Lesley S. Park

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

Comparison of Risk and Age at Diagnosis of Myocardial Infarction, End-Stage Renal Disease, and Non-AIDS-Defining Cancer in HIV-Infected Versus Uninfected Adults

BACKGROUND Although it has been shown that human immunodeficiency virus (HIV)-infected adults are at greater risk for aging-associated events, it remains unclear as to whether these events happen at similar, or younger ages, in HIV-infected compared with uninfected adults. The objective of this study was to compare the median age at, and risk of, incident diagnosis of 3 age-associated diseases in HIV-infected and demographically similar uninfected adults. METHODS The study was nested in the clinical prospective Veterans Aging Cohort Study of HIV-infected and demographically matched uninfected veterans, from 1 April 2003 to 31 December 2010. The outcomes were validated diagnoses of myocardial infarction (MI), end-stage renal disease (ESRD), and non-AIDS-defining cancer (NADC). Differences in mean age at, and risk of, diagnosis by HIV status were estimated using multivariate linear regression models and Cox proportional hazards models, respectively. RESULTS A total of 98 687 (31% HIV-infected and 69% uninfected) adults contributed >450 000 person-years and 689 MI, 1135 ESRD, and 4179 NADC incident diagnoses. Mean age at MI (adjusted mean difference, -0.11; 95% confidence interval [CI], -.59 to .37 years) and NADC (adjusted mean difference, -0.10 [95% CI, -.30 to .10] years) did not differ by HIV status. HIV-infected adults were diagnosed with ESRD at an average age of 5.5 months younger than uninfected adults (adjusted mean difference, -0.46 [95% CI, -.86 to -.07] years). HIV-infected adults had a greater risk of all 3 outcomes compared with uninfected adults after accounting for important confounders. CONCLUSIONS HIV-infected adults had a higher risk of these age-associated events, but they occurred at similar ages than those without HIV.

HIV as an Independent Risk Factor for Incident Lung Cancer

Background:It is unclear whether the elevated rate of lung cancer among HIV-infected persons is due to biological effects of HIV, surveillance bias, or excess smoking. We compared the incidence of lung cancer between HIV-infected and demographically similar HIV-uninfected patients, accounting for smoking and stage of lung cancer at diagnosis. Design:Data from the Veterans Aging Cohort Study Virtual Cohort were linked to data from the Veterans Affairs Central Cancer Registry, resulting in an analytic cohort of 37 294 HIV-infected patients and 75 750 uninfected patients. Methods:We calculated incidence rates of pathologically confirmed lung cancer by dividing numbers of cases by numbers of person-years at risk. We used Poisson regression to determine incidence rate ratios (IRRs), adjusting for age, sex, race/ethnicity, smoking prevalence, previous bacterial pneumonia, and chronic obstructive pulmonary disease. Results:The incidence rate of lung cancer in HIV-infected patients was 204 cases per 100 000 person-years [95% confidence interval (CI) 167–249] and among uninfected patients was 119 cases per 100 000 person-years (95% CI 110–129). The IRR of lung cancer associated with HIV infection remained significant after multivariable adjustment (IRR 1.7; 95% CI 1.5–1.9). Lung cancer stage at presentation did not differ between HIV-infected and uninfected patients. Conclusion:In our cohort of demographically similar HIV-infected and uninfected patients, HIV infection was an independent risk factor for lung cancer after controlling for potential confounders including smoking. The similar stage distribution between the two groups indicated that surveillance bias was an unlikely explanation for this finding.

HIV infection, aging, and immune function: implications for cancer risk and prevention.

Purpose of review Combination antiretroviral therapy (ART) has turned HIV infection into a complex chronic disease. This article documents cancer risk among HIV-infected persons, reviews immune system effects of HIV infection in relation to cancer risk, discusses implications for cancer prevention, and suggests future research directions. Recent findings There has been a shift in the cancer spectrum from AIDS-defining cancers (ADC) to non-ADC, although the burden of ADC remains high. Although a high prevalence of non-HIV cancer risk factors among HIV-infected persons contributes to cancer risk, substantial evidence has accumulated in favor of an independent association between HIV-induced immunodeficiency and elevated risk of many specific cancer types, most of viral cause, although further work is needed to disentangle immunodeficiency and smoking effects for lung cancer, and immunodeficiency and hepatitis virus effects for liver cancer. Relationships between cancer risk and two other immune system hallmarks of HIV infection, chronic inflammation, and immune dysfunction/senescence, remain poorly understood. Summary Early, sustained ART is a crucial component of cancer prevention. Continued epidemiologic monitoring is needed to detect possible effects on cancer risk of specific ART classes or medications, long-term exposure to systemic inflammation or immune dysfunction, or earlier or more effective ART.

Prevalence of non-HIV cancer risk factors in persons living with HIV/AIDS: a meta-analysis.

Objective:The burden of cancer among persons living with HIV/AIDS (PLWHA) is substantial and increasing. We assessed the prevalence of modifiable cancer risk factors among adult PLWHA in Western high-income countries since 2000. Design:Meta-analysis. Methods:We searched PubMed to identify articles published in 2011–2013 reporting prevalence of smoking, alcohol consumption, overweight/obesity, and infection with human papillomavirus (HPV), hepatitis C virus (HCV) and hepatitis B virus (HBV) among PLWHA. We conducted random effects meta-analyses of prevalence for each risk factor, including estimation of overall, sex-specific, and HIV-transmission-group-specific prevalence. We compared prevalence in PLWHA with published prevalence estimates in US adults. Results:The meta-analysis included 113 publications. Overall summary prevalence estimates were current smoking, 54% [95% confidence interval (CI) 49–59%] versus 20–23% in US adults; cervical high-risk HPV infection, 46% (95% CI 34–58%) versus 29% in US females; oral high-risk HPV infection, 16% (95% CI 10–23%) versus 4% in US adults; anal high-risk HPV infection (men who have sex with men), 68% (95% CI 57–79%), with no comparison estimate available; chronic HCV infection, 26% (95% CI 21–30%) versus 0.9% in US adults; and HBV infection, 5% (95% CI 4–5%) versus 0.3% in US adults. Overweight/obesity prevalence (53%; 95% CI 46–59%) was below that of US adults (68%). Meta-analysis of alcohol consumption prevalence was impeded by varying assessment methods. Overall, we observed considerable study heterogeneity in prevalence estimates. Conclusion:Prevalence of smoking and oncogenic virus infections continues to be extraordinarily high among PLWHA, indicating a vital need for risk factor reduction efforts.

HIV transmission rates in Thailand: evidence of HIV prevention and transmission decline.

Background:Analysis of HIV transmission rates has provided insight into the impacts of HIV-related prevention programing and policies in the United States by providing timely information beyond incidence or prevalence alone. The purpose of this analysis is to use transmission rates to assess past prevention efforts and explore trends of the epidemic in subpopulations within Thailand. Methods:Asian Epidemic Model HIV incidence and prevalence were used to calculate transmission rates over time nationally and among high-risk populations. Results:A national HIV/AIDS program implemented in Thailand in the 1990s that targeted sex workers and the general population was correlated with a decrease in new cases despite high prevalence. The turning point of the epidemic was in 1991 when the national transmission rate was 32%. By the late 1990s, the rate dropped to less than 4%. All subpopulations experienced a rate decline; however, sex workers still experienced higher transmission rates. Conclusions:The declining trend in HIV transmission rates despite ever-growing prevalence indicates prevention success correlated with the national HIV/AIDS program. Data from subgroup analyses provide stronger evidence of prevention success than incidence alone, as this measure demonstrates the effect of efforts and accounts for the burden of disease in the population.

EFFECTS OF ACTIVE HCV REPLICATION ON NEUROLOGIC STATUS IN HIV RNA VIRALLY SUPPRESSED PATIENTS

Background: Hepatitis C virus (HCV) is a frequent copathogen with HIV. Both viruses appear to replicate in the brain and both are implicated in neurocognitive and peripheral neuropathy syndromes. Interaction of the viruses is likely to be complicated and better understanding of the contributions of each virus will be necessary to make evidence-based therapeutic decisions. Methods: This study was designed to determine if active HCV infection, identified by quantitative HCV RNA determination, is associated with increased neurocognitive deficits or excess development of distal sensory peripheral neuropathy in HIV coinfected patients with stable HIV viral suppression. The AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT) study was the source of subjects with known HIV treatment status, neurocognitive and neuropathy evaluations, and HCV status. Subjects were selected based on HCV antibody status (249 positive; 310 negative). Results: HCV RNA viral loads were detectable in 172 participants with controlled HIV infection and available neurologic evaluations in the ALLRT. These participants were compared with 345 participants with undetectable HCV viral load and the same inclusion criteria from the same cohort. Neurocognitive performance measured by Trail-Making A or B and digit symbol testing was not dissimilar between the 2 groups. In addition, there was no significant association between active HCV replication and distal sensory neuropathy. Conclusion: Clinically significant neurocognitive dysfunction and peripheral neuropathy were not exacerbated by active hepatitis C virus infection in the setting of optimally treated HIV infection.

FIB-4 Index Is Associated with Hepatocellular Carcinoma Risk in HIV-Infected Patients

Background: Chronic inflammation caused by hepatitis B virus infection, hepatitis C virus infection, and/or heavy alcohol use can lead to fibrosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). FIB-4 is an index score calculated from platelet count, alanine transaminase, aspartate transaminase, and age that predicts fibrosis and cirrhosis. We hypothesized that high FIB-4 would be associated with development of HCC in HIV-infected persons, who are at high risk due to high prevalence of viral hepatitis and alcohol consumption, and possibly due to HIV infection itself. Methods: Using proportional hazards models, we tested this hypothesis among 22,980 HIV-infected men from the Veterans Aging Cohort Study. We identified incident HCC cases from the Veterans Affairs Central Cancer Registry. Results: During follow-up, there were 112 incident HCC diagnoses. The age- and race/ethnic group-adjusted HR was 4.2 [95% confidence interval (CI), 2.4–7.4] for intermediate FIB-4 and 13.0 (95% CI, 7.2–23.4) for high FIB-4, compared with low FIB-4. After further adjustment for enrollment year, CD4 count, HIV-1 RNA level, antiretroviral therapy use, hepatitis B and C virus infection, alcohol abuse/dependency, and diabetes, FIB-4 remained a strong, significant, independent risk factor for HCC. The multivariate-adjusted HR was 3.6 (95% CI, 2.1–6.4) for intermediate FIB-4 and 9.6 (95% CI, 5.2–17.4) for high FIB-4. Conclusions: Calculated from routine, noninvasive laboratory tests, FIB-4 is a strong, independent HCC risk factor in HIV-infected patients. Impact: FIB-4 might prove valuable as an easily measured index to identify those at highest risk for HCC, even prior to development of clinical cirrhosis. Cancer Epidemiol Biomarkers Prev; 20(12); 2512–7. ©2011 AACR.

Time trends in glioblastoma multiforme survival: the role of temozolomide

BACKGROUND In 2005, maximum safe surgical resection, followed by radiotherapy with concomitant temozolomide (TMZ), followed by adjuvant TMZ became the standard of care for glioblastoma (GBM). Furthermore, a modest, but meaningful, population-based survival improvement for GBM patients occurred in the US between 1999 (when TMZ was first introduced) and 2008. We hypothesized that TMZ usage explained this GBM survival improvement. METHODS We used national Veterans Health Administration (VHA) databases to construct a cohort of GBM patients, with detailed treatment information, diagnosed 1997-2008 (n = 1645). We compared survival across 3 periods of diagnosis (1997-2000, 2001-2004, and 2005-2008) using Kaplan-Meier curves. We used proportional hazards models to calculate period hazard rate ratios (HRs) and 95% confidence intervals (CIs), adjusted for demographic, clinical, and treatment covariates. RESULTS Survival increased over calendar time (stratified log-rank P < .0001). After adjusting for age and Charlson comorbidity score, for cases diagnosed in 2005-2008 versus 1997-2000, the HR was 0.72 (95% CI, 0.64-0.82; p-trend < .0001). Sequentially adding non-TMZ treatment variables (ie, surgery, radiotherapy, non-TMZ chemotherapy) to the model did not change this result. However, adding TMZ to the model containing age, Charlson comorbidity score, and all non-TMZ treatments eliminated the period effect entirely (HR = 1.01; 95% CI, 0.86-1.19; p-trend = 0.84). CONCLUSIONS The observed survival improvement among GBM patients diagnosed in the VHA system between 1997 and 2008 was completely explained by TMZ. Similar studies in other populations are warranted to test the generalizability of our finding to other patient cohorts and health care settings.

Time trends in cancer incidence in persons living with HIV/AIDS in the antiretroviral therapy era: 1997-2012

Objective:Utilizing the Veterans Aging Cohort Study, the largest HIV cohort in North America, we conducted one of the few comprehensive comparisons of cancer incidence time trends in HIV-infected (HIV+) versus uninfected persons during the antiretroviral therapy (ART) era. Design:Prospective cohort study. Methods:We followed 44 787 HIV+ and 96 852 demographically matched uninfected persons during 1997–2012. We calculated age-, sex-, and race/ethnicity-standardized incidence rates and incidence rate ratios (IRR, HIV+ versus uninfected) over four calendar periods with incidence rate and IRR period trend P values for cancer groupings and specific cancer types. Results:We observed 3714 incident cancer diagnoses in HIV+ and 5760 in uninfected persons. The HIV+ all-cancer crude incidence rate increased between 1997–2000 and 2009–2012 (P trend = 0.0019). However, after standardization, we observed highly significant HIV+ incidence rate declines for all cancer (25% decline; P trend <0.0001), AIDS-defining cancers (55% decline; P trend <0.0001), nonAIDS-defining cancers (NADC; 15% decline; P trend = 0.0003), and nonvirus-related NADC (20% decline; P trend <0.0001); significant IRR declines for all cancer (from 2.0 to 1.6; P trend <0.0001), AIDS-defining cancers (from 19 to 5.5; P trend <0.0001), and nonvirus-related NADC (from 1.4 to 1.2; P trend = 0.049); and borderline significant IRR declines for NADC (from 1.6 to 1.4; P trend = 0.078) and virus-related NADC (from 4.9 to 3.5; P trend = 0.071). Conclusion:Improved HIV care resulting in improved immune function most likely contributed to the HIV+ incidence rate and the IRR declines. Further promotion of early and sustained ART, improved ART regimens, reduction of traditional cancer risk factor (e.g. smoking) prevalence, and evidence-based screening could contribute to future cancer incidence declines among HIV+ persons.