Norah J. Shire

Cutting Edge: The Prevalence of Regulatory T Cells in Lymphoid Tissue Is Correlated with Viral Load in HIV-Infected Patients

Inadequate local cell-mediated immunity appears crucial for the establishment of chronic HIV infection. Accumulation of regulatory T cells (Treg) at the site of HIV replication, the lymphoid organs, may influence the outcome of HIV infection. Our data provide the first evidence that chronic HIV infection changes Treg tissue distribution. Several molecules characteristics of Treg (FoxP3, CTLA-4, glucocorticoid-induced TNFR family-related receptor, and CD25) were expressed more in tonsils of untreated patients compared with antiretroviral-treated patients. Importantly, most FoxP3+ cells expressed CTLA-4, but not CD69. Furthermore, a direct correlation between FoxP3 levels and viral load was evident. In contrast, FoxP3 expression was decreased in circulating T cells from untreated patients, but normalized after initiation of treatment. Functional markers of Treg activity (indoleamine 2,3-dioxygenase, TGF-β, and CD80) were markedly increased in the tonsils of untreated patients. Our data could provide a new basis for immune-based therapies that counteract in vivo Treg and thereby reinforce appropriate antiviral immunity.

OCCULT HEPATITIS B IN HIV-INFECTED PATIENTS

Prevalence of hepatitis B virus (HBV) markers, including occult HBV, has not been described in diverse cohorts among HIV-infected patients. The objective of this study was to assess prevalence and significance of active and occult HBV infection in an HIV-positive US cohort. A random sample was taken from 2 prospective multicenter treatment intervention cohorts. The sample population (n = 240) was HIV-1 infected and highly active antiretroviral therapy–naive. Prevalence of HBV serologic markers and quantitative HBV DNA were determined. Serum alanine aminotransferase (ALT) levels were measured to evaluate correlates of hepatocyte injury. A total of 64.6% of subjects demonstrated reactivity for any marker of current or past HBV infection or prior vaccination. Chronic HBV infection characterized by hepatitis B surface antigen (HBsAg) reactivity was present in 7.1% while 15.8% exhibited HB anticore IgG only. Approximately 10% of the latter group was HBV DNA positive by a polymerase chain reaction–based assay. Only patients with a serologic pattern of HBsAg or HB anticore alone reactivity had HBV DNA. Occult HBV was observed in approximately 10% of HIV-infected patients with HB anticore IgG antibody in a geographically representative national cohort. Though viral titers and serum ALT levels were low, screening of this subset of HIV-infected patients may have implications in terms of antiretroviral therapy and risk of immune reconstitution–associated flares.

Acute Hepatitis C Virus Infection: A Chronic Problem

Since the discovery of the hepatitis C virus (HCV) in the late 1980s, there has been an explosion of information regarding its natural history, treatment, and replication cycle. Nonetheless, there are still relatively few data regarding acute HCV infection. By convention, the term acute hepatitis refers to the presence of clinical signs or symptoms of hepatitis for a period of 6 months or fewer after the presumed time of HCV exposure. Early studies of posttransfusion patients who developed non-A, non-B hepatitis provide a clinical picture of early infection.1 Following the availability of specific serologic and virologic tests, most such patients were shown to have acute HCV infection. After acute infection, HCV RNA may become detectable in the serum/plasma in as little as 2 weeks (Fig. 1). Several weeks later, a high percentage of patients experience an increase in serum aminotransferase levels consistent with the development of acute hepatocellular injury. In the majority of cases, patients develop mild constitutional symptoms, including abdominal pain, nausea, vomiting, anorexia, and fatigue. During this acute infection, serum aminotransferases often peak below 1000 IU/mL and may return to normal levels. A minority develops sufficient elevations in bilirubin to lead to overt jaundice or the development of dark urine. Unless the clinical suspicion is high, few patients will be tested for HCV RNA or HCV antibody seroconversion. However, in the majority— but not all— of infected patients, HCV RNA persists, and a chronic disease state develops. Fig. 1 Natural history of HCV infection (upper panel) and immunologic responses to HCV infection (lower panel): (−) HCV RNA, (- - -) cellular response, and (· · ·) ALT. ALT indicates alanine aminotransferase; HCV, hepatitis C ... The reasons for the general lack of data regarding acute HCV infection are multifactorial and include (1) the relatively high percentage of asymptomatic or unrecognized early infections, (2) the lack of large-scale identification of chronic carriers in the general population who serve as a reservoir for infection, and (3) the decreased number of acute infections that occur in controlled clinical settings such as that of blood transfusions. These factors and the lack of nonprimate animal models necessitate reliance on retrospective studies in chronic carriers, the use of limited historical collections of banked sera, and the extrapolation of outcomes based on small disease outbreaks in unique settings (for example, transmission from a physician to a patient in the operating room setting or following parenteral exposure in healthcare workers). Moreover, there exist only a limited number of population cohorts that continue to experience high rates of HCV transmission (for example, Egypt); nonetheless, there is a growing body of information regarding the clinical presentation, natural history, and treatment outcomes of acute HCV infection. In this article, we review the current information regarding our understanding of the epidemiology, virology, and immunology of HCV with a particular emphasis on acute HCV infection. In addition, we review recent data related to interferon-based treatment intervention and propose an algorithm for the diagnosis and management of acute HCV infection.

Outcomes in liver transplant recipients with hepatitis B virus: Resistance and recurrence patterns from a large transplant center over the last decade

Hepatitis B virus (HBV) recurrence following liver transplantation (LTx) has been controllable primarily with the use of hepatitis B immune globulin (HBIg) and lamivudine (LAM). However, HBV resistance to LAM and/or HBIg has become an increasing problem prompting the use of newer antiviral agents. The purpose of our study was to investigate the association between therapy, HBV breakthrough, and allograft / patient survival in HBV‐positive liver transplant recipients. We performed a retrospective review of the medical records of patients that were transplanted for HBV from June 1994 to May 2003. A total of 92 patients, positive for either hepatitis B surface antigen (HBsAg) or HBV deoxyribonucleic acid (DNA) pretransplant, received LAM monotherapy or HBIg (6 months) plus LAM therapy post–liver transplant. HBV breakthrough post‐LTx was noted in 14 patients. All patients had detectable HBV DNA prior to liver transplantation; none of the patients that were HBV DNA negative prior to transplant had detectable HBV DNA posttransplant. Of these 14, 9 patients (64%) were switched from LAM to adefovir dipivoxil (ADF) and 5 patients (36%) to tenofovir disoproxil fumarate (TNV). In conclusion, pre‐LTx HBV viremia should be considered in planning post‐LTx prophylaxis. Trials to evaluate oral antiviral agents in combination with or without HBIg therapy are needed. (Liver Transpl 2004;10:1372–1378.)

Test–retest repeatability of MR elastography for noninvasive liver fibrosis assessment in hepatitis C

To conduct a rigorous evaluation of the repeatability of liver stiffness assessed by MR elastography (MRE) in healthy and hepatitis‐C‐infected subjects.

Factors that identify survival after liver retransplantation for allograft failure caused by recurrent hepatitis C infection

Hepatitis C virus (HCV) is becoming the most common indication for liver retransplantation (ReLTx). This study was a retrospective review of the medical records of liver transplant patients at our institution to determine factors that would identify the best candidates for ReLTx resulting from allograft failure because of HCV recurrence. The patients were divided into 2 groups on the basis of indication for initial liver transplant. Group 1 included ReLTx patients whose initial indication for LTx was HCV. Group 2 included patients who received ReLTx who did not have a history of HCV. We defined chronic allograft dysfunction (AD) as patients with persistent jaundice (> 30 days) beginning 6 months after primary liver transplant in the absence of other reasons. HCV was the primary indication for initial orthotopic liver transplantation (OLT) in 491/1114 patients (44%) from July 1996 to February 2004. The number of patients with AD undergoing ReLTx in Groups 1 and 2 was 22 and 12, respectively. The overall patient and allograft survival at 1 year was 50% and 75% in Groups 1 and 2, respectively (P = .04). The rates of primary nonfunction and technical problems after ReLTx were not different between the groups. However, the incidence of recurrent AD was higher in Group 1 at 32% versus 17% in Group 2 (P = .04). Important factors that predicted a successful ReLTx included physical condition at the time of ReLTx (P = .002) and Child‐Turcotte‐Pugh score (P = .008). In conclusion, HCV is associated with an increased incidence of chronic graft destruction with a negative effect on long‐term results after ReLTx. The optimum candidate for ReLTx is a patient who can maintain normal physical activity. As the allograft shortage continues, the optimal use of cadaveric livers continues to be of primary importance. The use of deceased donor livers in patients with allograft failure caused by HCV remains a highly controversial issue. (Liver Transpl 2004;10:1497–1503.)

The prevalence and significance of occult hepatitis B virus in a prospective cohort of HIV-infected patients.

Background:Occult hepatitis B virus (HBV) is defined as low-level HBV DNA without hepatitis B surface antigen (HBsAg). Prevalence estimates vary widely. We determined the prevalence of occult HBV at the University of Cincinnati Infectious Diseases Center (IDC). Methods:Patients in the IDC HIV database (n = 3867) were randomly selected using a 25% sampling fraction. Samples were pooled for HBV nucleic acid extraction. Pools were tested for HBV DNA by a real-time polymerase chain reaction (PCR) assay to coamplify core/surface protein regions. The PCR assay was run on all individual samples from each DNA+ pool. DNA+ samples were tested for HBV serologic markers. Results:A total of 909 patients without known HBV were selected. The mean CD4 count was 384 cells/mm3. Forty-three patients were HBV DNA+. Twelve of 43 were DNA+/HBsAg− (95% confidence interval for database: 0.58% to 1.90%). Five of 12 were negative for all serologic markers. Alanine aminotransferase, aspartate aminotransferase, and HBV DNA titers were elevated in HBsAg+ patients versus occult patients and versus HIV-monoinfected patients. No other significant differences were detected. No occult HBV patient was on treatment with anti-HBV activity. Conclusions:Forty-three percent of those with HBV were not previously identified as HBV+, indicating the need for ongoing screening in high-risk populations. Occult HBV may occur in persons with all negative serologic markers, representing a challenge for identification.

Distribution of hepatitis C virus genotypes in a diverse US integrated health care population

Hepatitis C virus (HCV) genotypes influence response to therapy, and recently approved direct‐acting antivirals are genotype‐specific. Genotype distribution information can help to guide antiviral development and elucidate infection patterns. HCV genotype distributions were studied in a diverse cross‐section of patients in the Northern California Kaiser Permanente health plan. Associations between genotype and race/ethnicity, age, and sex were assessed with multivariate logistic regression models. The 10,256 patients studied were median age 56 years, 62% male, 55% White non‐Hispanic. Overall, 70% were genotype 1, 16% genotype 2, 12% genotype 3, 1% genotype 4, <1% genotype 5, and 1% genotype 6. Blacks (OR 4.5 [3.8–5.5]) and Asians (OR 1.2 [1.0–1.4]) were more likely to have genotype 1 than 2/3 versus non‐Hispanic Whites. Women less likely had genotype 1 versus 2/3 than did men (OR 0.86 [0.78–0.94]). Versus non‐Hispanic Whites, Asians (OR 0.38 [0.31–0.46]) and Blacks (OR 0.73 [0.63–0.84]) were less likely genotype1a than 1b; Hispanics (OR 1.3 [1.1–1.5]) and Native Americans (OR 1.9 [1.2–2.8]) more likely had genotype 1a than 1b. Patients age ≥65 years less likely had genotype 1a than 1b versus those age 45–64 (OR 0.34 [0.29–0.41]). The predominance of genotype 1 among all groups studied reinforces the need for new therapies targeting this genotype. Racial/ethnic variations in HCV genotype and subtype distribution must be considered in formulating new agents and novel strategies to successfully treat the diversity of hepatitis C patients. J. Med. Virol. 84:1744–1750, 2012.

Response rates to pegylated interferon and ribavirin in HCV/HIV coinfection: a research synthesis

Summary.  Several recent trials have determined varying rates of response to pegylated interferon plus ribavirin (peg‐IFN + RIB) in hepatitis C virus (HCV)/human immunodeficiency virus‐coinfected patients. We sought to identify a pooled response rate and sources of interstudy variability. A literature search was conducted to identify randomized or prospective studies evaluating response rates to peg‐IFN + RIB in coinfected patients. A Bayesian hierarchical model was used to estimate overall response rate. Between‐study variance was calculated and sensitivity analyses were conducted. Meta‐regression was employed to identify sources of between‐study variability. The literature search yielded seven studies of 146, which matched keywords and inclusion criteria. The combined patient total was 784. Individual intention‐to‐treat response rates ranged from 27.3% to 44.2%. The pooled Bayesian estimate of percent response was 33.3%. Significant interstudy heterogeneity was detected. Meta‐regression yielded no significant effects of covariates on response rate. Subanalyses by CD4+, HCV viral load and genotype yielded sustained virological response (SVR) odds ratios of 0.73 for low CD4+, 0.41 for high viral load and 0.30 for genotype 1/4. The pooled response rate is not attributable to any one study. Response is poor compared with HCV‐monoinfected patients. Interstudy variability is not satisfactorily explained by factors influencing individual response, but may be due to differences between studies unavailable for inclusion in this analysis. However, both genotype 1/4 and high HCV viral load at baseline were significantly associated with a reduction in odds of SVR in pooled subanalysis. Improved treatments are needed in coinfected patients, especially with genotype 1/4 and high viral load.

Reproducibility of hepatic fat fraction measurement by magnetic resonance imaging

To evaluate the reproducibility of magnetic resonance imaging (MRI)‐determined hepatic fat fraction (%) across imaging sites with different magnet types and field strength. Reproducibility among MRI platforms is unclear, even though evaluating hepatic fat fractions (FFs) using MRI‐based methods is accurate against MR spectroscopy.