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Director's Report to the National Advisory Council on Drug Abuse - May, 2009

Research Findings - Research on Medical Consequences of Drug Abuse and Co-Occurring Infections (HIV/AIDS, HCV)

Accessing Antiretroviral Therapy Following Release From Prison

Interruption of antiretroviral therapy (ART) during the first weeks after release from prison may increase risk for adverse clinical outcomes, transmission of human immunodeficiency virus (HIV), and drug-resistant HIV reservoirs in the community. The extent to which HIV-infected inmates experience ART interruption following release from prison is unknown. The objectives of this study were to determine the proportion of inmates who filled an ART prescription within 60 days after release from prison and to examine predictors of this outcome. This was a retrospective cohort study of all 2115 HIV-infected inmates released from the Texas Department of Criminal Justice prison system between January 2004 and December 2007 and who were receiving ART before release. The study's main outcome measure was the proportion of inmates who filled an ART prescript-tion within 10, 30, and 60 days of release from prison. Among the entire study cohort (N=2115), an initial prescription for ART was filled by 115 (5.4%) inmates within 10 days of release (95% confidence interval [CI], 4.5%-6.5%), by 375 (17.7%) within 30 days (95% CI, 16.2%-19.4%), and by 634 (30.0%) within 60 days (95% CI, 28.1%-32.0%). In a multivariate analysis of predictors (including sex, age, race/ethnicity, viral load, duration of ART, year of discharge, duration of incarceration, parole, and AIDS Drug Assistance Program application assistance), Hispanic and African American inmates were less likely to fill a prescription within 10 days (adjusted estimated risk ratio [RR], 0.4 [95% CI, 0.2-0.8] and 0.4 [95% CI, 0.3-0.7], respectively) and 30 days (adjusted estimated RR, 0.7 [95% CI, 0.5-0.9] and 0.7 [95% CI, 0.5-0.9]). Inmates with an undetectable viral load were more likely to fill a prescription within 10 days (adjusted estimated RR, 1.8 [95% CI, 1.2-2.7]), 30 days (1.5 [95% CI, 1.2-1.8]), and 60 days (1.3 [95% CI, 1.1-1.5]). Inmates released on parole were more likely to fill a prescription within 30 days (adjusted estimated RR, 1.3 [95% CI, 1.1-1.6]) and 60 days (1.5 [95% CI, 1.4-1.7]). Inmates who received assistance completing a Texas AIDS Drug Assistance Program application were more likely to fill a prescription within 10 days (adjusted estimated RR, 3.1 [95% CI, 2.0-4.9]), 30 days (1.8 [95% CI, 1.4-2.2]), and 60 days (1.3 [95% CI, 1.1-1.4]). The authors conclude that only a small percentage of Texas prison inmates receiving ART while incarcerated filled an initial ART prescription within 60 days of their release. Baillargeon J, Giordano TP, Rich JD, Wu ZH, Wells K, Pollock BH, Paar DP. Accessing antiretroviral therapy following release from prison. JAMA. 2009;301(8):848-57.

HIV-1 Harboring Renal Tubular Epithelial Cell Interaction with T Cells Results in T Cell Trans-Infection

Renal biopsy data suggest that renal tubular cells may serve as a reservoir for HIV-1, however the mechanism underlying this finding has not been studied. Here the investigators show that primary human renal proximal tubular epithelial cells (HRPTECs) have the potential to harbor HIV-1 through the DEC-205 receptor. The interaction of HIV-1 with DEC-205 results in the rapid internalization of the virus for lysosomal degradation, without establishing a productive infection. However, a small fraction of incoming virus escapes degradation and can be rescued by T cells. Since pH-modulating agents and an inhibitor of endosomal transport increased HIV-1 accumulation and trans-infection to T cells, it appears that HRPTECs endocytic compartments may be the site of viral persistence and transmission to target cells. The ability of T cells to rescue the virus from HRPTECs further supports the hypothesis that these cells have the potential to serve as a reservoir for HIV-1. Mikulak J, Teichberg S, Faust T, Schmidtmayerova H, Singhal PC. Virology, 2009;Mar 1(385).

Recurrence of Primary Biliary Cirrhosis and Development of Autoimmune Hepatitis after Liver Transplant: A Blind Histologic Study

This long-term study aimed to evaluate recurrence and evolution of primary biliary cirrhosis (PBC) after orthotopic liver transplantation (OLT). The investigators reviewed "blindly" allograft biopsy specimens of women who underwent transplantation for PBC (n = 84), and women who received a transplant for chronic hepatitis C virus infection (CHCV) (n = 108). All needle liver biopsy specimens obtained more than 6 months post-OLT were examined, including 83 specimens from 44 PBC patients and 152 specimens from 58 CHCV patients. Granulomatous destructive cholangitis was found in five biopsies from four PBC patients (P = 0.0048). Non-necrotizing epithelioid cell granulomas were present in four biopsies from four PBC patients, and in two biopsies from one CHCV patient. Piecemeal necrosis (P = 0.0002), lobular necroinflammatory activity (P < 0.0001), steatosis (P < 0.0001) and fibrosis (P < 0.0001) were more prevalent in CHCV patients than PBC patients. Four PBC patients developed histologic evidence of autoimmune hepatitis (AIH), at a mean time of 3.66 years post-OLT. One of these patients had histologic features of AIH/PBC overlap syndrome. All four patients developed bridging fibrosis (n = 2) or cirrhosis (n = 2). No other PBC patient had evidence of cirrhosis after OLT. Histologic findings indicative of recurrent PBC were present in 15.9% of the PBC patients undergoing biopsy in this series. However, this group of patients did not suffer significant bile duct loss or fibrosis, as compared to the control group, suggesting that recurrent PBC is a mild or slowly progressive disease. Histologic evidence of AIH was observed in allograft biopsies of some PBC patients. Hytiroglou P, Gutierrez JA, Freni M, Odin JA, Stanca CM, Merati S, Thomas D, Branch AD, Thung SN. Hepatology Research. 2009;Jan 12. (Epub ahead of print).

Internal Initiation Stimulates Production of p8 Minicore, a Member of a Newly Discovered Family of Hepatitis C Virus Core Protein Isoforms

The hepatitis C virus (HCV) core gene is more conserved at the nucleic acid level than is necessary to preserve the sequence of the core protein, suggesting that it contains information for additional functions. The investigators used a battery of anticore antibodies to test the hypothesis that the core gene directs the synthesis of core protein isoforms. Infectious viruses, replicons, and RNA transcripts expressed a p8 minicore containing the C-terminal portion of the p21 core protein and lacking the N-terminal portion. An interferon resistance mutation, U271A, which creates an AUG at codon 91, upregulated p8 expression in Con1 replicons, suggesting that p8 is produced by an internal initiation event and that 91-AUG is the preferred, but not the required, initiation codon. Synthesis of p8 was independent of p21, as shown by the abundant production of p8 from transcripts containing an UAG stop codon that blocked p21 production. Three infectious viruses, JFH-1 (2a core), J6/JFH (2a core), and H77/JFH (1a core), and a bicistronic construct, Bi-H77/JFH, all expressed both p8 and larger isoforms. The family of minicores ranges in size from 8 to 14 kDa. All lack the N-terminal portion of the p21 core. In conclusion, the core gene contains an internal signal that stimulates the initiation of protein synthesis at or near codon 91, leading to the production of p8. Infectious viruses of both genotype 1 and 2 HCV express a family of larger isoforms, in addition to p8. Minicores lack significant portions of the RNA binding domain of p21 core. Studies are under way to determine their functions. Eng FJ, Walewski JL, Klepper AL, Fishman SL, Desai SM, McMullan LK, Evans MJ, Rice CM, and Branch AD. J Virology. 2009; April 3104-14.

Rare Birds in North America: Acute Hepatitis C Cohorts

This dynamic cohort was established in 2006 in response to the current HCV outbreak in New York City. It includes 35 subjects with acute HCV infection. Most are HIV-infected men who have sex with men (median age, 41 years). Acute HCV infection was defined using 3 criteria in combination: seroconversion, marked increases in ALT levels, and >1 log10 fluctuations in HCV viral load. The majority of infections were likely sexually acquired, although percutaneous exposures were reported by some subjects. A detailed risk factor questionnaire is administered at the initial visit and blood samples are collected for peripheral blood mononuclear cell, plasma, and serum analyses every 2 weeks during the initial 12-week observation period. Liver biopsy and treatment are offered if spontaneous clearance is not apparent within this period. Histopathology studies on this cohort showed that fibrogenesis occurred early and was markedly accelerated in this group of subjects: 17 of the first 20 biopsies, performed at a median of 4.3 months after the first noted increase in ALT levels, revealed stage 2 (of 4, Scheuer scale) fibrosis, a much greater number than reported in patients who acquired HCV infection before HIV infection. Age and male gender may contribute to this rapid fibrosis progression, but no other known risk factors for fibrosis explain these findings. Treatment with pegylated interferon and weight-based ribavirin during the acute phase resulted in a 70% sustained viral response rate. Early spontaneous clearance occurred in approximately 15% of patients, but was not related to the occurrence of symptomatic hepatitis. Ongoing work centers on understanding factors contributing to the accelerated fibrosis progression, maximizing treatment response, and characterizing factors that are contributing to this ongoing outbreak of acute HCV infection among HIV-infected men who have sex with men in New York City. Investigators of the Philadelphia Cohort collaborate in this study to characterize early immunologic responses in HIV-infected patients. Fierer D, Branch AD. Gastroenterology. 2009;1(136):26-31.

Mutations in the Hepatitis C Virus Core Gene Are Associated with Advanced Liver Disease and Hepatocellular Carcinoma

Hepatitis C virus (HCV) infection can promote the development of hepatocellular carcinoma (HCC). Published data implicate the HCV core gene in oncogenesis. The authors tested the hypothesis that core gene sequences from HCC patients differ from those of patients without cirrhosis/HCC. Full-length HCV sequences from HCC patients and controls were obtained from the investigators and GenBank and compared with each other. A logistic regression model was developed to predict the HCC risk of individual point mutations and other sequence features. Mutations in partial sequences (bases 36-288) from HCC patients and controls were also analyzed. The first base of the AUG start codon was designated position1. A logistic regression model developed through analysis of full-length core gene sequences identified seven polymorphisms significantly associated with increased HCC risk (36G/C, 209A, 271U/C, 309A/C, 435A/C, 481A, and 546A/C) and an interaction term (for 209A-271U/C) that had an odds ratio <1.0. Three of these polymorphisms could be analyzed in the partial sequences. Two of them, 36G/C and 209A, were again associated with increased HCC risk, but 271U/C was not. The odds ratio of 209A-271U/C was not significant. HCV core genes from patients with and without HCC differ at several positions. Of interest, 209A has been associated with IFN resistance and HCC in previous studies. These findings suggest that HCV core gene sequence data might provide useful information about HCC risk. Prospective investigation is needed to establish the temporal relationship between appearance of the viral mutations and development of HCC. Fishman SL, Factor SH, Balestrieri C, Fan X, DiBisceglie AM, Desai SM, Benson G, and Branch AD. Clin Cancer Res. 2009;15(9):3205-13.

Heroin in Brown, Black and White: Structural Factors and Medical Consequences in the US Heroin Market

Heroin coming into the United States historically comes from three widely dispersed geographical regions: Southwest Asia, Southeast Asia and Mexico. A fourth source of US-bound heroin, from Colombia, originated in the early 1990s. The fact that the four heroin sources produce differing morphologies and qualities of heroin has not been critically examined. In addition, it is not well established how the contemporary competing dynamics of interdiction, or restriction of heroin flows across international boundaries, and neoliberal, e.g., global expansion of free trade, policies are affecting heroin markets. This paper will highlight changes in the US heroin market, including source trends, the political economy of the now dominant source and the resultant effects on the heroin risk environment by US region. Using a structural and historical framework this paper examines two decades of secondary data sources, including government and drug control agency documents, on heroin flows together with published work on the political and economic dynamics in Latin America. Co-occurring neoliberal economic reforms may have contributed to paradoxical effects of US/Colombian interdiction efforts. Since entering the US market, heroin from Colombia has been distributed at a much higher quality and lower retail price. An increasingly exclusive market has developed with Mexican and Colombian heroin gaining market share and displacing Asian heroin. These trends have had dramatic effects on the risk environment for heroin consumers. An intriguing factor is that different global sources of heroin produce substantially different products. Plausible associations exist between heroin source/form and drug use behaviors and harms. For example, cold water-soluble powdered heroin (sources: Asia, Colombia) may be associated with higher HIV prevalence in the US, while low-solubility "black tar" heroin (BTH; source: Mexico) is historically used in areas with reduced HIV prevalence. BTH is associated with soft tissue infections caused by Clostridium bacteria. The authors conclude that the source and type of heroin are structural factors in the risk environment of heroin users: source dictates distribution and type predicts practice. How specific types of heroin are used and with what risk is therefore distributed geographically. Continued flux in the heroin market and its effects on the risk environment for drug users deserves further attention. Ciccarone D. International Journal of Drug Policy. 2009;3(20) 277-82.

C-terminal ADAMTS-18 Fragment Induces Oxidative Platelet Fragmentation, Dissolves Platelet Aggregates and Protects Against Carotid Artery Occlusion and Cerebral Stroke

Anti-platelet integrin GPIIIa49-66 Ab induces complement-independent platelet oxidative fragmentation and death by generation of platelet peroxide following NADPH oxidase activation. A C-terminal 385 amino acid fragment of ADAMTS-18 (A Disintegrin Metalloproteinase with Thrombospondin motifs produced in endothelial cells) induces oxidative platelet fragmentation in an identical kinetic fashion as anti-GPIIIa49-66 Ab. Endothelial cell ADAMTS-18 secretion is enhanced by thrombin and activated by thrombin cleavage to fragment platelets. Platelet aggregates produced ex vivo with ADP or collagen and fibrinogen are destroyed by the C-terminal ADAMTS-18 fragment. Anti-ADAMTS-18 Ab shortens the tail vein bleeding time. The C-terminal fragment protects against FeCI3 induced carotid artery thrombosis as well as cerebral infarction in a post-ischemic stroke model. Thus, a new mechanism is proposed for platelet thrombus clearance, via platelet oxidative fragmentation induced by thrombin cleavage of ADAMTS-18. Li Z, Nardi MA, Li YS, Zhang W, Pan R, Dang S, Yee H, Quarterma D, Jonas S, Karpatkin S. Blood. 2009; Feb (Epub ahead of print).

Medical Comorbidity in Patients with Schizophrenia and Alcohol Dependence

Schizophrenia and alcohol dependence are major risk factors for a variety of medical problems, yet there has been little research on the medical status of patients in whom both conditions coexist. The investigators assessed the prevalence and severity of medical illness in 80 patients with schizophrenia or schizoaffective disorder and comorbid alcohol use disorders who entered a controlled trial of monitored naltrexone treatment, and analyzed the relationship between medical illness burden and demographic variables, alcohol and other substance use, and psychosis. Participants underwent physical examination, laboratory tests, medical record review and standardized assessments of medical illness burden, alcohol and other substance use, and psychosis. Nested block multiple regression analyses were used to assess the contribution to illness burden made by demographic variables, alcohol and substance use, and psychosis severity. Eighty-three percent of participants had at least one chronic medical illness, hypertension being the most common (43%). Medical comorbidity in this cohort was more severe than for schizophrenia patients in the CATIE trial (Chwastiak L, Rosenheck R, McEvoy JP, Keefe RS, Swartz MS, Lieberman JA. Interrelationships of psychiatric symptom severity, medical comorbidity, and functioning in schizophrenia. Psychiatr Serv. 2006;57(8):1102-9.); the prevalence of hypertension, chronic obstructive pulmonary disease, and coronary artery disease, was more than twice greater. Medical illness burden correlated with alcohol use severity, but appeared to be independent of other substance use or psychosis severity. Patients with co-occurring alcohol use disorder may have significantly more medical illness burden than patients with schizophrenia or schizoaffective disorder alone. Interventions to reduce alcohol use may be necessary to lessen medical morbidity. Batki SL, Meszaros ZS, Strutynski K, Dimmock JA, Leontieva L, Ploutz-Snyder R, Canfield K, Drayer RA. Schizophr Res. 2009; 107(2-3):139-46.

Selection Pressure from Neutralizing Antibodies Drives Sequence Evolution during Acute Infection with Hepatitis C Virus

Despite recent characterization of hepatitis C virus-specific neutralizing antibodies, it is not clear to what extent immune pressure from neutralizing antibodies drives viral sequence evolution in vivo. This lack of understanding is particularly evident in acute infection, the phase when elimination or persistence of viral replication is determined and during which the importance of the humoral immune response has been largely discounted. The investigators analyzed envelope glycoprotein sequence evolution, and neutralization of sequential autologous hepatitis C virus pseudoparticles in eight individuals throughout acute infection. Amino acid substitutions occurred throughout the envelope genes, primarily within the hypervariable region 1 of E2. When individualized pseudoparticles expressing sequential envelope sequences were used to measure neutralization by autologous sera, antibodies neutralizing earlier sequence variants were detected at earlier time points than antibodies neutralizing later variants, indicating clearance and evolution of viral variants in response to pressure from neutralizing antibodies. To demonstrate the effects of amino acid substitution on neutralization, site-directed mutagenesis of a pseudoparticle envelope sequence revealed amino acid substitutions in hypervariable region 1 that were responsible for a dramatic decrease in neutralization sensitivity over time. In addition, high-titer neutralizing antibodies peaked at the time of viral clearance in all spontaneous resolvers, while chronically evolving subjects displayed low-titer or absent neutralizing antibodies throughout early acute infection. These findings indicate that during acute hepatitis C virus infection in vivo, virus-specific neutralizing antibodies drive sequence evolution and, in some individuals, play a role in determining the outcome of infection. Dowd KA, Netski DM, Wang XH, Cox AL, Ray SC. Gastroenterology. 2009; Mar. (Epub ahead of print).

Predictors of Insulin Resistance Among Hispanic Adults Infected with or At Risk of Infection with the Human Immunodeficiency Virus and Hepatitis C Virus

Both the human immunodeficiency (HIV) and hepatitis C (HCV) viruses have been associated with insulin resistance (IR). However, our understanding of the prevalence of IR, the underlying mechanisms and predisposing factors is limited, particularly among minority populations. The investigators conducted a study of 333 Hispanic adults including: 76 HIV mono-infected, 62 HCV mono-infected, 97 HIV/HCV co-infected and 98 uninfected controls with a specific focus on HCV infection and liver injury as possible predictors of IR. IR was measured using the Quantitative Insulin Sensitivity Check Index (QUICKI). The majority (55-69%) of participants in all groups had QUICKI values <0.350. Body mass index was associated with IR in all groups. Triglycerides were associated with IR in the uninfected control group only (-1.83, SE = 0.58, P = 0.0022). HCV was associated with IR in participants infected with HIV (-0.012, SE = 0.0046, P = 0.010). Liver injury, as measured by score to assess liver injury (FIB-4) score, was significantly associated with IR independently of HCV infection (-0.0035, SE = 0.0016, P = 0.027). In the HIV/HCV co-infected group, treatment with nucleoside reverse-transcriptase (RT) inhibitors plus non-nucleoside RT inhibitors (-0.021, SE = 0.080, P = 0.048), but not protease inhibitors (-0.000042, SE = 0.0082, P = 0.96) was associated with IR. HCV infection and antiretroviral agents, including nucleoside RT inhibitor plus non-nucleoside RT inhibitor treatment are contributors to IR in HIV infection. Liver injury, as measured by the FIB-4 score, is a predictor of IR independently of HCV infection. Castaneda-Sceppa C, Bermudez OI, Wanke C, Forrester JE. J Viral Hepat. 2008;15(12):878-87.

Short-Term Clarithromycin Administration Impairs Clearance and Enhances Pharmacodynamic Effects of Trazodone but Not of Zolpidem

The kinetic and dynamic interactions of 5 mg zolpidem and 50 mg trazodone with 500 mg clarithromycin (4 doses given over 32 h) were investigated in a 5-way double crossover study with 10 healthy volunteers. The five treatment conditions were: placebo + placebo; zolpidem + placebo; zolpidem + clarithromycin; trazodone+ placebo; and trazodone + clarithromycin. Coadministration of clarithromycin increased trazodone area under the curve, prolonged elimination half-life, increased peak plasma concentration (Cmax), and reduced oral clearance. In contrast, clarithromycin had no significant effect on any kinetic parameter for zolpidem. Clarithromycin did not potentiate sedation caused by zolpidem. However, clarithromycin coadministered with trazodone significantly increased self- and observer-rated sedation and ratings of feeling "spacey." Thus, short-term clarithromycin coadministration significantly impairs trazodone clearance, elevates plasma concentrations, and enhances sedative effects. However, clarithromycin has no significant kinetic or dynamic interaction with zolpidem. Clin Pharmacol Ther. 2009; advance online publication 25 February 2009. doi:10.1038/clpt.2008.293. Farkas D, Volak L, Harmatz J, von Moltke L, Court M, Greenblatt D. Clin Pharmacol Ther. 2009; Feb (Epub ahead of print).

Ritonavir Greatly Impairs CYP3A Activity in HIV Infection with Chronic Viral Hepatitis

Ritonavir is a powerful inhibitor of cytochrome P450 3A (CYP3A) that metabolizes many antiretrovirals. The investigators examined the effect of ritonavir and of chronic viral hepatitis (CVH) status on CYP3A activity. Twenty-six HIV-positive men (13 with CVH, 16 on chronic ritonavir-based highly active antiretroviral therapy) received oral and intravenous midazolam, a probe for CYP3A phenotypic activity. CYP3A activity was expressed as oral clearance of the midazolam probe. In HIV-positive subjects not on ritonavir, CYP3A activity (mean +/- SD) did not differ between subjects by CVH (no CVH, controls: 28.5 +/- 9.0 vs. CVH+: 23.2 +/- 6.2 mL/min/kg, not significant). In those on ritonavir (R), CYP3A activity was 7% of controls (R: 2.1 +/- 0.8 vs. no R 28.5 +/- 9.0 mL/min/kg, P < 0.0004). CYP3A activity in subjects on ritonavir and with CVH was further reduced to 4% of controls (no CVH, R+ 2.1 +/- 0.8 vs. R+, CVH+ 1.0 +/- 0.4 mL/min/kg, P < 0.006). Ritonavir markedly decreases CYP3A activity. In the presence of CVH, ritonavir-based therapy further reduces CYP3A activity by half. Coinfection with CVH impairs CYP3A activity in the presence of the CYP3A inhibitor ritonavir. Knox TA, Oleson L, von Moltke LL, Kaufman RC, Wanke CA, Greenblatt DJ. J Acquir Immune Defic Syndr. 2008;49(4):358-68.

Methamphetamine Enhances HIV-1 Infectivity in Monocyte Derived Dendritic Cells

The US is currently experiencing an epidemic of methamphetamine (Meth) use as a recreational drug. Recent studies also show a high prevalence of HIV-1 infection among Meth users. The investigators report that Meth enhances HIV-1 infectivity of dendritic cells as measured by multinuclear activation of a galactosidase indicator (MAGI) cell assay, p24 assay, and LTR-RU5 amplification. Meth induces increased HIV-1 infection in association with an increase in the HIV-1 coreceptors, CXCR4 and CCR5, and infection is mediated by downregulation of extracellular-regulated kinase (ERK2) and the upregulation of p38 mitogen-activated protein kinase (MAPK). A p38 inhibitor (SB203580) specifically reversed the Meth-induced upregulation of the CCR5 HIV-1 coreceptor. The dopamine D2 receptor antagonist RS +/- sulpiride significantly reversed the Meth-induced upregulation of CCR5, demonstrating that the Meth-induced effect is mediated via the D2 receptor. These studies report for the first time that Meth fosters HIV-1 infection, potentially via upregulating coreceptor gene expression. Further, Meth mediates its regulatory effects via dopamine receptors and via downregulating ERK2 with a reciprocal upregulation of p38 MAPK. Elucidation of the role of Meth in HIV-1 disease susceptibility and the mechanism through which Meth mediates its effects on HIV-1 infection may help to devise novel therapeutic strategies against HIV-1 infection in high-risk Meth-using HIV-1-infected subjects. Nair MP, Saiyed ZM, Nair N, Gandhi NH, Rodriguez JW, Boukli N, Provencio-Vasquez E, Malow RM, Miguez-Burbano MJ. J Neuroimmune Pharmacol. 2009;4(1):129-39.

Characteristics and Treatment Outcomes Among HIV-infected Individuals in the Australian Trial in Acute Hepatitis C

The Australian Trial in Acute Hepatitis C (ATAHC) is a National Institutes of Health-funded prospective cohort study of the natural history and efficacy of treatment in individuals with recently acquired hepatitis C. Enrollment is open to both human immunodeficiency virus (HIV)-infected and -uninfected individuals. The aim of this article was to evaluate characteristics and virological outcomes among HIV-infected individuals enrolled in ATAHC. Eligibility criteria included the first positive result of testing for anti-hepatitis C virus (HCV) antibody within 6 months and either clinical hepatitis diagnosed within the past 12 months or documented anti-HCV seroconversion within the past 24 months. Of the initial 103 patients enrolled, 27 (26%) were HIV infected. HIV-infected patients were more likely to be older, to have HCV genotype 1 infection and high levels of HCV RNA at baseline than were HCV-mono-infected patients. Sexual acquisition accounted for the majority (56%) of HCV infections among HIV-infected patients, compared with only 8% of HCV-mono-infected patients. The median duration from estimated HCV infection to treatment was 30 weeks. Treatment with 24 weeks of pegylated interferon and ribavirin resulted in rates of undetectability of HCV RNA of 95%, 90%, and 80% at weeks 12, 24, and 48, respectively. Undetectability at week 4 was achieved in 44% of patients and yielded positive and negative predictive values for sustained virological response of 100% and 33%, respectively. Significant differences were demonstrated between HIV-infected and HIV-uninfected individuals enrolled in ATAHC. Treatment responses among HIV-infected individuals with both acute and early chronic infection are encouraging and support regular HCV screening of high-risk individuals and early treatment for recently acquired HCV infection. Collaborators: Kaldor J, Dore G, Matthews G, Marks P, Lloyd A, Hellard M, Haber P, Ffrench R, White P, Rawlinson W, Day C, van Beek I, McCaughan G, Madden A, Dolan K, Farrell G, Crofts N, Sievert W, Baker D, Yeung B, Acraman B, Petoumenos K, Amin J, Doab A, Carroll T, Nguyen O, Teutsch S, Li H, Oon A, Cameron B, Jacka B, Pan Y, Flynn J, Goy K, Shaw D, Haber P, Sasadeusz J, Crawford D, Phung N, George J, Bloch M, Hughes B, Mollison L, Roberts S, Desmond P. Clin Infect Dis. 2009;48(5):650-8.

Exceeding the Limits of Liver Histology Markers

Alternatives to liver biopsy for staging liver disease caused by hepatitis C virus (HCV) have not appeared accurate enough for widespread clinical use. the investigators characterized the magnitude of the impact of error in the "gold standard" on the observed diagnostic accuracy of surrogate markers. The investigators calculated the area under the receiver operating characteristic curve (AUROC) for a surrogate marker against the gold standard (biopsy) for a range of possible performances of each test (biopsy and marker) against truth and a gradient of clinically significant disease prevalence. In the 'best' scenario where liver biopsy accuracy is highest (sensitivity and specificity of biopsy are 90%) and the prevalence of significant disease 40%, the calculated AUROC would be 0.90 for a perfect marker (99% actual accuracy) which is within the range of what has already been observed. With lower biopsy sensitivity and specificity, AUROC determinations >0.90 could not be achieved even for a marker that perfectly measured disease. The investigators demonstrate that error in the liver biopsy result itself makes it impossible to distinguish a perfect surrogate from ones that are now judged by some as clinically unacceptable. An alternative gold standard is needed to assess the accuracy of tests used to stage HCV-related liver disease. Mehta SH, Lau B, Afdhal NH, Thomas DL. J Hepat. 2009;50(1):36-41. Comment in J Hepatol. 2009;50(1):1-3.

Substance Use in Vulnerable Patients with Orofacial Injury: Prevalence, Correlates, and Unmet Service Needs

A large portion of injuries treated at urban trauma centers are preventable. Substance use presents as one of the most common antecedent risk factors. Substance use characteristics of vulnerable adults treated for intentional orofacial injury at a regional trauma center were investigated. Patients (N = 154) presenting with intentional facial injury were recruited. Patients were considered eligible for recruitment if they were adults, recently used alcohol or drugs, and had a fracture within the 30 days preceding recruitment that involved the jaw, orbit, nose, or cheekbone as determined by clinical history, examination, and radiographic findings and that injury was due to interpersonal violence. This patient cohort evidenced significant levels of alcohol use, with 58% of the patient cohort meeting the criteria for problem drinking. Although lower than alcohol use rates, the reported use of illicit drugs was substantial. Almost half of the sample reported other substance use in the previous month, with 24% meeting the criteria for problem drug use. Despite the very high percentage of individuals needing alcohol or drug treatment, only a small proportion of the patient sample reported having been seen by a professional for alcohol or drug treatment. Integrating substance use services into trauma care is warranted and is further discussed. Murphy DA, Shetty V, Resell J, Zigler C, Yamashita DD. J Trauma. 2009;66(2):477-84.

Naturally Occurring Dominant Resistance Mutations to Hepatitis C Virus Protease and Polymerase Inhibitors in Treatment-Na•ve Patients

Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitors in <1% of the viral quasispecies may still allow >1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-na•ve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant resistance mutations against specifically targeted antiviral therapy for HCV (STAT-C) in the population, HCV genome sequences were analyzed from 507 treatment-na•ve patients infected with HCV genotype 1 from the United States, Germany, and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication-competent, drug-resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir; the NS5B polymerase inhibitor AG-021541; and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multidrug resistance. Collectively, however, 8.6% of the patients infected with genotype 1a and 1.4% of those infected with genotype 1b carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug-resistant viral strains might achieve replication levels comparable to nonresistant viruses in vivo. The authors concluse that naturally occurring dominant STAT-C resistance mutations are common in treatment-na•ve patients infected with HCV genotype 1. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous nonresponse to peginterferon and ribavirin. Kuntzen T, Timm J, Berical A, Lennon N, Berlin AM, Young SK, Lee B, Heckerman D, Carlson J, Reyor LL, Kleyman M, McMahon CM, Birch C, Schulze Zur, Wiesch J, Ledlie T, Koehrsen M, Kodira C, Roberts AD, Lauer GM, Rosen HR, Bihl F, Cerny A, Spengler U, Liu Z, Kim AY, Xing Y, Schneidewind A, Madey MA, Fleckenstein JF, Park VM, Galagan JE, Nusbaum C, Walker BD, Lake-Bakaar GV, Daar ES, Jacobson IM, Gomperts ED, Edlin BR, Donfield SM, Chung RT, Talal AH, Marion T, Birren BW, Henn MR, Allen TM. Hepatology. 2008;48(6):1769-78.

The Risk of Emergency Room Treatment Due to Overdose in Injection Drug Users

This cohort study was conducted to identify risk factors for lifetime emergency room treatment due to overdose in injection drug users. Data of 1049 patients on admission for opioid detoxification were analyzed. More than every third injection drug user (34.7%) experienced emergency room treatment due to an overdose. Using multiple logistic regression not living with a significant other drug user (odds ratio [OR] = 1.78, P = .002), history of suicide attempt (OR = 3.0, P = .000), daily use of barbiturates (OR = 2.17, P = .006) and cannabis (OR = 1.89, P = .001) were independently associated with emergency room treatment, whereas shorter duration of opioid use (OR = 0.23, P = .001) was independently associated with lack of emergency room treatment. Suicidal thoughts and multiple use of central nervous system depressants should be considered in injection drug users entering the emergency room due to an overdose. The authors conclude that emergency rooms should be seen as important places for offering further assistance (e.g., counseling) or referral to an addiction unit to drug users. Backmund M, Schuetz C, Meyer K, Edlin BR, Reimer J. J Addict Dis. 2009;28(1):68-73.

Assessment of Liver Fibrosis by Transient Elastography in Persons with Hepatitis C Virus Infection or HIV-Hepatitis C Virus Coinfection

Transient elastography is a novel, noninvasive method for staging liver fibrosis. The investigators compared elastography with histologic methods among hepatitis C virus (HCV)-infected and human immunodeficiency virus (HIV)-HCV-coinfected participants in an urban, predominantly black study population. Participants recruited from the AIDS Linked to the Intravenous Experience and the Johns Hopkins HIV Clinical Cohort studies underwent elastography to determine liver stiffness measurements. Liver biopsy specimens were staged F0-F4 in accordance with the Metavir score. Diagnostic accuracy and determination of liver stiffness cutoff values, compared with histologic methods, were determined by receiver operating characteristic analysis. Logistic regression methods identified parameters associated with discordant classification status. Of 192 participants, 139 (72%) were coinfected with HIV and HCV, 121 (63%) had insignificant fibrosis, and 48 (25%) had cirrhosis. Overall, the area-under-the-curve receiver operating characteristic was 0.87 for detection of both significant fibrosis (95% confidence interval, 0.82-0.92) and cirrhosis (95% confidence interval, 0.81-0.93). With use of cutoff values of 9.3 kPa for fibrosis and 12.3 kPa for cirrhosis, 79%-83% of participants were correctly classified by liver stiffness measurement (compared with histologic methods); accuracy appeared to be higher among HIV-uninfected participants than among HIV-infected participants. Most discordance occurred when liver stiffness measurements indicated liver disease and histologic examination did not (in 16% of participants); the patients with these discordant results were more likely to have attributes that increased the odds of significant fibrosis, such as elevated serum fibrosis markers or HIV-related immunosuppression, compared with persons in whom low fibrosis was predicted by both examination of a biopsy specimen and elastography. The authors conclude that for most HCV-infected persons, fibrosis stage predicted by elastography is similar to that predicted by examination of a biopsy specimen. Elastography-based measurement of liver stiffness holds promise to expand liver disease screening and monitoring, particularly among injection drug users. Kirk GD, Astemborski J, Mehta SH, Spoler C, Fisher C, Allen D, Higgins Y, Moore RD, Afdhal N, Torbenson M, Sulkowski M, Thomas DL. Clin. Infect. Dis. 2009;48(7):963-72.

Safety and Antiviral Activity of Albinterferon Alfa-2b in Prior Interferon Nonresponders with Chronic Hepatitis C

Pegylated interferon alfa-2a/2b is used in combination with ribavirin to treat patients with chronic hepatitis C (CHC), although many do not achieve a sustained virologic response (SVR). Albinterferon alfa-2b, a recombinant protein consisting of interferon alfa-2b fused to human albumin, may increase drug exposure. This phase 2 study evaluated the safety/efficacy of albinterferon in CHC patients who had not responded to interferon-based regimens. A total of 115 patients were assigned to 5 groups given 1200 microg albinterferon every 4 weeks or 900, 1200, 1500, or 1800 microg every 2 weeks, plus oral ribavirin, for 48 weeks. The primary efficacy end point was achievement of an SVR after 24 weeks. Treatment was extended to 72 weeks for 6 slow responders who were negative for hepatitis C virus RNA after 24 weeks. The types of adverse events were similar across groups; the overall discontinuation rate as a result of adverse events was 10.4%. Reductions in absolute neutrophil counts were less frequent in the every 4 weeks group and comparable among the every 2 weeks groups. The overall SVR rate was 17% (11% for previous nonresponders to pegylated interferon-alfa/ribavirin with genotype 1 infection). An SVR occurred in 3 of 6 slow responders by 72 weeks. The greatest reductions in hepatitis C virus RNA in nonresponders to pegylated interferon-alfa/ribavirin with genotype 1 infection were observed in the 1800-microg group. In patients with CHC who did not respond to interferon-based regimens, higher doses of albinterferon had significant early antiviral activity and a low incidence of adverse events, with the types of adverse events similar to those observed with interferon. Nelson DR, Rustgi V, Balan V, Sulkowski MS, Davis GL, Muir AJ, Lambiase LR, Dickson RC, Weisner RH, Fiscella M, Cronin PW, Pulkstenis E, McHutchison JG, Subramanian GM. Clin. Gastroenterol. Hepatol. 2009;7(2):212-8.

Efficacy and Safety of Peginterferon Alfa-2a/Ribavirin in Methadone Maintenance Patients: Randomized Comparison of Direct Observed Therapy and Self-Administration

Adherence to chronic hepatitis C (CHC) treatment may be particularly challenging in methadone maintenance patients. The investigators assessed the safety, tolerability, and efficacy of peginterferon alfa-2a/ribavirin treatment in methadone maintenance patients previously untreated for CHC. Patients were randomized 1:1 to direct observed therapy (DOT) or self-administration (SA) of peginterferon alfa-2a. DOT patients were seen weekly at methadone clinics; SA patients were seen less frequently, only at investigative sites. Genotype 1-infected patients were treated for 48 wk with peginterferon alfa-2a (180 microg/wk)/ribavirin (1,000/1,200 mg/day); genotypes 2- and 3-infected patients were treated for 24 wk with peginterferon alfa-2a (180 microg/wk)/ribavirin (800 mg/day). Based on defined efficacy stopping rules, 77% (37/48) completed their targeted length of treatment, and 44% (21/48) achieved sustained virologic response (SVR). Two DOT and 3 SA patients were withdrawn for safety reasons and 6 and 9, respectively, for nonsafety reasons. Over 60% and 50% of each group were >80% compliant with the planned cumulative doses of peginterferon alfa-2a and ribavirin, respectively, and over 60% with overall treatment duration. SVR rates were 54% (13/24) for DOT and 33% (8/24) for SA; 23% (3/13) and 38% (6/16), respectively, for genotype 1 and 91% (10/11) and 25% (2/8), respectively, for genotypes 2 and 3. Stepwise logistic regression analysis, showed that DOT (vs SA; OR 3.27, 95% CI 0.90-11.91, P = 0.073) and Caucasian race (vs Other; OR 13.31, 95% CI 1.42-124.71, P = 0.023) were predictors of SVR. Peginterferon alfa-2a/ribavirin can be used safely and successfully in CHC patients receiving methadone maintenance. Bonkovsky HL, Tice AD, Yapp RG, Bodenheimer HC Jr, Monto A, Rossi SJ, Sulkowski MS. Am. J. Gastroenterol. 2008 Nov 103(11):2757-65.

Successful Treatment of Chronic Hepatitis C with Pegylated Interferon in Combination with Ribavirin in a Methadone Maintenance Treatment Program

Injection drug users constitute 60% of the more than 4 million people in the United States with hepatitis C virus (HCV), including many methadone maintenance patients. Few data exist describing clinical outcomes for patients receiving HCV treatment on-site in methadone maintenance settings. In this retrospective study, clinical outcomes for 73 patients receiving HCV treatment are described on-site in a methadone maintenance treatment program. Fifty-five percent of patients achieved end-of-treatment response, and 45% achieved sustained viral response. These treatment response rates are nearly equivalent to previously published HCV treatment response rates, despite high prevalences of ongoing drug use (49%), psychiatric comorbidity (67%), and HIV coinfection (32%). These data show that on-site HCV treatment with pegylated interferon and ribavirin is effective in methadone-maintained patients, many of whom are active drug users, psychiatrically ill, or HIV coinfected, and that methadone maintenance treatment programs represent an opportunity to safely treat chronic hepatitis C. Litwin AH, Harris KA Jr, Nahvi S, Zamor PJ, Soloway IJ, Tenore PL, Kaswan D, Gourevitch MN, Arnsten JH. J Subst Abuse Treat. 2008; Nov (Epub ahead of print).


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