Clinical Predictors and Outcomes of Invasive Anal Cancer for People With Human Immunodeficiency Virus in an Inception Cohort.

BACKGROUND: Due to the heterogeneity of risk for invasive anal cancer (IAC) among people with human immunodeficiency virus (PWH), we investigated predictors of IAC and described outcomes among those with a cancer diagnosis. METHODS: Using a longitudinal inception cohort of anal cancer screening, we evaluated risk factors and outcome probabilities for incident IAC in Cox models. Screening included anal cytology and digital anorectal examination, and, if results of either were abnormal, high-resolution anoscopy. RESULTS: Between 30 November 2006 and 3 March 2021, a total of 8139 PWH received care at the University of California, San Diego, with 4105 individuals undergoing screening and subsequently followed up over a median of 5.5 years. Anal cancer developed in 33 of them. IAC was more likely to develop in patients with anal high-grade squamous intraepithelial lesions (aHSILs) on initial or subsequent follow-up cytology (hazard ratio, 4.54) and a nadir CD4 cell count ≤200/µL (2.99). The joint effect of aHSILs and nadir CD4 cell count ≤200/µL amplified the hazard of IAC by 9-fold compared with the absence of both. PWH with time-updated cytology aHSIL and CD4 cell counts ≤200/µL had 5- and 10-year probabilities of IAC of 3.40% and 4.27%, respectively. Twelve individuals with cancer died, 7 (21% of the total 33) due to cancer progression, and they had clinical stage IIIA or higher cancer at initial diagnosis. CONCLUSIONS: PWH with both aHSIL and a nadir CD4 cell count ≤200/µL have the highest risk of IAC. PWH who died due to IAC progression had clinical stage IIIA cancer or higher at diagnosis, highlighting the importance of early diagnosis through high-resolution anoscopic screening.

Shared Decision-Making Concerning Anal Cancer Screening in Persons With Human Immunodeficiency Virus.

BACKGROUND: Anal high-grade squamous intraepithelial lesion (aHSIL) is the immediate precursor of anal cancer. Anal cytology is a recommended screening test to identify aHSIL among people with human immunodeficiency virus (HIV; PWH). Heterogeneity of risk for invasive anal cancer among PWH suggests the value of a shared decision-making framework regarding screening. METHODS: Using a longitudinal HIV cohort with a comprehensive anal cancer screening program, we estimated the adjusted probabilities of having aHSIL on the first anal cytology. We used logistic regression models with inverse probability weighting to account for differential screening in the cohort and to construct a predicted probability nomogram for aHSIL. Sensitivity analysis was performed to estimate aHSIL prevalence corrected for misclassification bias. RESULTS: Of 8139 PWH under care between 2007 and 2020, 4105 (49.8%) underwent at least 1 anal cytology test. First-time cytology aHSIL was present in 502 (12.2%) PWH. The adjusted probability of having aHSIL varied from 5% to 18% depending on patient characteristics. Prespecified factors in the aHSIL prediction model included nadir CD4 cell count, ethnicity, race, age, sex, gender identity, and HIV risk factors. The ability of the model to discriminate cytological aHSIL was modest, with an area under the curve of 0.63 (95% confidence interval, .60-.65). CONCLUSIONS: PWH are at increased risk for aHSIL and invasive anal cancer. Risk, however, varies by patient characteristics. Individual risk factor profiles predictive of aHSIL can be modeled and operationalized as nomograms to facilitate shared decision-making conversations concerning anal cancer screening.

At-Risk Alcohol Use Among HIV-Positive Patients and the Completion of Patient-Reported Outcomes.

Heavy drinking is prevalent among people living with HIV. Studies use tools like patient-reported outcomes (PROs) to quantify alcohol use in a detailed, timely manner. However, if alcohol misuse influences PRO completion, selection bias may result. Our study included 14,145 adult HIV patients (133,036 visits) from CNICS who were eligible to complete PROs at an HIV primary care visit. We compared PRO completion proportions between patients with and without a clinical diagnosis of at-risk alcohol use in the prior year. We accounted for confounding by baseline and visit-specific covariates. PROs were completed at 20.8% of assessed visits. The adjusted difference in PRO completion proportions was -3.2% (95% CI -5.6 to -0.8%). The small association between receipt of an at-risk alcohol use diagnosis and decreased PRO completion suggests there could be modest selection bias in studies using the PRO alcohol measure.

Validation of a questionnaire to monitor symptoms in HIV-infected patients during hepatitis C treatment.

BACKGROUND: Clinicians are incorporating patient-reported outcomes in the management of HIV-infected persons co-infected with hepatitis C virus (HCV), but there are no validated inventories to monitor symptoms of patients during HCV therapy. DESIGN: Five-year retrospective cohort analysis of persons living with HIV (PLWH) treated for HCV. METHODS: The HCV symptom-inventory (HCV-SI) was administered before, during, and after HCV treatment. Discriminant validity was assessed, separately, in mixed model linear regression of HCV-SI T-scores on treatment regimens (pegylated-interferon and ribavirin; pegylated-interferon, ribavirin, and telaprevir; and interferon-free antivirals); and side effect-related premature treatment discontinuation (SE-DC). RESULTS: From the 103 patients who completed the HCV-SI, 7% were female, 26% non-white, 32% cirrhotics and 91% had undetectable HIV viral loads. Most had genotype 1 (83%) and were HCV treatment-naïve (78%). We treated 19% of patients with pegylated-interferon and ribavirin, 22% with pegylated-interferon, ribavirin, and telaprevir and 59% received interferon-free antivirals. Overall, 77% achieved a sustained virologic response, and 6% discontinued HCV treatment due to side effects. In the treatment discrimination model, compared to the no treatment period, HCV-SI scores were significantly (p < 0.01) lower for interferon-free antivirals and higher for interferon-containing regimens. In the SE-DC model, the total HCV-SI, somatic and neuropsychiatric scores significantly predicted those patients who prematurely discontinued HCV treatment (P < 0.05). CONCLUSIONS: The HCV-SI effectively differentiated among treatment regimens known to vary by side effect profiles and between patients with and without treatment discontinuation due to side effects. The HCV-SI may have value as a patient-reported outcome instrument predicting the risk of HCV treatment discontinuation.

Effects of drug and hazardous alcohol use on having a detectable HIV viral load: An adherence mediation analysis.

Objectives: People living with HIV (PWH) with substance or alcohol use often have unsuppressed plasma HIV viral loads (pVL). The degree to which substance and alcohol use effects on HIV viral suppression are mediated through medication nonadherence is incompletely understood. Methods: We included PWH prescribed antiretroviral therapy and receiving care at an academic HIV clinic between 2014 and 2018 who completed both patient-reported outcomes (PRO) questionnaires and had subsequent pVL measurements. Measures included assessments of alcohol use (AUDIT-C), drug use (NIDA-ASSIST), and self-reported adherence measured using four different methods. Substances found in bivariate analysis to predict detectable pVL were modeled separately for mediation effects through adherence. We report natural direct (NDE) and indirect effect (NIE), marginal total effect (MTE), and percentage mediated. Results: Among 3125 PWH who met eligibility criteria, 25.8% reported hazardous alcohol use, 27.1% cannabis, 13.1% amphetamines, 1.9% inhalants, 5.3% cocaine, 4.5% sedative-hypnotics, 2.9% opioids, and 2.3% hallucinogens. Excellent adherence was reported by 58% of PWH, and 10% had detectable pVL. Except for sedatives, using other substances was significantly associated with worse adherence. Bivariate predictors of detectable pVL were [OR (95% CI)]: amphetamine use 2.4 (1.8-3.2) and opioid use 2.3 (1.3-4.0). The percent of marginal total effect mediated by nonadherence varied by substance: 36% for amphetamine use, 27% for opioid use, and 39% for polysubstance use. Conclusion: Use of amphetamines, opioids, and multiple substances predicted detectable pVL. Up to 40% of their effects were mediated by self-reported nonadherence. Confirmation using longitudinal measurement models will strengthen causal inference from this cross-sectional analysis.

Assessing the associations between known genetic variants and substance use in people with HIV in the United States.

BACKGROUND: The prevalence of substance use in people with HIV (PWH) in the United States is higher than in the general population and is an important driver of HIV-related outcomes. We sought to assess if previously identified genetic associations that contribute to substance use are also observed in a population of PWH. METHODS: We performed genome-wide association studies (GWAS) of alcohol, smoking, and cannabis use phenotypes in a multi-ancestry population of 7,542 PWH from the Center for AIDS Research Network of Integrated Clinical Systems (CNICS). We conducted multi-ancestry GWAS for individuals of African (n = 3,748), Admixed American (n = 1,334), and European (n = 2,460) ancestry. Phenotype data were self-reported and collected using patient reported outcomes (PROs) and three questions from AUDIT-C, an alcohol screening tool. We analyzed nine phenotypes: 1) frequency of alcohol consumption, 2) typical number of drinks on a day when drinking alcohol, 3) frequency of five or more alcoholic drinks in a 30-day period, 4) smoking initiation, 5) smoking cessation, 6) cigarettes per day, 7) cannabis use initiation, 8) cannabis use cessation, 9) frequency of cannabis use during the previous 30 days. For each phenotype we considered a) variants previously identified as associated with a substance use trait and b) novel associations. RESULTS: We observed evidence for effects of previously reported single nucleotide polymorphisms (SNPs) related to alcohol (rs1229984, p = 0.001), tobacco (rs11783093, p = 2.22E-4), and cannabis use (rs2875907, p = 0.005). We also report two novel loci (19p13.2, p = 1.3E-8; and 20p11.21, p = 2.1E-8) associated with cannabis use cessation. CONCLUSIONS: Our analyses contribute to understanding the genetic bases of substance use in a population with relatively higher rates of use compared to the general population.

Screening for Sexually Transmitted Infections During Hepatitis C Treatment to Predict Reinfection Among People With HIV.

BACKGROUND: Little is known about the risk of hepatitis C virus (HCV) reinfection among people with HIV (PWH) in the direct-acting antiviral (DAA) era. We evaluate HCV reinfection rates in the DAA era and characterize presustained virologic response (SVR) behavioral risk factors associated with reinfection among PWH at the University of California, San Diego (UCSD). METHODS: Observational longitudinal cohort of PWH treated with DAAs between 2014 and July 2019 who achieved SVR and had at least 1 subsequent HCV viral load measurement. HCV reinfection was defined as new HCV viremia after SVR. We examined whether screening for sexually transmitted infections (STIs) and substance use during the pre-SVR period could identify patients at greater risk for reinfection using exact Poisson regression to compare reinfection incidence rates between those with and without pre-SVR STIs and positive urine drug screens. RESULTS: Eight out of 200 PWH were reinfected with HCV a median ~26 weeks after SVR over 328.1 person-years of follow-up (PYFU), for an incidence rate of 2.44/100 PYFU. The observed HCV reinfection rate was highest among men who have sex with men who inject drugs (MSM IDU; 4.63/100 PFYU) and those aged 30-39 years (6.80/100 PYFU). Having a positive gonorrhea/chlamydia test during the pre-SVR period was a predictor of HCV reinfection. CONCLUSIONS: The HCV reinfection rate in the DAA era is similar to the rate observed in the interferon era in San Diego in PWH. STI screening during HCV treatment may help determine those at higher risk for HCV reinfection.

Low-density lipoprotein cholesterol response after statin initiation among persons living with human immunodeficiency virus.

BACKGROUND: Meta-analyses of general population studies report mean low-density lipoprotein cholesterol (LDL-C) reductions of 30% to <50% with moderate-intensity and ≥50% with high-intensity statins. Persons living with human immunodeficiency virus (PLWH) are at high risk for atherosclerotic cardiovascular disease (ASCVD), yet many have elevated LDL-C. OBJECTIVE: To evaluate LDL-C response after statin initiation among PLWH. METHODS: We conducted a retrospective cohort study of PLWH initiating statins between 2009 and 2013 (N = 706). Patients were categorized into mutually exclusive groups in the following hierarchy: history of coronary heart disease (CHD), diabetes, prestatin LDL-C ≥190 mg/dL, 10-year predicted ASCVD risk ≥7.5%, and none of the above (ie, unknown statin indication). The primary outcome was a ≥30% reduction in LDL-C after statin initiation. RESULTS: Among patients initiating statins, 5.8% had a history of CHD, 13.6% had diabetes, 6.2% had LDL-C ≥190 mg/dL, 35.4% had 10-year ASCVD risk ≥7.5%, and 39.0% had an unknown statin indication. Among patients with a history of CHD, 31.7% achieved a ≥30% LDL-C reduction compared with 25.0%, 59.1%, and 33.9% among those with diabetes, LDL-C ≥190 mg/dL, and 10-year ASCVD risk ≥7.5%, respectively. In multivariable adjusted analyses and compared to patients with an unknown statin indication, LDL-C ≥ 190 mg/dL was associated with a prevalence ratio for an LDL-C reduction ≥30% of 1.81 (95% confidence interval, 1.34-2.45), whereas no statistically significant association was present for history of CHD, diabetes, and 10-year ASCVD risk ≥7.5%. CONCLUSION: A low percentage of PLWH achieved the expected reductions in LDL-C after statin initiation, highlighting an unmet need for ASCVD risk reduction.

Physicians' attitudes toward homosexuality and HIV: survey of a California Medical Society- revisited (PATHH-II).

In 1982, Mathews et al. surveyed San Diego County Medical Society's (SDCMS) physicians about their attitudes toward homosexuality. They found significant differences in prevalence of homophobic attitudes by gender, year of medical school graduation, specialty, and practice setting. To assess current physicians' attitudes toward homosexuality and persons with HIV infection, an anonymous, self-administered, 17-item survey was mailed to all 4,385 members of the SDCMS and 1,271 UCSD physicians. The survey included items measuring attitudes toward homosexuality and toward entry to medical school and referral patterns, conditional on sexual orientation and HIV status of hypothetical referents. Only 3% of respondents would not admit a highly qualified homosexual applicant to medical school compared with 30% in 1982. Similarly, 9% would discontinue referrals to a gay pediatrician compared with 46% of respondents in 1982. Forty-two percent would not admit a "highly qualified but asymptomatic HIV-infected applicant with excellent response to antiretroviral therapy to medical school" and 66% would discontinue referral to a general surgeon known to be HIV infected. In multiple logistic regression analyses controlling for sex and medical school affiliation, significant (p < 0.05) independent predictors of being in the highest 10% on an HIV-phobia scale were year of graduation from medical school and degree of homophobia (model ROC = 0.77). This survey suggests a substantial reduction in homophobia since 1982. However, attitudes toward homosexuals and year of graduation from medical school appear to be significant predictors of attitudes toward persons with HIV infection.

Latent class profiles of internalizing and externalizing psychosocial health indicators are differentially associated with sexual transmission risk: Findings from the CFAR network of integrated clinical systems (CNICS) cohort study of HIV-infected men engaged in primary care in the United States.

OBJECTIVE: To examine whether latent class indicators of negative affect and substance use emerged as distinct psychosocial risk profiles among HIV-infected men, and if these latent classes were associated with high-risk sexual behaviors that may transmit HIV. METHODS: Data were from HIV-infected men who reported having anal intercourse in the past 6 months and received routine clinical care at 4 U.S. sites in the Centers for AIDS Research Network of Integrated Clinical Systems cohort (n = 1,210). Latent class membership was estimated using binary indicators for anxiety, depression, alcohol and/or drug use during sex, and polydrug use. Generalized estimating equations modeled whether latent class membership was associated with HIV sexual transmission risk in the past 6 months. RESULTS: Three latent classes of psychosocial indicators emerged: (a) internalizing (15.3%; high probability of anxiety and major depression); (b) externalizing (17.8%; high probability of alcohol and/or drug use during sex and polydrug use); (c) low psychosocial distress (67.0%; low probability of all psychosocial factors examined). Internalizing and externalizing latent class membership were associated with HIV sexual transmission risk, compared to low psychosocial class membership; externalizing class membership was also associated with higher sexual transmission risk compared to internalizing class membership. CONCLUSIONS: Distinct patterns of psychosocial health characterize this sexually active HIV-infected male patient population and are strongly associated with HIV sexual transmission risk. Public Health intervention efforts targeting HIV sexual risk transmission may benefit from considering symptom clusters that share internalizing or externalizing properties.

Screening for anal dysplasia associated with human papillomavirus.

Anal dysplasia associated with human papillomavirus (HPV) infection occurs in substantial proportions of HIV-infected men and women and poses risk for anal carcinoma. Whether to routinely screen for HPV-associated anal dysplasia in this population, however, remains a debated question. Anal dysplasia is detectable by Pap screening and colposcopic biopsy; as Pap testing results have relatively low reproducibility, 2 baseline tests may be prudent. Screening should also ascertain risk factors for dysplasia, degree of immunosuppression, and history of prior anal disease. Although treatment options for anal dysplasia are limited by morbidity and high recurrence rates, early detection may permit better tolerance of therapy, and current estimates indicate that routine screening for the condition would be cost-effective. In addition, emerging immunologic therapies offer hope of more effective future treatment. This article summarizes a presentation given by Wm. Christopher Mathews, MD, MSPH, at the November 2002 International AIDS Society-USA course in San Diego.

Use of human papillomavirus vaccine in HIV-infected men for the prevention of anal dysplasia and cancer.

There are two commercially available vaccines licensed worldwide for the prevention of cervical cancer and other human papillomavirus-associated cancers such as anal cancer. However, only two countries have implemented healthcare programs that include human papillomavirus vaccination for boys and men. Although most of the human papillomavirus-related cancers in the world are attributable to cervical cancer, in developed countries anal cancer accounts for a larger proportion of human papillomavirus-related cancers. Most cases of anal cancer occur in HIV-infected men who have sex with men. In this review, we discuss the burden of human papillomavirus-related cancers in men, the most plausible immune mechanism associated with the high efficacy of the human papillomavirus vaccine, and address key issues of vaccination for HIV-infected men. Finally, we review cost-effectiveness considerations for the use of the vaccine in boys and recent guidelines for vaccination in boys, with attention to HIV-infected men.

Comparative accuracy of anal and cervical cytology in screening for moderate to severe dysplasia by magnification guided punch biopsy: a meta-analysis.

BACKGROUND: The accuracy of screening for anal cancer precursors relative to screening for cervical cancer precursors has not been systematically examined. The aim of the current meta-analysis was to compare the relative accuracy of anal cytology to cervical cytology in discriminating between histopathologic high grade and lesser grades of dysplasia when the reference standard biopsy is obtained using colposcope magnification. METHODS AND FINDINGS: The outcome metric of discrimination was the receiver operating characteristic (ROC) curve area. Random effects meta-analysis of eligible studies was performed with examination of sources of heterogeneity that included QUADAS criteria and selected covariates, in meta-regression models. Thirty three cervical and eleven anal screening studies were found to be eligible. The primary meta-analytic comparison suggested that anal cytologic screening is somewhat less discriminating than cervical cytologic screening (ROC area [95% confidence interval (C.I.)]: 0.834 [0.809-0.859] vs. 0.700 [0.664-0.735] for cervical and anal screening, respectively). This finding was robust when examined in meta-regression models of covariates differentially distributed by screening setting (anal, cervical). CONCLUSIONS: Anal cytologic screening is somewhat less discriminating than cervical cytologic screening. Heterogeneity of estimates within each screening setting suggests that other factors influence estimates of screening accuracy. Among these are sampling and interpretation errors involving both cytology and biopsy as well as operator skill and experience.

Active methamphetamine use is associated with transmitted drug resistance to non-nucleoside reverse transcriptase inhibitors in individuals with HIV infection of unknown duration.

BACKGROUND: Frequent methamphetamine use among recently HIV infected individuals is associated with transmitted drug resistance (TDR) to non-nucleoside reverse transcriptase inhibitors (NNRTI); however, the reversion time of TDR to drug susceptible HIV may exceed 3 years. We assessed whether recreational substance use is associated with detectable TDR among individuals newly diagnosed with HIV infection of unknown duration. DESIGN: Cross-sectional analysis. METHODS: Subjects were enrolled at the University California, San Diego Early Intervention Program. Demographic, clinical and substance use data were collected using structured interviews. Genotypic resistance testing was performed using GeneSeq, Monogram Biosciences. We analyzed the association between substance use and TDR using bivariate analyses and the corresponding transmission networks using phylogenetic models. RESULTS: Between April 2004 and July 2006, 115 individuals with genotype data were enrolled. The prevalence of alcohol, marijuana and methamphetamine use were 98%, 71% and 64% respectively. Only active methamphetamine use in the 30 days prior to HIV diagnosis was independently associated with TDR to NNRTI (OR: 6.6; p=0.002). CONCLUSION: Despite not knowing the duration of their HIV infection, individuals reporting active methamphetamine use in the 30 days prior to HIV diagnosis are at an increased risk of having HIV strains that are resistant to NNRTI.

Survey of Physician Well-Being and Health Behaviors at an Academic Medical Center.

PURPOSE: The study aims were to ascertain, among attending and house staff at a single academic medical center, the prevalence of and risk factors for psychiatric symptoms and disorders and for personal health behaviors. METHODS: A self-administered, anonymous 72-item survey of physicians was conducted in February 2003. RESULTS: Response rate was 37.6%. The prevalence of current depressive symptoms was 29%. AUDIT scores consistent with high likelihood of harmful alcohol consumption were prevalent in 6%. Almost 5% acknowledged use of sedatives or hypnotics without a prescription in the prior 12 months. Characteristics independently associated with current depressive symptoms included: living alone, full time salaried faculty status, not having a primary care physician, female sex, and age < 50 years. Factors associated with high risk of harmful alcohol consumption included: male sex, house staff status, and not being exclusively heterosexual. CONCLUSIONS: The prevalence of recent depressive symptoms among responding physicians was nearly 30%. Interventions to engage physicians in primary care relationships and social support to confidentially disclose potentially stigmatizing characteristics may facilitate earlier case finding of those at risk for depression, suicide, and substance abuse.

Incidence of and risk factors for clinically significant methicillin-resistant Staphylococcus aureus infection in a cohort of HIV-infected adults.

OBJECTIVES: Outbreaks of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) have been noted in multiple sites in the United States. This study's purpose was to estimate trends in the incidence of and risk factors for clinically significant MRSA (CS-MRSA) infection in a cohort of HIV-infected adults. DESIGN: A retrospective clinic-based cohort (January 1, 2000-December 31, 2003) study. METHODS: We ascertained all initial episodes of CS-MRSA and categorized them by primary site. Incidence rates were estimated by half year. Risk factors for CA-MRSA infection were identified using Cox modeling. RESULTS: Of 126 potential events, 94 were CS. Their primary sources were 83% skin or soft tissue, 10% blood, 6% respiratory, and 1.0% other sites. Among these, 60% were CA and 40% were nosocomial. Of antibiotics tested, only cotrimoxazole resistance was associated with nosocomial acquisition. The 3455 patients contributed 7003 person-years at risk. The incidence of CS-MRSA infection increased 6.2-fold from the first to the last half year. In multivariate analysis, independent predictors of CA-MRSA infection included HIV transmission by men who have sex with men or by injection drug use, CD4 count <50 cells/muL, log10 HIV plasma viral load, and absence of cotrimoxazole prophylaxis. CONCLUSIONS: The incidence of initial CS-MRSA events increased more than 6-fold in a 4-year period. The associations between CA-MRSA infection and HIV severity indicators merit examination in other cohorts.