Vincent Lo Re

A Simple, Dynamic Measure of Antiretroviral Therapy Adherence Predicts Failure to Maintain HIV-1 Suppression

BACKGROUND High levels of antiretroviral therapy adherence are important for human immunodeficiency virus type 1 (HIV-1) suppression, yet the magnitude of adherence required to maintain it is less well characterized. Furthermore, methods to accommodate changes in adherence over time are lacking. In the present study, our objective was to determine the magnitude of antiretroviral therapy adherence needed to maintain HIV-1 suppression by use of a time-updated adherence measure that has the potential to be of use in a clinical setting. METHODS We examined a population-based cohort of HIV-1-infected subjects > or =18 years of age, residing in British Columbia, Canada, who started receiving antiretroviral therapy between 1 August 1996 and 30 September 2003, who had at least 2 consecutive viral loads <500 copies/mL and who had prescriptions filled at least 3 times during a follow-up period ending 30 September 2004. Virological failure was defined as the second of 2 consecutive viral loads >1000 copies/mL. Cox proportional hazards model was used to determine the relationship between virological failure and refill-based, time-updated surrogate measure of adherence. RESULTS Among the 1634 participants > or =18 years of age who initiated triple combination therapy during the study, 606 virological failure events were identified. In multivariate analyses, subjects with < or =95% adherence were 1.66 (95% confidence interval, 1.38-2.01) times more likely to experience virological failure than those with >95% adherence. CONCLUSIONS The highest levels of antiretroviral therapy adherence are associated with higher rates of maintained virological suppression. This simple, dynamic surrogate measure of adherence overcomes the limitation of single-point-in-time calculations of adherence and may be useful in real time to determine whether an individual is exhibiting incomplete adherence.

The treatment cascade for chronic hepatitis C virus infection in the United States: a systematic review and meta-analysis.

Background Identifying gaps in care for people with chronic hepatitis C virus (HCV) infection is important to clinicians, public health officials, and federal agencies. The objective of this study was to systematically review the literature to provide estimates of the proportion of chronic HCV-infected persons in the United States (U.S.) completing each step along a proposed HCV treatment cascade: (1) infected with chronic HCV; (2) diagnosed and aware of their infection; (3) with access to outpatient care; (4) HCV RNA confirmed; (5) liver fibrosis staged by biopsy; (6) prescribed HCV treatment; and (7) achieved sustained virologic response (SVR). Methods We searched MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews for articles published between January 2003 and July 2013. Two reviewers independently identified articles addressing each step in the cascade. Studies were excluded if they focused on specific populations, did not present original data, involved only a single site, were conducted outside of the U.S., or only included data collected prior to 2000. Results 9,581 articles were identified, 117 were retrieved for full text review, and 10 were included. Overall, 3.5 million people were estimated to have chronic HCV in the U.S. Fifty percent (95% CI 43–57%) were diagnosed and aware of their infection, 43% (CI 40–47%) had access to outpatient care, 27% (CI 27–28%) had HCV RNA confirmed, 17% (CI 16–17%) underwent liver fibrosis staging, 16% (CI 15–16%) were prescribed treatment, and 9% (CI 9–10%) achieved SVR. Conclusions Continued efforts are needed to improve HCV care in the U.S. The proposed HCV treatment cascade provides a framework for evaluating the delivery of HCV care over time and within subgroups, and will be useful in monitoring the impact of new screening efforts and advances in antiviral therapy.

Hepatic Decompensation in Antiretroviral-Treated Patients Co-Infected With HIV and Hepatitis C Virus Compared With Hepatitis C Virus–Monoinfected Patients: A Cohort Study

Context Patients with HIV are often co-infected with hepatitis C virus (HCV). Whether treatment of HIV with antiretroviral therapy (ART) can improve HCV outcomes is a topic of interest. Contribution In a Veterans Affairs study, patients co-infected with HIV and HCV who had HIV RNA levels less than 1000 copies/mL had a lower rate of hepatic decompensation than those with less HIV suppression. However, the rate was still higher than that in HCV-monoinfected patients. Caution Few women were studied. Implication Patients co-infected with HIV and HCV remain at greater risk for poor outcomes from HCV infection than HCV-monoinfected patients despite viral suppression by ART. The Editors Co-infection with chronic hepatitis C virus (HCV) occurs in 10% to 30% of HIV-infected patients (14). The course of chronic HCV is accelerated in patients co-infected with HIV, with more rapid progression of liver fibrosis than in HCV-monoinfected patients (57). Consequently, HCV-related liver complications, particularly hepatic decompensation (defined by the presence of ascites, spontaneous bacterial peritonitis, variceal hemorrhage, or hepatic encephalopathy [8]), have emerged as important causes of illness in co-infected patients (9, 10). Despite the importance of HCV-related end-stage liver disease, few longitudinal studies have evaluated the incidence and determinants of hepatic decompensation among patients co-infected with HIV and HCV during the antiretroviral therapy (ART) era. Previous studies suggest that ART slows progression of HCV-associated liver fibrosis, possibly by reducing HIV-related inflammation and immune dysfunction and inhibiting the ability of HIV to directly infect hepatocytes (1013). However, whether rates of hepatic decompensation and other severe liver events (for example, hepatocellular carcinoma [HCC] or liver-related death) in co-infected patients receiving ART are similar to those in HCV-monoinfected patients remains unclear. Furthermore, the determinants of hepatic decompensation among co-infected patients receiving ART are unknown. Determination of these factors could help define the mechanisms of decompensation in co-infected patients and could suggest interventions to reduce the risk for end-stage liver disease in this population. We first compared the incidence of hepatic decompensation between antiretroviral-treated patients co-infected with HIV and HCV and HCV-monoinfected patients. We hypothesized that rates of decompensation would remain higher in co-infected patients despite ART. We then evaluated host and viral factors associated with decompensation among co-infected patients. Methods Study Design and Data Source We conducted a retrospective cohort study among antiretroviral-treated patients co-infected with HIV and HCV and HCV-monoinfected patients in the VACS-VC (Veterans Aging Cohort Study Virtual Cohort) between 1 January 1997 and 30 September 2010 (14). The VACS-VC consists of electronic medical record data from HIV-infected patients receiving care at Veterans Affairs (VA) medical facilities across the United States. Each HIV-infected patient is matched on age, sex, race/ethnicity, and site to 2 HIV-uninfected persons. Data include hospital and outpatient diagnoses (recorded using International Classification of Diseases, Ninth Revision [ICD-9], codes), procedures (recorded using CPT [Current Procedural Terminology] codes), laboratory results, and pharmacy data. Clinically confirmed cancer diagnoses are available from the VA Central Cancer Registry. Deaths are identified from the VA Vital Status file, which uses data from the Social Security Death Master File, Medicare Vital Status Files, and VA Beneficiary Identification and Records Locator Subsystem. For patients who died, principal cause of death can be determined by linkage with the National Death Index (15). In addition, U.S. Medicare and Medicaid claims data are available for veterans also enrolled in these programs and have been merged with VACS-VC data. Study Patients Co-infected patients were included if they had detectable HCV RNA, had recently initiated ART (defined as use of 3 antiretrovirals from 2 classes [16] or 3 nucleoside analogues [a previously accepted ART regimen] [17]) within the VA system, had an HIV RNA level greater than 500 copies/mL within 180 days before starting ART (to identify those who newly initiated ART [18]), and had been observed for at least 12 months in the VACS-VC after starting ART. Monoinfected patients had detectable HCV RNA, no recorded HIV ICD-9 diagnosis or antiretroviral prescriptions, and at least 12 months of observation in the VACS-VC. Patients were excluded if, during the baseline period (defined in the Statistical Analysis section), they had hepatic decompensation, HCC, or liver transplantation or received interferon-based HCV therapy (because treatment reduces the risk for hepatic decompensation [19, 20]). Study Outcomes The primary outcome was incident hepatic decompensation, which was defined by 1 ICD-9 diagnosis of ascites, spontaneous bacterial peritonitis, or esophageal variceal hemorrhage at hospital discharge or 2 such outpatient diagnoses in the VACS-VC (Supplement 1). A prior study validated this determination, with 91% of events confirmed by medical records (21). The requirement of 2 outpatient diagnoses aimed to exclude events that were suspected but not subsequently confirmed at follow-up visits. On the basis of the results of the prior validation study (21), we did not include ICD-9 diagnoses for hepatic encephalopathy and jaundice, which could indicate decompensation, because these diagnoses frequently were linked to unrelated conditions (for example, narcotic overuse, stroke recorded as encephalopathy, or biliary obstruction or atazanavir-associated hyperbilirubinemia recorded as jaundice). Date of decompensation was defined as the hospital discharge date (if identified by hospital diagnosis) or initial outpatient diagnosis date (if identified by outpatient diagnosis). Supplement 1. ICD-9, ICD-10, and CPT Codes Secondary outcomes included incident hepatic decompensation (determined by the aforementioned ICD-9based definition) within the VACS-VC, Medicare, or Medicaid data (to capture outcomes occurring at non-VA hospitals that did not result in transfer to a VA facility; this outcome was secondary because non-VA events have not been validated); HCC; and severe liver events, a composite outcome of hepatic decompensation within the VACS-VC, HCC, or liver-related death. Hepatocellular carcinoma was determined using the VA Central Cancer Registry, which confirmed diagnoses by histologic or cytologic evaluation or consistent radiography. We classified deaths as liver-related if the underlying cause from the National Death Index was recorded as hepatic decompensation, liver cancer, alcoholic liver disease, viral hepatitis, or nonalcoholic liver disease (Supplement 1) (15). Data Collection Baseline data (Table 1) included age, sex, race/ethnicity, VA center patient volume, body mass index (BMI), diabetes mellitus, alcohol dependence or abuse, injection or noninjection drug use, hepatitis B surface antigen status, HCV genotype, HCV RNA level, pre-ART CD4 cell count, pre-ART plasma HIV RNA level, and baseline antiretroviral regimen. Diabetes was defined as a random glucose level of at least 200 mg/dL or antidiabetic medication use (22, 23). Alcohol dependence or abuse (24) and injection or noninjection drug use (24, 25) were defined by previously validated ICD-9 diagnoses (Supplement 1). Baseline serum creatinine, hemoglobin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels and platelet count were collected from dates closest to but before the start of follow-up. Baseline FIB-4 score, a noninvasive measure of advanced hepatic fibrosis, was determined as follows: [age in yearsAST level in U/L] / [(platelet count in109/L)(ALT level in U/L)1/2] (26). Because liver fibrosis can progress by 1 stage as early as within 4 years for antiretroviral-treated patients co-infected with HIV and HCV (7) and within 5 years for HCV-monoinfected persons (27), we determined baseline FIB-4 scores by using ALT levels, AST levels, and platelet counts within a 2-year period around the start of follow-up. Scores less than 1.45 indicate no or minimal fibrosis, and scores greater than 3.25 indicate advanced hepatic fibrosis or cirrhosis in co-infected (26) and HCV-monoinfected patients (28). Table 1. Characteristics of the Study Cohorts Longitudinal data included hepatitis B surface antigen status, plasma HIV RNA level, diabetes, and liver transplantation (determined by diagnosis and procedural codes) (Supplement 1). Statistical Analysis The 12 months before the start of follow-up represented the baseline period for both cohorts. Follow-up began 12 months after ART initiation for co-infected patients and after 12 months in the VACS-VC for monoinfected patients. The rationale for defining the baseline period as the first year of receipt of ART for co-infected patients was that many of these patients initially entered care at the time of ART initiation, which was shortly after their HIV diagnosis. Follow-up continued until a study end point, death, initiation of HCV therapy, or the last visit before 30 September 2010, whichever came first. For descriptive purposes, we estimated incidence rates (events per 1000 person-years) of end points with 95% CIs, standardized by the age and race/ethnicity distribution of co-infected patients (29). We then used Cox models to estimate adjusted hazard ratios (HRs) for outcomes in co-infected compared with monoinfected patients (30). We controlled for all available clinically relevant variables in Table 1. The proportionality of hazards was evaluated by plots of Schoenfeld residuals (31). In a sensitivity analysis, we addressed the potential for informative censoring by using inverse probability of censoring weights and Cox regression (Supplement

Validity of diagnostic codes and liver-related laboratory abnormalities to identify hepatic decompensation events in the Veterans Aging Cohort Study

The absence of validated methods to identify hepatic decompensation in cohort studies has prevented a full understanding of the natural history of chronic liver diseases and impact of medications on this outcome. We determined the ability of diagnostic codes and liver‐related laboratory abnormalities to identify hepatic decompensation events within the Veterans Aging Cohort Study (VACS).

Prevalence and risk factors for significant liver fibrosis among HIV-monoinfected patients.

BackgroundHIV-monoinfected patients may be at risk for significant liver fibrosis, but its prevalence and determinants in these patients are unknown. Since HIV-monoinfected patients do not routinely undergo liver biopsy, we evaluated the prevalence and risk factors of significant hepatic fibrosis in this group using the aspartate aminotransferase (AST)-to-platelet ratio index (APRI).MethodsWe conducted a cross-sectional study among HIV-infected patients negative for hepatitis B surface antigen and hepatitis C antibody in the Penn Center for AIDS Research Adult/Adolescent Database. Clinical and laboratory data were collected from the database at enrollment. Hypothesized determinants of significant fibrosis were modifiable risk factors associated with liver disease progression, hepatic fibrosis, or hepatotoxicity, including immune dysfunction (i.e., CD4 T lymphocyte count <200 cells/mm3, HIV viremia), diseases associated with hepatic steatosis (e.g., obesity, diabetes mellitus), and use of antiretroviral therapy. The primary outcome was an APRI score >1.5, which suggests significant hepatic fibrosis. Multivariable logistic regression identified independent risk factors for significant fibrosis by APRI.ResultsAmong 432 HIV-monoinfected patients enrolled in the CFAR Database between November 1999 and May 2008, significant fibrosis by APRI was identified in 36 (8.3%; 95% CI, 5.9 - 11.4%) patients. After controlling for all other hypothesized risk factors as well as active alcohol use and site, detectable HIV viremia (adjusted OR, 2.56; 95% CI, 1.02 - 8.87) and diabetes mellitus (adjusted OR, 3.15; 95% CI, 1.12 - 10.10) remained associated with significant fibrosis by APRI.ConclusionsSignificant fibrosis by APRI score was found in 8% of HIV-monoinfected patients. Detectable HIV viremia and diabetes mellitus were associated with significant fibrosis. Future studies should explore mechanisms for fibrosis in HIV-monoinfected patients.

Risk of hip fracture associated with hepatitis c virus infection and hepatitis C/human immunodeficiency virus coinfection

Hepatitis C virus (HCV) infection has been associated with reduced bone mineral density, but its association with fracture rates is unknown, particularly in the setting of human immunodeficiency virus (HIV) coinfection. Our aims were to determine whether persons with HCV infection alone are at increased risk for hip fracture, compared to uninfected individuals, and to examine whether the risk of hip fracture is higher among HCV/HIV‐coinfected persons, compared to those with HCV alone, those with HIV alone, and those uninfected with either virus. We conducted a cohort study in 36,950 HCV/HIV‐coinfected, 276,901 HCV‐monoinfected, 95,827 HIV‐monoinfected, and 3,110,904 HCV/HIV‐uninfected persons within the U.S. Medicaid populations of California, Florida, New York, Ohio, and Pennsylvania (1999‐2005). Incidence rates of hip fracture were lowest among uninfected persons (1.29 events/1,000 person‐years), increased with the presence of either HIV infection (1.95 events/1,000 person‐years) or HCV infection (2.69 events/1,000 person‐years), and were highest among HCV/HIV‐coinfected individuals (3.06 events/1,000 person‐years). HCV/HIV coinfection was associated with an increased relative hazard (adjusted hazard ratio [HR] [95% confidence interval; CI]) of hip fracture, compared to HCV‐monoinfected (HR, 1.38; 95% CI: 1.25‐1.53), HIV‐monoinfected (females: HR, 1.76; 95% CI: 1.44‐2.16; males: HR, 1.36; 95% CI: 1.20‐1.55), and HCV/HIV‐uninfected persons (females: HR, 2.65; 95% CI: 2.21‐3.17; males: HR, 2.20; 95% CI: 1.97‐2.47). HCV monoinfection was associated with an increased risk of hip fracture, compared to uninfected individuals, and the relative increase was highest in the youngest age groups (females, 18‐39 years: HR, 3.56; 95% CI: 2.93‐4.32; males, 18‐39 years: HR, 2.40; 95% CI: 2.02‐2.84). Conclusion: Among Medicaid enrollees, HCV/HIV coinfection was associated with increased rates of hip fracture, compared to HCV‐monoinfected, HIV‐monoinfected, and HCV/HIV‐uninfected persons. HCV‐monoinfected patients had an increased risk of hip fracture, compared to uninfected individuals. (HEPATOLOGY 2012;56:1688–1698)

The Yale cTAKES extensions for document classification: architecture and application.

BACKGROUND Open-source clinical natural-language-processing (NLP) systems have lowered the barrier to the development of effective clinical document classification systems. Clinical natural-language-processing systems annotate the syntax and semantics of clinical text; however, feature extraction and representation for document classification pose technical challenges. METHODS The authors developed extensions to the clinical Text Analysis and Knowledge Extraction System (cTAKES) that simplify feature extraction, experimentation with various feature representations, and the development of both rule and machine-learning based document classifiers. The authors describe and evaluate their system, the Yale cTAKES Extensions (YTEX), on the classification of radiology reports that contain findings suggestive of hepatic decompensation. RESULTS AND DISCUSSION The F(1)-Score of the system for the retrieval of abdominal radiology reports was 96%, and was 79%, 91%, and 95% for the presence of liver masses, ascites, and varices, respectively. The authors released YTEX as open source, available at http://code.google.com/p/ytex.

Validity of The Health Improvement Network (THIN) for epidemiologic studies of hepatitis C virus infection.

Before using computerized databases to study hepatitis C virus (HCV) epidemiology, the validity of the diagnosis must be assessed. We determined the accuracy of HCV diagnostic codes within The Health Improvement Network (THIN), an electronic database containing medical record data from general medical practices in the United Kingdom.

PREVALENCE, RISK FACTORS, AND OUTCOMES FOR OCCULT HEPATITIS B VIRUS INFECTION AMONG HIV-INFECTED PATIENTS

Background:Occult hepatitis B virus (HBV) is defined by the presence of HBV DNA in individuals with HBV core antibodies (anti-HBc) but without HBV surface antigen (HBsAg). The prevalence of occult HBV in HIV-infected patients remains controversial, and the risk factors and clinical significance are unknown. Objectives:To determine the prevalence, risk factors, and clinical significance of occult HBV among HIV-infected patients. Hypothesized risk factors include chronic hepatitis C virus (HCV), CD4 count <200 cells/mm3, HIV RNA level >1000 copies/mL, and lack of use of anti-HBV antiretrovirals. Methods:We examined randomly selected HBsAg−/anti-HBc+ HIV-infected patients in the Penn Center for AIDS Research Adult/Adolescent Database and Specimen Repository. HBV DNA was qualitatively detected using a transcription-mediated amplification assay. Risk factors and transaminases were ascertained at the time sera were collected. Results:A total of 699 HBsAg−/anti-HBc+ HIV-infected patients were identified. Of 179 randomly selected subjects, 17 (10%; 95% confidence interval [CI]: 5% to 14%) had occult HBV. Differences in the prevalence of HBV surface antibody (anti-HBs) between those with (7 [41%]) and without (94 [58%]) occult HBV were not statistically significant (P = 0.3). An HIV RNA level >1000 copies/mL (adjusted odds ratio [OR] = 4.88, 95% CI: 1.01 to 30.26) and the absence of chronic HCV (adjusted OR = 0.26, 95% CI: 0.05 to 0.95) were associated with occult HBV. Occult HBV did not increase the risk of transaminitis (adjusted OR = 0.42, 95% CI: 0.12 to 1.45). Conclusions:Occult HBV occurred in a sizable proportion of HIV-infected patients and was associated with detectable HIV and the absence of chronic HCV. It did not increase the risk of transaminitis. The presence of anti-HBs does not rule out occult HBV. Future studies should examine the long-term clinical implications of occult HBV in HIV-infected patients.

Liver Fibrosis Progression in Hepatitis C Virus Infection After Seroconversion

IMPORTANCE Knowing the rate of liver fibrosis progression in hepatitis C virus (HCV)-infected persons can help inform patients and providers (clinicians, medical institutions or organizations, and third-party payers) in making treatment decisions. OBJECTIVE To determine the rate and factors associated with liver fibrosis progression and hepatic decompensation in persons after acquiring HCV infection. DESIGN, SETTING, AND PARTICIPANTS Secondary data analysis of persons in the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), a national Veterans Affairs (VA) database, between 2002 and 2012. Among 610 514 persons in ERCHIVES (half were HCV positive), we identified those with an initial negative and subsequent positive test result for HCV antibody and positive HCV RNA test result (HCV+). Controls had 2 negative HCV antibody test results (HCV-) in a comparable time frame and were matched 1:1 on age (in 5-year blocks), race, and sex. We excluded persons with human immunodeficiency virus, hepatitis B, less than 24 months of follow-up, hepatocellular carcinoma, and cirrhosis at baseline. MAIN OUTCOMES AND MEASURES Progression of liver fibrosis as estimated by the Fibrosis-4 (FIB-4) index; development of cirrhosis, defined by a FIB-4 score greater than 3.5; and development of hepatic decompensation. RESULTS The evaluable data set consisted of 1840 persons who were HCV+ and 1840 HCV- controls. The HCV+ persons were younger and had a lower mean (SD) body mass index (27.39 [5.51] vs 29.49 [6.16]; P < .001), a higher prevalence of alcohol and drug abuse and dependence diagnoses, and higher serum aminotransferase levels, but had a lower prevalence of diabetes and hypertension. Fibrosis progression started early after infection among HCV+ persons and tapered off after 5 years. A total of 452 cirrhosis and 85 hepatic decompensation events were recorded. After 10 years of follow-up, HCV+ persons were more likely to have a diagnosis of cirrhosis compared with HCV- controls (18.4% vs 6.1%). Nine years after diagnosis of cirrhosis, hepatic decompensation events were uncommon but had a higher rate in the HCV+ group (1.79% vs 0.33%). CONCLUSIONS AND RELEVANCE Persons who seroconverted for HCV have a more rapid progression of liver fibrosis and accelerated time to development of cirrhosis after seroconversion compared with HCV- controls. Fibrosis progression occurs early after infection; however, hepatic decompensation is uncommon after diagnosis of cirrhosis.