Purpose of review
The purpose of this review is to highlight new findings published in 2010-11 related to noninvasive fibrosis assessment in HIV/HCV co-infected patients. Overall, in 2010-11, 15 papers were published, of which two were excluded because they were published in languages other than English.
11 papers focused on serum marker panels. Papers sought to either 1) validate established panels in HIV/HCV co-infected patients often by comparing multiple serum marker panels in the same population; 2) establish new marker panels using combinations of markers used in previously validated panels; and 3) develop new marker panels using novel methodology. Overall, all panels performed within similar ranges of diagnostic accuracy as measured by the area under the receiver operating characteristic curve (AUROC) but the Fibrometer panel and its derivations achieved the highest performance. Four studies focused on transient elastography (TE). Two papers confirmed its accuracy for identifying fibrosis and cirrhosis and two papers confirmed that misclassification rates are higher in the presence of elevated triglycerides and steatosis.
Overall, performance of TE appeared superior to the majority of serum marker panels for the detection of significant fibrosis and cirrhosis in HIV/HCV co-infected patients. Challenges of widespread application of TE remain high misclassification in some subgroups, lack of standardized cutpoints and lack of widespread availability. Panels that were newly developed in 2010-11 specifically for HIV/HCV appeared to perform better than existing panels such as APRI and FIB-4; however additional external validation will be needed to confirm their accuracy.
hepatitis C virus; liver fibrosis; HIV; elastography; serum markers
The authors characterized human immunodeficiency virus (HIV) and hepatitis C virus (HCV) incidence and prospective changes in self-reported risk behavior over 2 years among 1,158 injection drug users (IDUs) recruited in Chennai, India, in 2005–2006. At baseline, HIV prevalence was 25.3%, and HCV prevalence was 54.5%. Seropositive persons with prevalent HIV infection were used to estimate baseline HIV incidence by means of the Calypte HIV-1 BED Incidence EIA (Calypte Biomedical Corporation, Portland, Oregon). Longitudinal HIV and HCV incidence were measured among 865 HIV-negative IDUs and 519 HCV antibody-negative IDUs followed semiannually for 2 years. Participants received pre- and posttest risk reduction counseling at each visit. Estimated HIV incidence at baseline was 2.95 per 100 person-years (95% confidence interval (CI): 1.21, 4.69) by BED assay; observed HIV incidence over 1,262 person-years was 0.48 per 100 person-years (95% CI: 0.17, 1.03). HCV incidence over 645 person-years was 1.71 per 100 person-years (95% CI: 0.85, 3.03). Self-reported risk behaviors declined significantly over time, from 100% of participants reporting drug injection at baseline to 11% at 24 months. In this cohort with high HIV and HCV prevalence at enrollment, the authors observed low incidence and declining self-reported risk behavior over time. While no formal intervention was administered, these findings highlight the potential impact of voluntary counseling and testing in a high-risk cohort.
cohort studies; hepacivirus; HIV; India; risk-taking; substance abuse, intravenous
Background & Objectives:
We characterized HCV antibody prevalence, viral persistence, genotype and liver disease prevalence among IDUs in Chennai, India as the study of the association of HIV with each of these states is important and there are no data available.
Between 2005-2006, 1158 IDUs were recruited and followed semi-annually. All were tested for HCV antibodies at baseline; a random sample of 400 antibody positives (200 HIV-positive and 200 HIV-negative) were tested for HCV RNA; 13 of these were sequenced. Assessment of asparate amino transferase (AST)-to-platelet ratio index (APRI) was done on 557 IDUs. Prevalence ratios of each outcome were examined.
Median age was 35 yr; 99 per cent were male. HCV antibody prevalence was 55 per cent and was associated with older age, being unmarried, longer injection history, tattoo and injecting at a dealer’s place. Of the 400 HCV antibody positive IDUs, 281 (70.3%) had persistent infection which was less common among hepatitis B-infected persons but not associated with HIV. Of the 13 samples sequenced, 11 (85%) were HCV genotype 3a. Fibrosis prevalence according to APRI was: HIV/HCV-uninfected, 4 per cent; HIV mono-infected, 3 per cent; HCV mono-infected, 11 per cent; HIV/HCV co-infected, 12 per cent (P<0.001). In addition to being associated with HCV and HIV/HCV, fibrosis prevalence was higher among those drinking alcohol frequently; daily marijuana use was protective.
Interpretation & Conclusions:
Our findings show that IDUs in Chennai have high HCV prevalence and associated disease burden. The burden will increase as access to antiretroviral therapy improves particularly given the high prevalence of HIV, HCV and alcohol use.
APRI; HCV genotype; hepatitis C virus; HIV; injection drug users; liver disease
Injection drug users (IDUs) have estimated mortality rates over 10 times higher than the general population; much of this excess mortality is HIV associated. Few mortality estimates among IDUs from developing countries, including India, exist.
IDUs (1158) were recruited in Chennai from April 2005 to May 2006; 293 were HIV positive. Information on deaths and causes was obtained through outreach workers and family/network members. Mortality rates and standardized mortality ratios were calculated; multivariate Poisson regression was used to identify predictors of mortality.
We observed 85 deaths over 1998 person-years (p-y) of follow-up [incidence rate (IR) 4.25 per 100 p-y; 95% confidence interval (CI) 3.41, 5.23]. The overall standardized mortality ratio was 11.1; for HIV-positive IDUs, the standardized mortality ratio was 23.9. Mortality risk among HIV-positive IDUs (IR 8.88 per 100 p-y) was nearly three times that of negative IDUs (IR 3.03 per 100 p-y) and increased with declining immune status (CD4 cells > 350: 5.44 per 100 p-y vs. CD4 cells ≤ 200: 34.5 per 100 p-y). This association persisted after adjustment for potential confounders. The leading causes of mortality in both HIV negative and positive IDUs were overdose (n = 22), AIDS (n = 14), tuberculosis (n = 8) and accident/trauma (n = 9).
Substantial mortality was observed in this cohort with the highest rates among HIV-positive IDUs with CD4 cells less than 350. Although in these 2 years, non-AIDS deaths outnumbered AIDS-related deaths, the relative contribution of AIDS-associated mortality is likely to increase with advancing HIV disease progression. These data reinforce the need for interventions to reduce the harms associated with drug use and increase HAART access among IDUs in Chennai.
HIV; India; injection drug users; mortality; overdose
To examine temporal trends and predictors of linkage to HIV care, longitudinal retention in care and viral suppression among injection drug users (IDUs) infected with HIV.
Community-based, prospective cohort study
We prospectively studied 790 HIV-infected IDUs participating in the AIDS Linked to the Intravenous Experience (ALIVE) study from 1998 through 2011. IDUs were considered linked to care if they attended any HIV care visit during follow-up and retained in care if they reported HIV clinic attendance at every semiannual study visit. We used logistic regression to identify predictors of poor retention in care and failure to achieve sustained viral suppression in response to ART.
Of 790 HIV-infected IDUs studied, 740 (93.6%) were ever linked to care. The majority of IDUs (76.7%) received ART at some point during observation and of these, most (85.4%) achieved viral suppression. However, over a median of 8.7 years of follow-up, only 241 (30.5%) IDUs were continuously retained with no 6-month lapses in HIV care and only 63 (10.2%) had sustained viral suppression at every study visit after first receiving ART. Suboptimal engagement in care was associated with poor access to medical care, active drug use, and incarceration.
Compared with national estimates of retention in care and virologic suppression in the United States, IDUs are substantially less likely to remain fully engaged in HIV care. Strategies to optimize HIV care should acknowledge the elevated risk of poor engagement in care among IDUs.
antiretroviral therapy; drug users; human immunodeficiency virus; primary care; retention in care
We characterized HCV treatment knowledge, experience and barriers in a cohort of community-based injection drug users (IDUs) in Baltimore, MD. In 2005, a questionnaire on HCV treatment knowledge, experience and barriers was administered to HCV-infected IDUs. Self-reported treatment was confirmed from medical records. Of 597 participants, 71% were male, 95% African-American, 31% HIV co-infected and 94% were infected with HCV genotype 1; 70% were aware that treatment was available, but only 22% understood that HCV could be cured. Of 418 who had heard of treatment, 86 (21%) reported an evaluation by a provider that included a discussion of treatment of whom 30 refused treatment, 20 deferred and 36 reported initiating treatment (6% overall). The most common reasons for refusal were related to treatment-related perceptions and a low perceived need of treatment. Compared to those who had discussed treatment with their provider, those who had not were more likely to be injecting drugs, less likely to have health insurance, and less knowledgeable about treatment. Low HCV treatment effectiveness was observed in this IDU population. Comprehensive integrated care strategies that incorporate education, case-management and peer support are needed to improve care and treatment of HCV-infected IDUs.
Hepatitis C virus; Injection drug use; Antiviral therapy; Health care access
To evaluate the relationship between regional body composition and liver disease (fibrosis or steatosis) in HIV/HCV co-infected individuals.
Whole body dual-energy X-ray absorptiometry (DXA) was performed in 173 HIV/HCV co-infected persons within 12 months of a liver biopsy. Significant fibrosis was defined as a METAVIR stage greater than 1. Steatosis was graded as: 0, none; 1, steatosis involving less than 5% of hepatocytes; 2, 5–29%; 3, 30–60%; 4 greater than 60%, and was defined as more than 0. Poisson regression with robust variance was used to estimate prevalence ratios of the outcome measures.
The population was 62% male and 84% black with a median body mass index of 25.2 kg/m2 (interquartile range 22.5, 29.3 kg/m2). No differences in regional body fat or fat distribution were observed in 42 patients with significant fibrosis compared to others with less fibrosis. However, the 77 individuals (45%) with steatosis had greater central fat than those without steatosis [prevalence ratio 1.04 per kg trunk fat; 95% confidence interval (CI) 1.04, 1.11], after adjusting for hepatic fibrosis (prevalence ratio 1.77; 95% CI 1.29, 2.42), uncontrolled HIV replication (viral load >400 copies/ml) (prevalence ratio 1.57; 95% CI 1.12, 2.22), age, sex, race and diabetes mellitus.
In HIV/HCV co-infected individuals, measures of regional body fat or fat distribution were not associated with hepatic fibrosis. In contrast, increased central adiposity by DXA, as well as concomitant fibrosis and uncontrolled HIV, were associated with hepatic steatosis. The extent to which weight loss and effective antiretroviral therapy can reduce the risk of steatosis deserves further investigation.
body composition; hepatic fibrosis; hepatitis C; HIV; steatosis
Fractures and cirrhosis are major causes of morbidity and mortality among HIV–HCV-coinfected individuals. It is not known whether vitamin D deficiency is associated with these outcomes.
Between 2005 and 2007, 116 HIV–HCV- coinfected individuals underwent dual-energy X-ray absorptiometry within 1 year of a liver biopsy. 25-Hydroxy-vitamin D (25OHD) and parathyroid hormone were measured from archived samples. Low bone mineral density (BMD) was defined as BMD≥2 standard deviations lower than age-, sex- and race-matched controls (Z-score ≤−2.0) at the total hip, femoral neck or lumbar spine. Histological fibrosis staging was assessed according to the METAVIR system (0 [no fibrosis] to 4 [cirrhosis]).
The cohort was 87% African-American and 63% male. The median age (IQR) was 49.9 years (46.5–53.3). A total of 89% had a CD4+ T-cell count >200 cells/mm3 and 64% were receiving HAART. The median 25OHD was 19 ng/ ml (IQR 11.0–26.0). Hypovitaminosis D (25OHD≤15 ng/ml) was present in 41% and secondary hyperparathyroidism, defined by parathyroid hormone >65 pg/ml, was present in 24%. In total, 27% had low BMD (Z-score ≤−2) at the spine, femoral neck or total hip, and 39% had significant hepatic fibrosis (METAVIR≥2). In multivariate analysis, vitamin D deficiency was not associated with significant fibrosis or with BMD at any site.
Vitamin D deficiency was highly prevalent in this mostly African-American HIV–HCV-coinfected population, but was not related to BMD or liver disease severity. These data suggest that efforts to increase vitamin D levels in this population may not improve bone or liver outcomes.
Proteinuria occurs commonly among HIV-infected and -uninfected injection drug users (IDUs) and is associated with increased mortality risk. Vitamin D deficiency, highly prevalent among IDUs and potentially modifiable, may contribute to proteinuria. To determine whether vitamin D is associated with proteinuria in this population, we conducted a cross-sectional study in the AIDS Linked to the IntraVenous Experience (ALIVE) Study.
25(OH)-vitamin D levels were measured in 268 HIV-infected and 614 HIV-uninfected participants. The association between vitamin D deficiency (<10 ng/mL) and urinary protein excretion was evaluated by linear regression. The odds of persistent proteinuria (urine protein-to-creatinine ratio >200 mg/g on two occasions) associated with vitamin D deficiency was examined using logistic regression.
One-third of participants were vitamin D-deficient. Vitamin D deficiency was independently associated with higher urinary protein excretion (P<0.05) among HIV-infected and diabetic IDUs (P-interaction<0.05 for all). Persistent proteinuria occurred in 18% of participants. Vitamin D deficiency was associated with >6-fold odds of persistent proteinuria among diabetic IDUs (odds ratio [OR]=6.29, 95% confidence interval [CI]: 1.54, 25.69) independent of sociodemographic characteristics, co-morbid conditions, body mass index, and impaired kidney function (estimated GFR <60 mL/min|1.73 m2); no association, however, was observed among non-diabetic IDUs (OR=1.06, 95% CI: 0.64, 1.76) (P-interaction<0.05).
Vitamin D deficiency was associated with higher urinary protein excretion among those with HIV infection and diabetes. Vitamin D deficiency was independently associated with persistent proteinuria among diabetic IDUs, although not in non-diabetic persons. Whether vitamin D repletion ameliorates proteinuria in these patients requires further study.
Vitamin D deficiency; proteinuria; HIV; injection drug use; diabetes
Hepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person’s lifetime risk of cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and in persons with a genetic variant near IL28B, the genetic basis is not well understood.
To evaluate the host genetic basis for spontaneous resolution of HCV infection.
Two-stage genome wide association study (GWAS).
13 international multicenter study sites.
919 individuals with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 individuals with serum HCV antibodies and RNA (persistence).
Frequencies of 792,721 SNPs.
Differences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL28B and included rs12979860 (overall per-allele OR = 0.45, P = 2.17 × 10−30) and 10 additional SNPs spanning 55,000 bases. On chromosome 6, allele frequency differences localized near genes for class II human leukocyte antigens (HLA) and included rs4273729 (overall per-allele OR= 0.59, P = 1.71 × 10−16) near DQB1*03:01 and an additional 116 SNPs spanning 1,090,000 base pairs. The associations in chromosomes 19 and 6 were independent, additive, and explain an estimated 14.9% (95% CI: 8.5–22.6%) of the variation in HCV resolution in those of European-Ancestry, and 15.8% (95% CI:4.4–31.0%) in individuals of African-Ancestry. Replication of the chromosome 6 SNP, rs4272729 in an additional 746 individuals confirmed the findings (p=0.015).
Epigenetic effects were not studied.
IL28B and HLA class II are independently associated with spontaneous resolution of HCV infection and SNPs marking IL28B and DQB1*03:01 may explain ~15% of spontaneous resolution of HCV infection.
Chronic hepatitis C virus (HCV) infection is complicated by hepatic fibrosis. Hypothesizing that early fibrogenic signals may originate in cells susceptible to HCV infection, hepatocyte gene expression was analyzed from persons with chronic HCV at different stages of liver fibrosis. Four HCV-infected subjects with pre-cirrhotic liver fibrosis (Ishak fibrosis 3–5) were matched for age, race, and gender to five HCV-infected subjects with no evidence of fibrosis (Ishak fibrosis 0). Hepatocytes from each subject were isolated from liver biopsies using laser capture microdissection. Transcriptome profiling was performed on hepatocyte RNA using hybridization arrays. We found that hepatocytes in pre-cirrhotic fibrosis were depleted for genes involved in small molecule and drug metabolism, especially butyrylcholinesterase (BCHE), a gene involved in the metabolism of drugs of abuse. Differential expression of BCHE was validated in the same tissues and cross-sectionally in an expanded cohort of 143 HCV-infected individuals. In a longitudinal study, serum BCHE activity were already decreased at study inception in 19 fibrosis progressors compared to 20 fibrosis non-progressors (p<0.05). Non-progressors also had decreased BCHE activity over time compared to initial values, but these evolved a median (range) 8.6 (7.8–11.4) years after the study period inception(p<0.05). Laser captured portal tracts were enriched for immune related genes when compared to hepatocytes but pre-cirrhotic livers lost this enrichment.
Overall, we found that chronic HCV is associated with hepatocyte BCHE loss years before hepatic synthetic function is impaired. These results indicate that BCHE may be involved in the pathogenesis of HCV-related fibrosis among injection drug users.
butyrylcholinesterase; Hepacivirus; chronic HCV infection; laser capture microdissection; portal tract
Background & Aims
Microparticles released into the bloodstream upon activation or apoptosis of CD4+ and CD8+ T cells correlate with inflammation, determined by histologic analysis, in patients with chronic hepatitis C (CHC). Patients with nonalcoholic fatter liver (NAFL) or nonalcoholic steatohepatitis (NASH) can be differentiated from those with CHC based on activation of distinct sets of immune cells in the liver.
We compared profiles of circulating microparticles from patients with NAFL and NASH (n=67) to those with CHC (n=42), compared with healthy individuals (controls) using flow cytometry; the profiles were correlated with inflammation grade and fibrosis stage, based on histologic analyses. We assessed the ability of the profiles determine the severity of inflammation and fibrosis, based on serologic and histologic analyses.
Patients with CHC had increased levels of microparticles from CD4+ and CD8+ T cells; the levels correlated with disease severity, based on histologic analysis and levels of alanine aminotransferase (ALT). Patients with NAFL or NASH had significant increases in numbers of microparticles from invariant natural killer T (iNKT) cells and macrophages/monocytes (CD14+), which mediate pathogenesis of NASH. Microparticles from CD14+ and iNKT cells correlated with levels of ALT and severity of NASH (based on histology). Levels of microparticles could differentiate between patients with NAFL or NASH and those with CHC, or either group of patients and controls (area under the receiver operating characteristic curves ranging from 0.56 to 0.99).
Quantification of immune cell microparticles from serum samples can be used to assess the extent and characteristics of hepatic inflammation in patients with chronic liver disease.
Biomarker; CD1c; CD4+; CD8+; CD14+; CD15+; CD41+; CD16+; ectosome; fibrosis; HCV; inflammation; iNKT; NKT; liver; macrophage; microparticle; monocyte; NASH; plasma; serum; T cell; non-invasive assay; lymphocyte; serum assay; biomarker assay
Overdose is a leading cause of death among illicit drug users. 924 injection drug users (IDUs) in Baltimore, Maryland, were interviewed to characterize overdose events and determine the circumstances under which they lead to drug treatment. Overall, 366 (39.7%) reported at least one non-fatal drug overdose. Most (96.2%) used heroin on the day of their last overdose and almost half (42.6%) used heroin and alcohol but few (4.1%) used tranquilizers or benzodiazepines. Five percent were in drug treatment when the overdose occurred and 7.1% had been incarcerated two weeks prior. One in four IDUs (26.2%) sought drug treatment within 30 days after their last overdose of whom 75% enrolled. Speaking with someone about drug treatment after the overdose was associated with treatment seeking (AOR 5.22; 95% CI: 3.12, 8.71). Family members were the most commonly cited source of treatment information (53.7%) but only those who spoke with spouses, crisis counselors and hospital staff were more likely to seek treatment. Not being ready for treatment (69.6%) and not viewing drug use as a problem (30.7%) were the most common reasons for not seeking treatment and being placed on a waiting list was the most common reason for not subsequently enrolling in treatment (66.7%). Of the IDUs treated by emergency medical technicians, emergency room staff, or hospital staff, only 17.3%, 26.2% and 43.2% reported getting drug treatment information from those sources, respectively. Interventions that provide drug treatment information and enhance motivation for treatment in the medical setting and policies that reduce barriers to treatment entry among motivated drug users are recommended.
Persons with HIV infection have been reported to develop age-related diseases at younger ages than those without HIV. Whether this finding is related to HIV infection or failure to control for other risk factors is unknown.
To investigate whether persons with HIV infection develop hepatitis C virus (HCV)–related liver disease at younger ages than similar persons without HIV.
Comparison of the severity of liver fibrosis by age among persons who have HCV with and without HIV followed concurrently in the same protocol.
Observational cohort from Baltimore, Maryland, participating in the ALIVE (AIDS Linked to the IntraVenous Experience) study.
1176 current and former injection drug users with antibodies to HCV.
Liver fibrosis assessed semiannually from 2006 to 2011 by elastography (FibroScan, Echosens, Paris, France) and using previously validated thresholds for clinically significant fibrosis and cirrhosis; concurrent assessment of medical history, alcohol and illicit drug use, HCV RNA levels, hepatitis B virus surface antigen level, body mass index, and (for those with HIV) CD4+ lymphocyte count and HIV RNA levels.
Among 1176 participants with antibodies to HCV, the median age was 49 years and 34% were coinfected with HIV and HCV. Participants contributed 5634 valid liver fibrosis measurements. The prevalence of clinically significant fibrosis without cirrhosis (12.9% vs. 9.5%) and of cirrhosis (19.5% vs. 11.0%) was greater in persons coinfected with HIV and HCV than in those with only HCV (P < 0.001). Increasing age and HIV infection were independently associated with liver fibrosis, as were daily alcohol use, chronic hepatitis B virus infection, body mass index greater than 25 kg/m2, and greater plasma HCV RNA levels. When these factors were kept constant, persons with HIV had liver fibrosis measurements equal to those of persons without HIV, who were, on average, 9.2 years older.
The process of liver fibrosis began before the study in most persons.
In this cohort, persons who have HCV with HIV have liver fibrosis stages similar to those without HIV who are nearly a decade older.
There are few published data characterizing patterns of liver stiffness measurements (LSMs) among HCV-infected persons and their potential impact on clinical decisions (for example, deferring treatment and hepatocellular carcinoma surveillance).
A total of 591 HCV-infected injection drug users (IDUs) in a community-based cohort had four LSMs. We used semi-parametric latent class growth modelling to identify patterns, which then became a gold standard against which we characterized validity of information from the initial measurements.
Median age was 49, 68% were male, 92% African-American and 33% HIV-coinfected. The median LSM at visit 1 was 6.7 kPa (IQR 5.3–8.8). Over a median 1.75 years, LSM measures were stable; median change between visits was 0 kPa (IQR -1.4–1.7). Only 3% had evidence of fibrosis progression. Other groups included stable patterns of 1) no fibrosis (59%), 2) moderate fibrosis (21%), 3) severe fibrosis (7%) and 4) cirrhosis (9%). Individuals with fibrosis progression were more likely to be HIV-infected than those with stable low fibrosis (P<0.001). The diagnostic accuracy of the first LSM for identification of need for cancer surveillance (cirrhosis ≥12.3 kPa) was high (positive predictive value = 97%). Although no single low LSM had high negative predictive value for significant fibrosis (metavir <2), individuals with two or more low results rarely had progression.
These data underscore the stability of liver fibrosis in a cohort of predominantly African-American HCV-infected persons over 1.75 years, support using LSMs to monitor untreated persons at risk for progression and assess need for hepatocellular carcinoma surveillance.
The joint effects of multiple exposures on an outcome are frequently of interest in epidemiologic research. In 2001, Hernán, Brumback, and Robins (JASA 2001; 96: 440–448) presented methods for estimating the joint effects of multiple time-varying exposures subject to time-varying confounding affected by prior exposure using joint marginal structural models. Nonetheless, the use of these joint models is rare in the applied literature. Minimal uptake of these joint models, in contrast to the now widely used standard marginal structural model, is due in part to a lack of examples demonstrating the method. In this paper, we review the assumptions necessary for unbiased estimation of joint effects as well as the distinction between interaction and effect measure modification. We demonstrate the use of marginal structural models for estimating the joint effects of alcohol consumption and injection drug use on HIV acquisition, using data from 1,525 injection drug users in the AIDS Link to Intravenous Experience cohort study. In the joint model, the hazard ratio (HR) for heavy drinking in the absence of any drug injections was 1.58 (95% confidence interval= 0.67–3.73). The HR for any drug injections in the absence of heavy drinking was 1.78 (1.10–2.89). The HR for heavy drinking and any drug injections was 2.45 (1.45–4.12). The P values for multiplicative and additive interaction were 0.7620 and 0.9200, respectively, indicating a lack of departure from effects that multiply or add. However, we could not rule out interaction on either scale due to imprecision.
In cross-sectional analysis of 287 human immunodeficiency virus–infected persons with high hepatitis C virus prevalence, liver fibrosis defined by elastography was associated with higher CD4+ T-cell percentages relative to absolute CD4+ number; this discordance was most apparent in persons with marked lymphopenia.
Background. Cirrhosis of the liver can induce splenic sequestration of peripheral blood cells, recently suggested to reduce the number but not percentage of circulating CD4+ T cells in persons uninfected with human immunodeficiency virus (HIV). We investigated whether earlier stages of liver fibrosis prior to cirrhosis were associated with discordance between CD4 count (CD4N) and CD4 percentage (CD4%) in HIV-infected patients.
Methods. In cross-sectional analysis of 287 HIV-infected participants of the AIDS Linked to the Intravenous Experience cohort, we evaluated CD4N, CD4%, and transient elastography staging of liver fibrosis. High CD4+ lymphocyte discordance was defined as higher CD4% relative to CD4N based on accepted clinical cutoffs; multivariable logistic regression was used to determine covariates associated with discordance.
Results. Of 287 participants, 99 (34.4%) had high CD4+ discordance, which increased to 76% of 114 participants with marked lymphopenia (total lymphocyte count [TLC] ≤1200 cells/μL). In multivariable analysis, the odds of having high CD4+ discordance was increased in persons with significant liver fibrosis compared to those without fibrosis (odds ratio, 1.69; 95% confidence interval [CI], .95–2.96); the odds ratio of discordance increased to 2.66 (95% CI, 1.11–6.40) among the subset of participants with TLC ≤1200 cells/μL. The odds for discordance associated with cirrhosis were of similar magnitude as those observed with significant fibrosis.
Conclusions. In HIV-infected persons, liver fibrosis is associated with discordant peripheral CD4+ lymphocyte results, especially in the setting of marked lymphopenia. Clinicians should also consider CD4% when interpreting absolute CD4+ counts of HIV-infected persons with known or suspected liver disease, particularly if TLC is <1200 cells/μL.
To evaluate whether HAART is associated with subsequent sexual and drug-related risk behavior compensation among injection drug users (IDUs).
A community-based cohort study of 362 HIV-infected IDUs initiating HAART in Baltimore, Maryland.
HAART use and risk behavior was assessed at 8316 biannual study visits (median 23). Using logistic regression with generalized estimating equations (GEE), we examined the effect of HAART initiation on changes in risk behavior while adjusting for sociodemographics, alcohol use, CD4+ cell count, year of initiation and consistency of HAART use.
At HAART initiation, participants were a median of 44.4 years old, 71.3% men and 95.3% African–American. In multivariable analysis, HAART initiation was associated with a 75% reduction in the likelihood of unprotected sex [adjusted odds ratio (aOR) 0.25; 95% confidence interval (CI), 0.19–0.32] despite no change in overall sexual activity (aOR 0.95; 0.80–1.12). Odds of any injecting decreased by 38% (aOR 0.62; 0.51–0.75) after HAART initiation. Among the subset of persistent injectors, needle-sharing increased nearly two-fold (aOR 1.99; 1.57–2.52). Behavioral changes were sustained for more than 5 years after HAART initiation and did not differ by consistency of HAART use. Reporting specific high-risk behaviors in the year prior to initiation was a robust predictor of engaging in those behaviors subsequent to HAART.
Overall, substantial declines in sexual risk-taking and active injecting argue against significant behavioral compensation among IDUs following HAART initiation. These data also provide evidence to support identifying persons with risky pre-HAART behavior for targeted behavioral intervention.
antiretroviral therapy; HIV prevention; injecting; injection drug users; risk compensation; sexual behavior
Background & objectives:
Sustainability of free antiretroviral therapy (ART) roll out programmes in resource-limited settings is challenging given the need for lifelong therapy and lack of effective vaccine. This study was undertaken to compare treatment outcomes among HIV-infected patients enrolled in a graduated cost-recovery programme of ART delivery in Chennai, India.
Financial status of patients accessing care at a tertiary care centre, YRGCARE, Chennai, was assessed using an economic survey; patients were distributed into tiers 1- 4 requiring them to pay 0, 50, 75 or 100 per cent of their medication costs, respectively. A total of 1754 participants (ART naïve = 244) were enrolled from February 2005-January 2008 with the following distribution: tier 1=371; tier 2=338; tier 3=693; tier 4=352. Linear regression models with generalized estimating equations were used to examine immunological response among patients across the four tiers.
Median age was 34; 73 per cent were male, and the majority were on nevirapine-based regimens. Median follow up was 11.1 months. The mean increase in CD4 cell count within the 1st three months of HAART was 50.3 cells/μl per month in tier 1. Compared to those in tier 1, persons in tiers 2, 3 and 4 had comparable increases (49.7, 57.0, and 50.9 cells/μl per month, respectively). Increases in subsequent periods (3-18 and >18 months) were also comparable across tiers. No differential CD4 gains across tiers were observed when the analysis was restricted to patients initiating ART under the GCR programme.
Interpretation & conclusions:
This ART delivery model was associated with significant CD4 gains with no observable difference by how much patients paid. Importantly, gains were comparable to those in other free rollout programmes. Additional cost-effectiveness analyses and mathematical modelling would be needed to determine whether such a delivery programme is a sustainable alternative to free ART programmes.
ART; cost-recovery programme; HIV; India; treatment outcomes
To characterize factors associated with injection cessation, relapse and initiation.
MIDACS is a prospective cohort of injection drug users (IDUs) recruited in 2005–06 with semi-annual follow-up through 2009. Discrete-time survival models were used to characterize predictors of time to first injection cessation and relapse.
855 IDUs who reported injecting in the six months prior to baseline and had > 1 follow-up visit.
Cessation was defined as the first visit where no injection drug use was reported (prior six months) and relapse as the first visit where drug injection (prior six months) was reported after first cessation.
All participants were male; median age was 35. Over three years, 92.7% reported cessation (incidence rate [IR]: 117 per 100 person-years). Factors positively associated with cessation included daily injection and incarceration and factors negatively associated with cessation included marriage, alcohol and homelessness. Of those who reported cessation, 24% relapsed (IR: 19.7 per 100 person-years). Factors positively associated with relapse included any education, injection in the month prior to baseline, sex with a casual partner, non-injection drug use, incarceration and homelessness. Alcohol was negatively associated with relapse. The primary reasons for cessation were medical conditions (36%) and family pressure (22%). The majority initiated with non-injection drugs, transitioning to injection after a median 4 years.
Injection drug users in Southern India demonstrate a high rate of injection cessation over three years, but relapse is not uncommon. Compensatory increases in alcohol use indicate that cessation of injection does not mean cessation of all substance use. Family pressure, concerns about general health, fear of HIV infection, and a history of non-injection drug use are important correlates of cessation.
natural history; drug use; India; injection drug users; cohort
Frailty is associated with morbidity and premature mortality among elderly HIV-uninfected adults, but the determinants and consequences of frailty in HIV-infected populations remain unclear. We evaluated the correlates of frailty, and the impact of frailty on mortality in a cohort of aging injection drug users (IDUs).
Frailty was assessed using standard criteria among HIV-infected and uninfected IDUs in 6-month intervals from 2005 to 2008. Generalized linear mixed-model analyses assessed correlates of frailty. Cox proportional hazards models estimated risk for all-cause mortality.
Of 1230 participants at baseline, the median age was 48 years and 29% were HIV-infected; the frailty prevalence was 12.3%. In multivariable analysis of 3,365 frailty measures, HIV-infected IDUs had an increased likelihood of frailty (OR, 1.66; 95% CI, 1.24–2.21) compared to HIV-uninfected IDUs; the association was strongest (OR, 2.37; 95% CI, 1.62–3.48) among HIV-infected IDUs with advanced HIV disease (CD4<350 cells/mm3 and detectable HIV RNA). No significant association was seen with less advanced disease. Sociodemographic factors, comorbidity, depressive symptoms, and prescription drug abuse were also independently associated with frailty. Mortality risk was increased with frailty alone (HR 2.63, 95% CI, 1.23–5.66), HIV infection alone (HR 3.29, 95% CI, 1.85–5.88), and being both HIV-infected and frail (HR, 7.06; 95%CI 3.49–14.3).
Frailty was strongly associated with advanced HIV disease, but IDUs with well-controlled HIV had a similar prevalence to HIV-uninfected IDUs. Frailty was independently associated with mortality, with a marked increase in mortality risk for IDUs with both frailty and HIV infection.
Human immunodeficiency virus (HIV)-infected persons, especially those with advanced immune suppression or uncontrolled viremia, experienced increased numbers of multimorbid non-AIDS-defining conditions compared with epidemiologically comparable HIV-uninfected persons. Many of these clinically identified chronic diseases were unrecognized and untreated.
Background. Despite an increasing burden of age-associated non-AIDS outcomes, few studies have investigated the prevalence or correlates of multimorbidity among aging human immunodeficiency virus (HIV)–infected and epidemiologically comparable at-risk populations.
Methods. Among 1262 AIDS Linked to the IntraVenous Experience (ALIVE) study participants followed in a community-based observational cohort, we defined the prevalence of 7 non-AIDS-defining chronic conditions (diabetes, obstructive lung disease, liver disease, anemia, obesity, kidney dysfunction, and hypertension) using clinical and laboratory criteria. Ordinal logistic regression was used to model the odds of increased multimorbidity associated with demographic, behavioral, and clinical factors. Self-reported prevalence was compared with clinically defined prevalence.
Results. Participants were a median of 48.9 years of age; 65.1% were male, 87.5% were African-American, and 28.7% were HIV infected. In multivariable analysis, HIV infection (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.13–1.99) was positively associated with increased multimorbidity. Among HIV-infected participants, multimorbidity was increased with lower nadir CD4 T-cell count (OR, 1.14 per 100-cell decrease; 95% CI, 1.00–1.29) and higher current HIV RNA (OR, 1.32 per log10 increase; 95% CI, 1.08–1.60). Older age, being female, not using cigarettes or drugs, and having depressive symptoms were also associated with increased multimorbidity. A substantial proportion of multimorbid conditions in HIV-infected and HIV-uninfected participants were unrecognized and untreated.
Conclusions. HIV-infected participants experienced increased numbers of multimorbid conditions; risk increased with advanced immunosuppression and higher viremia. These results underscore the heavy burden of multimorbidity associated with HIV and highlight the need for incorporating routine assessment and integrated management of chronic diseases as part of comprehensive healthcare for aging, HIV-infected persons.
Despite reports of increasing non-medical prescription drug use, relatively few studies have systematically evaluated the prevalence and correlates of non-medical prescription drug use, particularly in populations that might be especially vulnerable (e.g., injection drug users [IDUs]). We examined factors associated with non-medical prescription drug use among a community-based cohort of current and former IDUs in Baltimore (The ALIVE Study). We conducted a cross-sectional analysis of data from cohort participants that responded to a survey that included questions on non-medical prescription drug use between 2005–06 (n=1320). Non-medical prescription drug use was considered to be use of any of the following: Opiates (Oxycontin, Percocet), Benzodiazepines or Clonidine, purchased on the street and taken orally within the last six months. Data on other covariates of interest (e.g., demographics, substance use, general health) was obtained through a standardized interview. The median age was 46 years; 66% were male, 85% were African-American. Twenty one percent reported any non-medical prescription drug use; 12% reported using more than one drug. Non-medical use of opiates was most common (17%). In multivariate analysis, non-medical prescription drug use was significantly associated with Caucasian race (prevalence ratio [PR]: 1.79), self-reported bodily pain (PR: 1.58), hazardous alcohol use (PR: 1.47), marijuana use (PR: 1.65), non-injection cocaine/heroin use (PR: 1.70), diverted use of buprenorphine (PR: 1.51) or methadone (PR: 2.51), and active injection drug use (PR: 3.50; p<0.05 for all). The association between bodily pain and non-medical prescription drug use was stronger among persons that were not using substances (marijuana, injecting drugs, snorting/smoking heroin, cocaine, using crack) as compared to those using these substances. The high prevalence of non-medical prescription drug use among this population warrants further research and action. Information on the risks of nonmedical prescription drug use especially overdose, should be incorporated into interventions targeted at IDUs.
non-medical prescription drug use; poly-drug use; injection drug users; substance abuse; Baltimore
To determine the incidence of long-term injection cessation and its association with residential relocation and neighborhood deprivation.
ALIVE (AIDS Linked to the Intravenous Experience) is a prospective cohort with semi-annual follow-up since 1988. Multi-level discrete time-to-event models were constructed to investigate individual and neighborhood-level predictors of long-term injection cessation.
1,697 active injectors from ALIVE with at least 8 semi-annual study visits.
Long-term injection cessation was defined as three consecutive years without self-reported injection drug use.
706 (42%) injectors achieved long-term cessation (incidence = 7.6 per 100 person-years). After adjusting for individual-level factors, long-term injection cessation was 29% less likely in neighborhoods in the third quartile of deprivation (Hazard Ratio [HR] =0.71, 95% CI:0.53–0.95) and 43% less likely in the highest quartile of deprivation (HR=0.57, 95% CI:0.43, 0.76) as compared to the first quartile. Residential relocation was associated with increased likelihood of long-term injection cessation (HR=1.55, 95% CI:1.31, 1.82); however the impact of relocation varied depending on the deprivation in the destination neighborhood. Compared to those who stayed in less deprived neighborhoods, relocation from highly deprived to less deprived neighborhoods had the strongest positive impact on long-term injection cessation (HR=1.96, 95% CI:1.50, 2.57), while staying in the most deprived neighborhoods was detrimental (HR=0.76, 95% CI:0.63, 0.93).
Long-term cessation of injection of opiates and cocaine occurred frequently following a median of 9 years of injection and contextual factors appear to be important. Our findings suggest that improvements in the socio-economic environment may improve the effectiveness of cessation programs.
To evaluate the prevalence and risk factors for low bone mineral density (BMD) in persons co-infected with HIV and Hepatitis C.
HIV/HCV co-infected study participants (n=179) were recruited into a prospective cohort and underwent dual-energy X-ray absorptiometry (DXA) within 1 year of a liver biopsy. Fibrosis staging was evaluated according to the METAVIR system. Osteoporosis was defined as a T-score ≤ −2.5. Z-scores at the total hip, femoral neck, and lumbar spine were used as the primary outcome variables to assess the association between degree of liver disease, HIV-related variables, and BMD.
The population was 65% male, 85% Black with mean age 50.3 years. The prevalence of osteoporosis at either at the total hip, femoral neck, or lumbar spine was 28%, with 5% having osteoporosis of the total hip, 6% at the femoral neck, 25% at the spine. The mean Z-scores (standard deviation) were −0.42 (1.01) at the total hip, −0.16 (1.05) at the femoral neck, and −0.82 (1.55) at the lumbar spine. In multivariable models, controlled HIV replication (HIV RNA < 400 copies/mL vs ≥400 copies/mL) was associated with lower Z-scores (mean ± standard error) at the total hip (−0.44±0.17, p=0.01), femoral neck (−0.59±0.18, p=0.001), and the spine (−0.98±0.27, p=0.0005). There was no association between degree of liver fibrosis and Z-score.
Osteoporosis was very common in this population of predominately African-American HIV/HCV co-infected patients, particularly at the spine. Lower BMD was associated with controlled HIV replication, but not liver disease severity.
hepatitis C; bone mineral density; hepatic fibrosis; HIV