IL-1b. Studies examining the impact of colchicine on knee OA have yielded varying results, with some reporting pain relief, others improvement of inflammatory markers, and none assessing synovial effusions. We report the interim, blinded results of our ongoing colchicine trial for knee OA.
Method(s): CLOAK is a randomized, double-blind, placebo-controlled trial of colchicine (once daily for 3 months) (Figure 1). We are enrolling subjects >= 40 years of age, with symptomatic knee OA, Kellgren-Lawrence grade 2 or 3 radiographs, and willingness to forego other anti-inflammatory therapy during the trial. The primary outcome is the change in knee pain by visual analog scale (VAS) after 3 months of treatment, comparing the colchicine and placebo groups. Secondary outcomes include pre to post treatment Knee Injury and Osteoarthritis Outcome Score (KOOS), mean doses of analgesics used, and changes in plasma and peripheral blood leukocyte inflammatory markers. Patients undergo knee ultrasound (US) pre-and post-treatment to assess synovitis and effusion. We aspirate synovial fluid when appropriate, and will analyze all available blood and synovial samples after study completion.
Result(s): To date, 715 potential subjects have been contacted, 82 screened, and 71 enrolled. Among 60 who have completed the study, 51.6% are male, 60% White, 30% Black, 3.3% Asian and 6.7% other, with mean BMI of 27.6 kg/m2 and age of 66.8 years. The mean VAS pain score among all completing participants (subjects and controls combined) improved Figure 1. Flow diagram of study plan. Figure 2. Subject improvement in KOOS score from beginning to end of study, according to high or low baseline severity as measured by VAS and KOOS scores and presence of synovial effusion. by 0.98 units in the index knee, and mean KOOS scores improved for symptoms, pain, activities of daily living (ADL), sports activity, and quality of life (QOL). Overall 36 (60%) demonstrated VAS improvement (mean improvement 2.3) whereas 24 (40%) demonstrated no change or worsening. Overall, subjects whose VAS improved showed concordant improvement in the KOOS: mean symptoms by 10.5, pain by 12.4, ADL by 14.8, sports activity by 5.8 and QOL by 11.4 units. The subsets of patients with baseline VAS >=6 and baseline KOOS <=60 (i.e., more severe) showed significantly more 3-month KOOS pain improvement, even with the blinded inclusion of placebo (Figure 2). All underwent US at baseline and 3 months. Among 36 patients with VAS improvement over 3 months, 6 had baseline synovial effusions >=4 mm (in longitudinal and transverse views) and 5 of these effusions were smaller on US post-treatment and one remained stable.
Conclusion(s): The results of this blinded analysis are consistent with a potential benefit of colchicine for pain, function and effusion in subjects not taking other anti-inflammatory agents. Enrollment is ongoing and the study will be unblinded and fully analyzed after completion

Background. In-vitro neutralizing antibody (Ab) titers correlated with ~250 IU/ mL Spike Ig Ab level for the Delta COVID-19 variant, establishing the 2021 French and Swiss cutoff for booster guidance. In a New York City healthcare clinic where those guidelines were adopted, we aimed to quantify vaccination responses in HIV + and HIV- individuals to assess the utility of quantifying antibodies to guide booster timing. Methods. Adults who were fully vaccinated against SARS-CoV-2 virus (i.e., 2 Pfizer, 2 Moderna or 1 J&J vaccine) were included if >1 Roche SARS-CoV-2 Semi-Quant Spike Ig Ab test was performed >21 days after vaccination and before any booster (through 03DEC2021). Vaccine response was assessed at the first Ab test and considered adequate (>250 IU/mL) or inadequate (low: >=51 to <=250 IU/ mL; no response: < 51 IU/mL). The rate of Ab decline was estimated with linear regression, using all sequential Ab tests over the first 6 months between vaccination and boosting. Analyses were stratified by vaccine type, HIV status and CD4 count in HIV+ ( >200 cells/muL cutoff). Results. Out of 1979 patients, 869 completed their primary vaccinations, of whom 825 (95%) had >=1 eligible Ab test (HIV+: 512; HIV-: 313; Table). Overall, 83% had an adequate immune response to vaccination (Pfizer: 82%, Moderna: 94%, J&J: 51%), with similar findings regardless of HIV status and CD4 count (Figure 1). In those with >=2 Ab tests within six months between vaccination and boosting, Ab levels declined at a rate of 91 IU/mL per month (95% CI: -138, -44). While some variation was observed, rates of Ab decay were generally consistent across vaccine, HIV status and CD4 count strata (Figure 2). Only 1/7 breakthrough COVID-19 infections occurred post booster (6 days later Conclusion. In the pre-omicron era, primary COVID immunization with a mRNA vaccine generally yielded adequate Ab responses, although inadequate responses were observed in 19% of Pfizer, 6% of Moderna, and 49% of J&J vaccine recipients. Ab levels decreased at an average rate of 91 IU/mL per month after primary immunization. Variability in vaccine responses and Ab declines show the utility of measuring spike Ig Ab levels rather than using empiric time frames for booster guidance. Omicron-specific quantitative IgG neutralization levels must be established to inform preventative care

Background: There is currently a paucity of data on urethral-related outcomes in metoidioplasty and phalloplasty gender affirming surgery (MaPGAS) with urethral lengthening (UL)and vaginectomy.
Method(s): A systematic review was performed utilizing MEDLINE, Web of Science, Cochrane Library, Europe PMC, OSF Preprints, and EMBASE. Methodologic quality was scored using Methodological Index for Non-Randomized Studies (MINORS) criteria. Four independent reviewers performed the article evaluation, data extraction, and methodologic quality assessment. Primary outcomes included standing to urinate/pee (STP), penile length, glanular meatus, urethral stricture, fistula, and flap necrosis. Results were summarized qualitatively with descriptive statistics.
Result(s): A total of 2,881 articles of which 11 retrospective reviews of 13 cohorts met criteria; 4.3/16 average (avg) MINORS score. Six metoidioplasty cohorts had an average penile length of 6 cm, 74% reported successful STP, and a quarter developed stricture or fistula. Phalloplasty cohorts included radial forearm flap (RF) and Anterolateral Thigh flap (ALT). Of the 4 RF studies nearly a third developed a stricture or fistula and only one study reported 99% STP with a glanular meatus. Three ALT studies reported no length but had 80-90% STP with a glanular meatus and a quarter with stricture or fistula.
Conclusion(s): Urethral complications in MaPGAS-UL in a cohort with prior vaginectomy are common and variably reported. Patient centered outcome measures as well as clearly defined outcome metrics created in partnership with community members are needed.
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Introduction: Inborn errors of immunity are a group of primary immunodeficiency disorders caused by over 400 genetic defects. Enteropathy has been common in PID patients, which presents with chronic diarrhea, malabsorption, growth delay, iron deficiency, and failure to thrive. This article systemically reviewed the clinical presentations, treatments, and genetic defects of enteropathy observed in PIDD.
Method(s): We have reviewed published cases with the clinical diagnosis of both enteropathy and PIDD using 3 databases (Pubmed, Scopus, EMBASE). A total of 346 cases met our inclusion criteria.
Result(s): The most common enteropathy-associated PIDD is common variable immunodeficiency (32.4%), IPEX (21%), selective IgA deficiency (18.1%), and hypogammaglobulinemia (7.9%; Figure). Celiac disease (26.2%) is the most common enteropathy presentation in PIDD, followed by IPEX (20.7%), autoimmune enteropathy (6.4%), and CVID enteropathy (5.8%). Selective IgA deficiency and CD/Celiac like disease were also frequently reported. More than half of documented PIDD-related CD showed positive serology test results and histopathological findings. Eighty-eight percent of PIDD-related CD cases are responsive to a gluten-free diet. FOXP3 mutation (70) was the most common gene mutation in PIDD, followed by CTLA-4 (17), CD55 (8), NFKB1 (8), GoF-STAT1 (5), GoF-STAT3 (5), and C1-INH (4; Table)). CTLA-4 mutation was found related to CVID, hypogammaglobulinemia, and autoimmune enteropathy. NFKB1was found mainly linked to CVID. We observed frequent giardiasis (21), norovirus (3), CMV (4), Candidiasis (2), and histoplasmosis (2) infections causing enteropathy in PIDD. No significant difference in treatments of the enteropathy between PIDD and non-PIDD was noticed.
Conclusion(s): Enteropathy can be common clinical presentations in IEIs. With early recognition of clinical manifestations and enteropathy-associated gene mutation, PIDD can be diagnosed and treated timely, preventing complications and mortalities

Introduction: Biloma is an extrahepatic bile collection secondary to iatrogenic or traumatic biliary tree disruption. It is a rare complication of laparoscopy cholecystectomy with an incidence rate of approximately 2.5%. Without proper management, biloma can become infected and cause life-threatening complications such as peritonitis, biliary fistula, bilhemia and hemobilia. Here we described a case of complicated biloma after laparoscopic cholecystectomy. Case Description/Methods: The patient was a 24-year-old female with a past medical history of hypertension, obesity, and recent laparoscopic cholecystectomy complicated by hepatic subcapsular biloma. It was managed by biliary stent placement via endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous drainage during the previous hospitalization. However, 6 days later, she presented with fever, chills, nausea, and right upper quadrant pain. Vital signs were fever 102.3 F and tachycardia 110 to 120 per min. The CT abdomen revealed decreased size in perihepatic fluid collection with air bubbles (14 x 11 x 18 cm; Figure). It also showed a common bile duct stent in place and a percutaneous drainage catheter tip in the inferior aspect of the collection. Lab results showed leukocytosis to 10.3, normal AST/ALT, total/direct bilirubin 2.1/12 mg/dL, and GGT 152 U/L. Broad-spectrum antibiotics were given in ED. The surgery team performed a laparoscopic lavage and discovered that the drain was not connected with the biloma. Two new drains were placed during the operation. She was discharged with PO antibiotics, and an outpatient follow-up was scheduled for drain removal.
Discussion(s): The management of biloma depends on the severity of the disease. Endoscopic therapy, such as a transpapillary biliary stent placement, can decrease the transpapillary pressure gradient, thus allowing preferential transpapillary bile flow rather than accumulation at the leaking site. However, given that stent placement does not reabsorb formed collection, patients failing ERCP should undergo percutaneous drainage or bile duct repair.Iatrogenic biloma can be detected by post-operational physical exams and image studies. Laparoscopic lavage with drainage should be considered in unresolved or infected biloma due to the high risk of peritonitis

Introduction: Mimicking physiological pan-creatic pulsatile insulin secretion has led to the concept of pulsatile insulin infusion therapy (PIT).
Method(s): This exploratory pilot study investigated the effect of PIT for three months once weekly on kidney function in patients with type 2 diabetes and chronic renal failure (glomerular filtration rate (GFR) < 60 ml/min or GFR < 75 ml/min with mac-roproteinurea).
Result(s): Seventeen type 2 patients com-pleted the trial per protocol (7 women, 10 men, age: 69 +/- 7 yrs., HbA1c: 7.9 +/- 1.0 %). After three months, mean GFR improved by 12 % (from 47.6 +/- 10.0 ml/ min to 53.3 +/- 11.9 ml/min, p < 0.01) while mean serum creatinine decreased by 7 % (1.4 +/- 0.3 mg/dl/1.3 +/- 0.3 mg/dl, p < 0.05). Blood pressure medication was kept constant during the study; systolic blood pressure improved by 6 % (p < 0.05) while HbA1c and body weight remained stable. Treatment satisfaction scores improved from 3.7 +/- 2.7 to 2.7 +/- 2.1 (p < 0.005). The PIT procedures were well tolerated; only few cases of muscle cramps were consid-ered related to the treatments.
Conclusion(s): Improvements in kidney func-tion, systolic blood pressure and treatmensatisfaction were observed. These results will now be used to plan for appropriately designed controlled confirmatory studies.
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Objectives GEN-1, an IL-12 DNA plasmid formulated with a synthetic carrier is being evaluated with neoadjuvant platinumtaxane chemotherapy (NACT) in patients with advanced epithelial ovarian cancer. OVATION 2 is a multi-center, randomized, open-label phase I/II study evaluating the safety, antitumor activity, and immunological response to GEN-1 at a dose of 100 mg/m2 intraperitoneal (IP) actively enrolling at 20 centers in USA and Canada. Methods Up to 130 patients will be randomized 1:1 to receive either NACT plus GEN-1 or NACT alone. The phase I portion will evaluate safety in at least 6 patients administered in 8 weekly infusions starting at cycle 1 week 2 in combination with three 21-day cycles of carboplatin AUC 6 with paclitaxel 175 mg/m2 (PC). Following interval cytoreductive surgery an additional 9 weekly GEN-1 IP infusions starting at cycle 4 week 1 with three 21-day cycles of PC. If no dose limiting toxicities are found, then the study will continue into the phase II portion. To evaluate biological activity a subgroup of patients will have tumor tissue at initial biopsy/laparoscopy collected and at interval cytoreductive surgery. Tissue will be analyzed for the density of CD8, FoxP3, IDO-1, PD-1, and PDL-1 cells. Blood, peritoneal fluid/wash will be collected before and after treatment in a subgroup of patients to quantify for levels of IFN-g. The primary endpoint is PFS. Results Trial in progress: there are no available results at the time of submission. Conclusions Trial in progress: there are no available conclusions at the time of submission