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Hepatitis D Virus; Triply Infected HIV/HBV/HCV Progress More Quickly
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Reported by Jules Levin
Ten Year Follow-up of 126 Consecutive Italian Patients With Hepatitis Delta (HDV)-Related Compensated Cirrhosis
R. Romeo1; A. Sangiovanni1; E. Del Ninno1; M. Colombo1
1. Gastroenterology, Maggiore Hospital, Milan, Italy.
Background: Data have been accumulating, showing that chronic infection with HDV is less aggressive than previously reported, often leading to slowly evolving almost inactive compensated cirrhosis.
Aim: to give more insights into the evolutionary course of patients with HDV-related compensated cirrhosis. Patients: 126 consecutive patients with HDV compensated liver cirrhosis, diagnosed between 1985 and 2005, were followed for a mean of 121 months (range 10-240). There were 100 males, mean age was 42 yrs (range 23-73); 93 patients (74%) were Child-Pugh A and 33 were Child-Pugh B. 23 (18%) had HCV, 7 (5.5%) had HIV, alcohol intake was > 80 gr in 11 (9%), 12 (9%) had HBeAg and 33 (26%) had IgM anti-HBc. All patients were either HDV-RNA serum positive or displayed HDV-Ag in the liver on immunofluorescence. All patients were under surveillance with clinical exams and abdominal ultrasound every 6 months.
Results: During follow-up, HCC developed in 37 (29%), ascites in 25 (20%), jaundice in 19 (15%), variceal bleeding in 4 (3%) and encephalopathy in 1 (1%), corresponding to a mean yearly incidence of 3.2%, 2.1%, 1.6%, 0.3% and 0.1%, respectively. HCC was a single node in 19 (51%) with a mean diameter of 25mm. During follow-up, 14 (11%) patients progressed from Child-Pugh class A to B and 9
(7%) from Child B to C. 36 patients (28%) died, corresponding to a yearly mortality rate of 2.4%. Causes of death were liver failure in 22 (61%), HIV infection in 4 (11%), HCC in 2 (5%), variceal bleeding in 2 (5%), extrahepatic malignancies in 3 (8%), non liver related causes in 3 (8%).
Conclusion: HDV-related cirrhosis is a long-lasting compensated disease, whose major cause of death is liver decompensation.
Liver Disease Progression Among HIV-infected Patients with Viral Hepatitis
HIV-infected patients with both HBV and HCV are more likely to progress to ESLD compared to those with HIV/HBV or HIV/HCV. Cirrhosis is also more likely to be seen in this population.
E. Seremba1; R. K. Joshi1; N. Attar1; W. M. Lee1; M. K. Jain1
1. Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Background: Co-infection with viral hepatitis B (HBV), C (HCV) or both is common in HIV-infected patients due to shared routes of transmission. Little is known about the risk of liver disease progression among those coinfected with HIV/HCV, HIV/HBV or triply infected with HIV/HBV/HCV.
Methods: Medical records of 151 HIV-infected patients including 67 HIV/HBV, 43 HIV/HCV, and 41 triply infected patients were reviewed for demographics, CD4 cell count, HIV viral load, liver function tests, hepatitis B, C, and hepatitis delta (HDV) serologies, and radiologic images. Charts were reviewed in 124 for evidence of progression to end stage liver disease (ESLD) and alcohol consumption. HBV DNA was quantified using VERSANT HBV 3.0 (bDNA) and HCV RNA with VERSANT HCV RNA 3.0 (Siemens Diagnostics, Tarrytown NY) from stored sera. Eighty samples were obtained prior to start on antiretroviral therapy (ART) and were thus considered baseline. ANOVA was used to compare continuous variables across the three groups and chi square for dichotomous variables.
Results: ESLD and cirrhosis was seen more frequently in those with HIV/HCV/HBV compared to those with HIV/HCV or HIV/HBV (p=0.02 and 0.03, respectively). Log HCV load was similar in those with HIV/HCV (5.08) vs. triple (5.37). Log HBV DNA was lower in those with triple (2.58) compared to those with HIV/HBV (7.25), p=<0.001, however many samples in the triple group were obtained while patients were on ART, often using nucleosides with anti-HBV activity. Baseline samples [HIV/HBV (n=55); HIV/HCV(n=12); triple (n=13)] were examined and showed no difference in HCV viral load between HIV/HCV and triple infection, but log HBV viral load was slightly lower in those with triple infection compared to those with HIV/HBV ( 5.06 vs. 7.25, p=0.07). A history of alcohol abuse was more frequent in those with HIV/HCV than other groups (p=0.06).
Conclusions: HIV-infected patients with both HBV and HCV are more likely to progress to ESLD compared to those with HIV/HBV or HIV/HCV. Cirrhosis is also more likely to be seen in this population. Most HIV-infected patients will receive anti-HBV as part of ART. Triply infected patients should be considered additionally for HCV treatment, given the propensity for disease progression.
Anti-HBV Therapy Can Reduce Hepatitis Delta Replication in HIV Co-Infected Patients
J. García-Samaniego1; J. Sheldon2; C. Toro2; B. Ramos2; P. Rios2; J. Martinez-Alarcon2; M. Romero1; V. Soriano2
1. Hepatology Unit CIBEREHD, Carlos III Hospital, Madrid, Spain.
2. Infectious Diseases, Hospital Carlos III, Madrid, Spain.
Background:
HDV has a unique replication process using the host cellular polymerase. For this reason together with its high pathogenic potential, chronic hepatitis Delta (CHD) is very challenging. No specific inhibitor of HDV has so far been developed, and treatment is currently limited to intensive interferon based therapy. However, the role of potent nucleos(t)ide analogues against chronic HDV infection has not been well examined.
Methods:
A longitudinal study was carried out in all HIV-positive patients with CHD whom attended our hospital. Serum HBV DNA for each patient was longitudinally determined using Cobas HBV Taqman PCR (Roche, LLD 12 IU/ml), and serum HDV RNA was quantified using an in-house real time PCR assay (LLD, 100 cop/ml) at yearly intervals. Treatment regimens, plasma HIV and when pertinent HCV RNA, CD4 counts, ALT/AST levels and liver fibrosis measured by FibroScan were also assessed. All statistical analyses were made using SPSS v12.
Results:
A total of 18 HIV-positive patients with CHD were identified, the majority male (83%) and previous IDUs (83%). Median age was 33 years and baseline ALT, HIV RNA, HBV DNA, and CD4 were 98 IU/ml, 1.69 log10 copies/ml, 1.19 log10 IU/ml, and 344 cells/ml, respectively. Median follow-up was 6 years. All had detectable serum HDV RNA before receiving any anti-HBV treatment (median: 6.5 log10 cop/ml). A statistical significant correlation between HBV and HDV viral load was found (r=0.259; p=0.005). Anti-HBV drugs used were lamivudine (n=17), tenofovir (n=11) and/or emtricitabine (n=5). Overall, 11 patients showed good response to anti-HBV therapy achieving undetectable HBV DNA for a minimum of 2 years. Moreover, all of them showed a statistically significant decrease in plasma HDV RNA (mean: 1.44 log10 cop/ml, p=0.038) and ALT levels (mean: 45 IU/ml, p=0.022). In fact, 3 of these patients (1 received lamivudine and 2 lamivudine + tenofovir) achieved undetectable HDV RNA (<100 cop/ml) after a mean of 5.6 years of HBV antiviral therapy.
Conclusion:
Patients undergoing successful anti-HBV therapy with potent nucleoside analogs seem to have an indirect benefit for suppressing HDV replication, albeit not very efficient. Hypothetically, a significant and sustained reduction in serum HDV RNA may only be seen when a reduction in HBV cccDNA or HBsAg is achieved, which may require long periods of successful anti-HBV therapy. To our knowledge, this is the first clear evidence of benefit of potent anti-HBV nucleos(t)ide analogue therapy in CHD.
Management of Chronic Hepatitis B Virus (HBV)Infection by Primary Care Physicians in Urban Hospitals and Clinics in New York City
The rates of testing for HCVAb, HAVAb, HDVAb and HIV were 52.0%, 47.3%, 3.8% and 22.8%, respectively.
H. Pollack1; K. Wan1; T. Miyoshi1; S. Tawdekar1; P. Baker1; D. McEwen2; C. Weinbaum3; S. R. Bialek3; G. Fryer1; R. Low4
1. Pediatrics, NYU School of Medicine, New York, NY, USA.
2. Denver Health, Denver, CO, USA.
3. Division of Viral Hepatitis, Center for Disease Control and Prevention, Atlanta, GA, USA.
4. NYC Health and Hospitals Corporation, New York, NY, USA.
Current primary care physician practices with respect to the management of persons with chronic HBV infection are largely unknown and comprehensive recommendations directed to primary care physicians are lacking. In this pilot study we examined chronic hepatitis B disease management practices in primary care settings in New York City HHC South Manhattan Network Hospitals and clinics. Analysis was conducted, retrospectively, through electronic medical record review. We present preliminary results for patients 19-49 years of age who first visited primary care clinics in affiliated facilities during January 2005-December 2006. For the purposes of this analysis, chronic HBV infection was defined as a positive test for hepatitis B surface antigen (HBsAg). The minimum adequate evaluation for chronic HBV infection was defined as testing for HBeAg, VL and ALT. Among the 18,457 patients, 42.4% (7,826) were screened for HBsAg. 893 were HBsAg+. The mean age of HBV-infected patients was 31.8 ±7.4 years, 57.8% were men. The HBV-infected patients were overwhelmingly APIs (83.9%), followed by Blacks (7.8%), Hispanics (3.6%), and Whites (0.9%). 97.9% of HBV-infected persons were tested for ALT, 71.0% for HBeAg, 68.2% for viral load, and 63.6% for AFP. The rates of testing for HCVAb, HAVAb, HDVAb and HIV were 52.0%, 47.3%, 3.8% and 22.8%, respectively. Approximately one third of the patients (37.8%) received an abdominal ultrasound exam, 9.9% had a CT scan and 0.6% had a MRI. 564 patients (63.2%) had HBeAg, VL and ALT measurements and 306 patients (34.3%) had all three measurements and an ultrasound exam. 83.1% of those with abnormal ALTs had HBeAg and VL tests, higher than 58.5% among those with normal ALTs, p<0.01. Management practices did not differ by patient sex (p=0.51), race/ethnicity (p=0.07), age (p=0.18) or country of birth (p=0.82). Patients at hospital facilities were more likely to receive the minimum adequate evaluation (68.6%, and 64.9%, respectively), compared to patients at community clinics (45.5%, and 29.3%, respectively), p<0.01. In conclusion, the management of patients with chronic HBV infection by primary care physicians in this study was suboptimal according to practice guidelines established by the AASLD. Additional education and training of primary care physicians in the proper management of these patients needs to be implemented and evaluated in order to decrease the long-term morbidity and mortality of persons chronically infected with HBV.
HDV-Specific IP-10 Responses but not IP-10 Serum Levels Correlate with Response to PEG-IFNA-2A Treatment of Delta Hepatitis: Results from the HEP-NET/International HIDIT-1 Study
H. Wedemeyer1; C. Yurdaydin2; A. Ciner1; P. Hoffmann3; P. Buggisch4; N. Aslan1; K. Zachou1; S. Zeuzem3; M. P. Manns1
1. Gastroenterology, Medizinische Hochschule Hannover, Hannover , Germany.
2. Ankara University, Ankara, Turkey.
3. University of Frankfurt, Frankfurt, Germany.
4. University of Hamburg, Hamburg, Germany.
Introduction: Pegylated interferon therapy of HDV infection is associated with sustained virological responses in about 25% of patients as we have shown in the HIDIT-1 trial on 90 delta hepatitis patients (Wedemeyer et al., EASL 2007). Cellular immune responses in hepatitis D virus (HDV) infection are largely undefined and HDV-specific T cell responses during antiviral therapy of hepatitis D have not been studied at all. Serum IP-10 levels have been shown to be negatively associated with treatment outcome to IFN-based therapies in HCV monoinfection (DITTO-trial) and HCV/HIV coinfection.
Methods: 19 patients treated in the HIDIT-1 trial were studied for HDV-specific T cell responses (7 IFN-responder, 7 IFN-nonresponder; 5 adefovir monotherapy patients) using 51 overlapping 15mer peptides spanning the entire HDV genome. Peptides were synthesized from a genotype 1 consensus sequence and all patients were confirmed to be infected with HDV genotype 1. Each individual was studied at 5 time-points (baseline, weeks 12, 24, 48 and FU-24). Ag-specific cytokine responses were studied in the supernatant after 6 days by bead arrays for 10 type 1 and 2 cytokines. In addition, serum cytokine levels for four cytokines including IP-10 in 50 patients during the trial.
Results: While the frequency and strength of HDV-specific interferon gamma responses was not different between interferon responder and nonresponders patients (overall detectable in 12/19 patients), HDV peptide-specific IP-10 secretion was detected significantly more often in IFN-responder (7/7patients positive; 63 positive assays) than in nonresponder patients (2/7 patients positive; 19 positive assays). IP-10 secretion in the two nonresponders patients was accompanied by HDV-specific IL-10 responses which was not the case in responder patients. Amino acids 81-120 of the HD-antigen were recognized most often followed by the C-terminal part (aa 161-214). Delta-specific immune responses for all cytokines and peptide pools declined in frequency and strength during interferon treatment and increased again after therapy. Serum cytokine levels did not differ between IFN-responder and nonresponders patients or individuals receiving adefovir alone.
Conclusion: This first study on HDV-specific cellular immune responses in individuals receiving interferon therapy for delta hepatitis showed that a differential cytokine pattern of antigen-specific T cell responses discriminates responder and nonresponder patients. In particular HDV-specific IP-10 and IL-10 production clearly predicts treatment response. In contrast to hepatitis C, IP-10 serum levels were not associated with treatment outcome.
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