William C. Mathews

Cumulative Incidence of Cancer Among Persons With HIV in North America: A Cohort Study

BACKGROUND Cancer is increasingly common among persons with HIV. OBJECTIVE To examine calendar trends in cumulative cancer incidence and hazard rate by HIV status. DESIGN Cohort study. SETTING North American AIDS Cohort Collaboration on Research and Design during 1996 to 2009. PARTICIPANTS 86 620 persons with HIV and 196 987 uninfected adults. MEASUREMENTS Cancer type-specific cumulative incidence by age 75 years and calendar trends in cumulative incidence and hazard rates, each by HIV status. RESULTS Cumulative incidences of cancer by age 75 years for persons with and without HIV, respectively, were as follows: Kaposi sarcoma, 4.4% and 0.01%; non-Hodgkin lymphoma, 4.5% and 0.7%; lung cancer, 3.4% and 2.8%; anal cancer, 1.5% and 0.05%; colorectal cancer, 1.0% and 1.5%; liver cancer, 1.1% and 0.4%; Hodgkin lymphoma, 0.9% and 0.09%; melanoma, 0.5% and 0.6%; and oral cavity/pharyngeal cancer, 0.8% and 0.8%. Among persons with HIV, calendar trends in cumulative incidence and hazard rate decreased for Kaposi sarcoma and non-Hodgkin lymphoma. For anal, colorectal, and liver cancer, increasing cumulative incidence, but not hazard rate trends, were due to the decreasing mortality rate trend (-9% per year), allowing greater opportunity to be diagnosed. Despite decreasing hazard rate trends for lung cancer, Hodgkin lymphoma, and melanoma, cumulative incidence trends were not seen because of the compensating effect of the declining mortality rate. LIMITATION Secular trends in screening, smoking, and viral co-infections were not evaluated. CONCLUSION Cumulative cancer incidence by age 75 years, approximating lifetime risk in persons with HIV, may have clinical utility in this population. The high cumulative incidences by age 75 years for Kaposi sarcoma, non-Hodgkin lymphoma, and lung cancer support early and sustained antiretroviral therapy and smoking cessation.

Structures of Care in the Clinics of the HIV Research Network

As the HIV epidemic has evolved to become a chronic, treatable condition the focus of HIV care has shifted from the inpatient to the outpatient arena. The optimal structure of HIV care in the outpatient setting is unknown. Using the HIV Research Network (HIVRN), a federally sponsored consortium of 21 sites that provide care to HIV-infected individuals, this study attempted to: (1) document key features of the organization of care in HIVRN adult clinics and (2) estimate variability among clinics in these parameters. A cross-sectional survey of adult clinic directors regarding patient volume, follow-up care, provider characteristics, acute patient care issues, wait times, patient safety procedures, and prophylaxis practices was conducted from July to December 2007. All 15 adult HIVRN clinic sites responded: 9 academic and 6 community-based. The results demonstrate variability in key practice parameters. Median (range) of selected practice characteristics were: (1) annual patient panel size, 1300 (355-5600); (2) appointment no-show rate, 28% (8%-40%); (3) annual loss to follow-up, 15% (5%-25%); (4) wait time for new appointments, 5 days (0.5-22.5), and follow-up appointment, 8 days (0-30). The majority of clinics had an internal mechanism to handle acute patient care issues and provide a number of onsite consultative services. Nurse practitioners and physician assistants were highly utilized. These data will facilitate improvements in chronic care management of persons living with HIV.

Estimating the accuracy of anal cytology in the presence of an imperfect reference standard.

Background The study aim is to estimate sensitivity and specificity of anal cytology for histologic HSIL in analyses adjusted for the imperfect biopsy reference standard. Methods and Principal Findings Retrospective cohort study of an anal dysplasia screening program for HIV infected adults. We estimated the prevalence of histologic HSIL by concurrent cytology category and the associated cytology ROC area. Cytology operating characteristics for HSIL were estimated and adjusted for the imperfect reference standard by 3 methodologies. The study cohort included 261 patients with 3 available measures: (1) referral cytology; (2) HRA cytology; and (3) HRA directed biopsy. The prevalence of biopsy HSIL varied according to the concurrent HRA cytology result: 64.5% for HSIL or ASC-H, 12.6% for LSIL, 10.9% for ASCUS, and 6.3% for no abnormality. The cytology ROC area was 0.78. The observed prevalence of HSIL was 37% (referral cytology), 24% (HRA cytology), and 24% (HRA biopsy). Unadjusted estimates of sensitivity and specificity of cytology were 0.66 and 0.90, respectively. Adjusted estimates varied from 0.47–0.89 (sensitivity) and 0.89—1.0 (specificity). Conclusions Analysis of a single dataset yields widely different estimates of anal cytology operating characteristics that depend on difficult to verify assumptions regarding the accuracy of the imperfect reference standard.

The Hepatitis C Cascade of Care among HIV Infected Patients: A Call to Address Ongoing Barriers to Care

Background The aims were to investigate the hepatitis C (HCV) cascade of care among HIV-infected patients and to identify reasons for not referring for and not initiating HCV therapy after completion of HCV treatment staging. Design and Methods Retrospective cohort analysis of HIV-infected patients under care at the University of California, San Diego (UCSD). We identified patients screened for and diagnosed with active HCV infection. Logistic regression analyses were used to identify factors associated with lack of referral for HCV therapy. Electronic medical records were reviewed to ascertain reasons for not initiating HCV therapy. Results Between 2008 and 2012, 4725 HIV-infected patients received care at the UCSD Owen clinic. Most patients [4534 (96%)] were screened for HCV, 748 (16%) patients had reactive serum HCV antibodies but only 542 patients had active HCV infection. Lack of engagement in care was the most important predictor of non-referral for HCV therapy [odds ratio (OR): 5.08, 95% confidence interval 3.24–6.97, p<0.00001]. Other significant predictors included unstable housing (OR: 2.26), AIDS (OR: 1.83), having a detectable HIV viral load (OR: 1.98) and being non-white (OR: 1.67). The most common reason (40%) for not initiating or deferring HCV therapy was the presence of ongoing barriers to care. Conclusions Screening for HCV in HIV-infected patients linked to care is high but almost half of patients diagnosed with HCV are not referred for HCV therapy. Despite improvements in HCV therapy the benefits will not be realized unless effective measures for dealing with barriers to care are implemented.

Age at Entry Into Care, Timing of Antiretroviral Therapy Initiation, and 10-Year Mortality Among HIV-Seropositive Adults in the United States

BACKGROUND The goal of targeted antiretroviral therapy initiation is to minimize disease progression among patients with human immunodeficiency virus while minimizing the therapeutic burden on these patients. We examine whether the effect of delaying therapy initiation from 500 cells/mm(3) to 350 or 200 cells/mm(3) is modified by age at entry into care. METHODS We used the parametric g-formula to compare 10-year mortality under 3 CD4 cell count thresholds for therapy initiation among 3532 patients who entered care at 1 of 8 sites in the United States between 1998 and 2013. Results are reported separately for patients 18 to 34, 35 to 44, and 45 to 65 years of age at study entry. RESULTS In the observed data, 10-year mortality was 13% (165 deaths). Mortality increased from 11% under therapy initiation at 500 cells/mm(3) to 12% at 350 cells/mm(3) (risk difference [RD]: 0.87; 95% confidence interval [CI]: .56, 2.17) and to 14% at 200 cells/mm(3) (RD: 2.71; 95% CI: 1.79, 5.38). The effect of delaying therapy became greater with age: RDs comparing the 350-cells/mm(3) threshold with the 500-cells/mm(3) threshold ranged from -0.03 (95% CI: -0.15, 1.76) for patients 18 to 34 years of age to 0.99 (95% CI: -.27, 1.98) for patients 35 to 44 and to 2.30 (95% CI: 1.29, 5.42) for patients 45 to 65. CONCLUSIONS Delaying therapy increased 10-year mortality in the full cohort. Subgroup analysis highlights that patients entering care at older ages may be more vulnerable to the consequences of delayed ART initiation than younger patients.

Assessing and refining myocardial infarction risk estimation among patients with human immunodeficiency virus: A study by the Centers for AIDS Research Network of Integrated Clinical Systems

Importance Persons with human immunodeficiency virus (HIV) that is treated with antiretroviral therapy have improved longevity but face an elevated risk of myocardial infarction (MI) due to common MI risk factors and HIV-specific factors. Despite these elevated MI rates, optimal methods to predict MI risks for HIV-infected persons remain unclear. Objective To determine the extent to which existing and de novo estimation tools predict MI in a multicenter HIV cohort with rigorous MI adjudication. Design, Setting, and Participants We evaluated the performance of standard of care and 2 new data-derived MI risk estimation models in 5 Centers for AIDS Research Network of Integrated Clinical Systems sites across the United States where a multicenter clinical prospective cohort of 19 829 HIV-infected adults received care in inpatient and outpatient settings since 1995. The new risk estimation models were validated in a separate cohort from the derivation cohort. Exposures Traditional cardiovascular risk factors, HIV viral load, CD4 lymphocyte count, statin use, antihypertensive use, and antiretroviral medication use were used to calculate predicted event rates. Main Outcomes and Measures We observed MI rates over the course of follow-up that were scaled to 10 years using the Greenwood-Nam-D’Agostino Kaplan-Meier approach to account for dropout and loss to follow-up before 10 years. Results Of the 11 288 patients with complete baseline data, 6904 were white and 9250 were men. Myocardial infarction rates were higher among black men (6.9 per 1000 person-years) and black women (7.2 per 1000 person-years) than white men (4.4 per 1000 person-years) and white women (3.3 per 1000 person-years), older participants (7.5 vs 2.2 MI per 1000 person-years for adults 40 years and older vs < 40 years old at study entry, respectively), and participants who were not virally suppressed (6.3 vs 4.7 per 1000 person-years for participants with and without detectable viral load, respectively). The 2013 Pooled Cohort Equations, which predict composite rates of MI and stroke, adequately discriminated MI risk (Harrell C statistic = 0.75; 95% CI, 0.71-0.78). Two data-derived models incorporating HIV-specific covariates exhibited weak calibration in a validation sample and did not discriminate risk any better (Harrell C statistic = 0.72; 95% CI, 0.67-0.78 and 0.73; 95% CI, 0.68-0.79) than the Pooled Cohort Equations. The Pooled Cohort Equations were moderately calibrated in the Centers for AIDS Research Network of Clinical Systems but predicted consistently lower MI rates. Conclusions and Relevance The Pooled Cohort Equations discriminated MI risk and were moderately calibrated in this multicenter HIV cohort. Adding HIV-specific factors did not improve model performance. As HIV-infected cohorts capture and assess MI and stroke outcomes, researchers should revisit the performance of risk estimation tools.

Estimation of the Standardized Risk Difference and Ratio in a Competing Risks Framework: Application to Injection Drug Use and Progression to AIDS After Initiation of Antiretroviral Therapy

There are few published examples of absolute risk estimated from epidemiologic data subject to censoring and competing risks with adjustment for multiple confounders. We present an example estimating the effect of injection drug use on 6-year risk of acquired immunodeficiency syndrome (AIDS) after initiation of combination antiretroviral therapy between 1998 and 2012 in an 8-site US cohort study with death before AIDS as a competing risk. We estimate the risk standardized to the total study sample by combining inverse probability weights with the cumulative incidence function; estimates of precision are obtained by bootstrap. In 7,182 patients (83% male, 33% African American, median age of 38 years), we observed 6-year standardized AIDS risks of 16.75% among 1,143 injection drug users and 12.08% among 6,039 nonusers, yielding a standardized risk difference of 4.68 (95% confidence interval: 1.27, 8.08) and a standardized risk ratio of 1.39 (95% confidence interval: 1.12, 1.72). Results may be sensitive to the assumptions of exposure-version irrelevance, no measurement bias, and no unmeasured confounding. These limitations suggest that results be replicated with refined measurements of injection drug use. Nevertheless, estimating the standardized risk difference and ratio is straightforward, and injection drug use appears to increase the risk of AIDS.

Didanosine Exposure and Noncirrhotic Portal Hypertension in a HIV Clinic in North America: a Follow-up Study

AIMS: To describe: 1) our cohort of patients diagnosed with NCPH in a HIV academic clinic in North America, and 2) longitudinal follow-up and outcomes of patients following NCPH diagnosis. STUDY DESIGN: Retrospective case series. PLACE AND DURATION OF STUDY: Owen clinic, University of California, San Diego, United States, between October 1990 and December 2010. METHODOLOGY: We describe a cohort of patients diagnosed with NCPH in a HIV academic clinic with emphasis on their follow-up and outcomes after NCPH diagnosis. RESULTS: During the study period, eight HIV-infected men were diagnosed with NCPH. All patients were exposed to Didanosine (ddI) for a median of 37 months. One patient died soon after NCPH diagnosis due to a condition unrelated to NCPH. The other seven patients have received B-blocker therapy and annual esophago-gastro-duodenectomy screenings with banding of esophageal varices when indicated and remain still alive. Three patients were on ddI at the time of NCPH diagnosis. In one patient ddI was discontinued shortly after NCPH diagnosis. The other two patients continued to use ddI after NCPH diagnosis and developed recurrent upper gastrointestinal bleeding in the subsequent 2 years, requiring revascularization interventions. The four patients that were already off ddI at the time of NCPH diagnosis have been followed for a median of 6 years. These four patients remained minimally symptomatic for up to 16 years of follow-up from NCPH diagnosis. CONCLUSION: When ddI was discontinued before portal hypertension was clinically apparent the progression of NCPH appeared to subside without major clinical complications.

Increased Risk of Myocardial Infarction in HIV-Infected Individuals in North America Compared With the General Population

Background: Previous studies of cardiovascular disease (CVD) among HIV-infected individuals have been limited by the inability to validate and differentiate atherosclerotic type 1 myocardial infarctions (T1MIs) from other events. We sought to define the incidence of T1MIs and risk attributable to traditional and HIV-specific factors among participants in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) and compare adjusted incidence rates (IRs) to the general population Atherosclerosis Risk in Communities (ARIC) cohort. Methods: We ascertained and adjudicated incident MIs among individuals enrolled in 7 NA-ACCORD cohorts between 1995 and 2014. We calculated IRs, adjusted incidence rate ratios (aIRRs), and 95% confidence intervals of risk factors for T1MI using Poisson regression. We compared aIRRs of T1MIs in NA-ACCORD with those from ARIC. Results: Among 29,169 HIV-infected individuals, the IR for T1MIs was 2.57 (2.30 to 2.86) per 1000 person-years, and the aIRR was significantly higher compared with participants in ARIC [1.30 (1.09 to 1.56)]. In multivariable analysis restricted to HIV-infected individuals and including traditional CVD risk factors, the rate of T1MI increased with decreasing CD4 count [≥500 cells/&mgr;L: ref; 350–499 cells/&mgr;L: aIRR = 1.32 (0.98 to 1.77); 200–349 cells/&mgr;L: aIRR = 1.37 (1.01 to 1.86); 100–199 cells/&mgr;L: aIRR = 1.60 (1.09 to 2.34); <100 cells/&mgr;L: aIRR = 2.19 (1.44 to 3.33)]. Risk associated with detectable HIV RNA [<400 copies/mL: ref; ≥400 copies/mL: aIRR = 1.36 (1.06 to 1.75)] was significantly increased only when CD4 was excluded. Conclusions: The higher incidence of T1MI in HIV-infected individuals and increased risk associated with lower CD4 count and detectable HIV RNA suggest that early suppressive antiretroviral treatment and aggressive management of traditional CVD risk factors are necessary to maximally reduce MI risk.

Natural history of anal dysplasia in an HIV-infected clinical care cohort: estimates using multi-state Markov modeling.

Objectives (1) To model the natural history of anal neoplasia in HIV-infected patients using a 3-state Markov model of anal cancer pathogenesis, adjusting for cytology misclassification; and (2) to estimate the effects of selected time-varying covariates on transition probabilities. Design A retrospective cytology-based inception screening cohort of HIV-infected adults was analyzed using a 3-state Markov model of clinical pathogenesis of anal neoplasia. Methods Longitudinally ascertained cytology categories were adjusted for misclassification using estimates of cytology accuracy derived from the study cohort. Time-varying covariate effects were estimated as hazard ratios. Results (1) There was a moderate to high probability of regression of the high grade squamous intraepithelial lesion (HSIL) state (27–62%) at 2 years after initial cytology screening; (2) the probability of developing invasive anal cancer (IAC) during the first 2 years after a baseline HSIL cytology is low (1.9–2.8%); (3) infrared coagulation (IRC) ablation of HSIL lesions is associated with a 2.2–4.2 fold increased probability of regression to <HSIL; and (4) antiretroviral therapy, suppressed HIV plasma viral load, and CD4 ≥350/mm3 are each associated with reduced probability of progression from <HSIL to HSIL. Conclusions The finding of moderate to high rates of regression of the HSIL state accompanied by low rates of progression to IAC should inform both screening and precursor treatment guideline development. There appears to be a consistent and robust beneficial effect of antiretroviral therapy, suppressed viral load, and higher CD4 on the transition from the <HSIL state to the HSIL state.