 |
|
|
| |
Coinfection Report from ICAAC 2005: 33% of coinfected with normal ALT had advanced liver disease in Spanish study
|
| |
| |
Report by Jules Levin
--patients with cirrhosis are more likely to experience hepatoxicity (30% vs 20%)
--4% in Spanish study experienced hepatoxicity after starting HAART. There was no difference in rates of hepatoxicity between the regimens patients were taking.
--33% of coinfected Spanish patients in study with normal ALT had advanced liver disease (fibrosis) upon liver biopsy
-- Weight loss is associated with interferon/ribavirin therapy. In this study coinfected patients had a greater issue of weight loss than monoinfected patients on HCV therapy. HCV/HIV coinfected patients were more likely to experience weight loss on HCV therapy than HCV monoinfected patients (76% vs 39%, defined as loss of 5% or more of baseline weight), and coinfected patients lost more weight (5 kg vs 3 kg after 6 months & 7 kg vs 2.5 kg after 12 months), and HIV+ patients on ART.
--a new nuke, PSI-6130 demonstrated potent against Hepatitis C Virus in vitro, in test tube
--using a new diagnostic test, (FibroScan), this study found higher drug levels for certain HAART medications in coinfected patients with cirrhosis compared to non-cirrhotic coinfected patients, suggesting that TDM (checking HIV drug levels) may be useful in coinfected patients
Study in 226 Coinfected Spanish patients finds patients with cirrhosis are more likely to experience hepatoxicity (30% vs 20%)
(hepatoxicity defined as ALT >3.5 times the upper limit of normal, which is approximately greater than 120)
"Risk of Haart-Associated Hepatotoxicity in HIV/HCV Co-Infected Patients with Cirrhosis"
ICAAC Dec 2005.
Author: L. ARANZABAL, Ramon y Cajal Hosp., Madrid, Spain. Poster: H-1489
This is a prospective cohort study of 226 HIV/HCV co-infected patients who underwent a liver biopsy between October 2000 and December 2004. Liver fibrosis was staged using a scoring system of 0 (no fibrosis) to 4 (cirrhosis). Hepatotoxicity was defined as an increase in AST/ALT levels over five times the upper limit of normal, 3.5 fold increase if baseline levels were abnormal, or with clinical symptoms of liver toxicity.
Mean age of study patients was was 40 yrs, and 88% were former IDUs. A histological diagnosis (liver biopsy) of cirrhosis was observed in 32 pts (14%). There were no differences in age, risk factor for HIV/HCV infection, RNA HCV, HCV genotype, nadir CD4+ count or increase, HIV RNA level, prior AIDS diagnosis, or baseline liver enzyme levels between patients with cirrhosis or those with fibrosis 0-3.
However, cirrhotic patients were predominantly male (97% vs 87%, p=0.004), had a longer duration of HCV infection (21 vs 17 yrs, p<0.001), a higher liver histological activity index (HAI) (7 vs 5, p=0.04), and increased bilirubin levels (1.4 vs 0.8, p=0.001).
Mean time on HAART was similar according to fibrosis degree (5.6 yrs in cirrhotic vs 4.5 yrs).
Overall, the rate of liver toxicity was higher in patients with cirrhosis (31% vs 20%; 5.6 vs 4.4 episodes per 100 patient-yrs; p=0.1).
Liver toxicity was more frequently observed in patients in the Child-Pugh score B or C than in score A (40% vs 16%; p=0.2) According to the regimen used, a higher rate of hepatotoxicity was observed in patients with cirrhosis receiving nevirapine in comparison with r/lopinavir (12 vs 4.6 episodes per 100 patient-years).
Nearly one third of HIV/HCV co-infected patients with cirrhosis could develop liver toxicity during HAART, although with important differences according to the regimen used and the severity of cirrhosis.
Hepatotoxicity in HIV-Infected Patients Starting HAART: 4% rate of hepatoxicity in this Spanish study
(hepatoxicity defined as 5x ULN, which equals ALT of approximately 200).
ICAAC, Dec 2005.
Author: L. ARANZABAL, Ramon y Cajal Hosp, Madrid, Spain
Poster H-1485
Background: The current incidence of hepatotoxicity in patients starting HAART is unknown, due to the introduction of new antiretroviral regimens.
This was a prospective, multicenter study. A total of 256 HIV-treatment-naïve patients starting HAART during 2004 were included. Hepatotoxicity was defined as an increase in AST/ALT level over 5 times the upper limit of normal.
Mean age of study patients was 40 years, 79% were male, 27% were former IDUs, and 30% were co-infected by HCV. At baseline, CD4+ count was 176 cells/mm3 (10-459) and HIV RNA level was 107,996 copies/ml (4587-1,027,979). The most frequent regimens included r/lopinavir (39%), efavirenz (43%), or abacavir (31%) as third drug. A four-drug regimen was used in 11%.
Overall, there were 10 episodes of hepatotoxicity (4%) in a median time of 100 days (21-169). All the events were asymptomatic. There was no association between liver toxicity and age, sex, risk practice, CD4+ count at baseline or increase, or HIV RNA level.
Only HCV coinfection was associated with hepatotoxicity, with 89% of episodes (RR 3.3, 95% CI 2.5-4.4; p<0.01). Baseline liver enzyme levels did not predict hepatotoxicity (note from Jules Levin: many studies have found that having elevated liver enzyme levels before starting HAARt is associated with a risk for experiencing hepatoxicity on HAART).
There was no association between liver toxicity and a specific drug or regimen (r/lopinavir 6%, efavirenz 2%, nevirapine 7%, abacavir 4%, or use of 4 drugs 3%), but the risk was higher for HCV-positive patients.
The authors concluded that the current use of antiretroviral regimens is associated to a lower rate of liver toxicity than previously described. HCV coinfection continues to be the main risk factor for hepatotoxicity in our population.
33% of Coinfected Patients with Normal ALT have Advanced Fibrosis, Serious Liver Disease and Therefore Should Be Considered for Peginterferon/ribavirin Therapy
"Liver Fibrosis Stage in HIV/HCV-Coinfected Patients with Persistently Normal Transaminases Levels"
ICAAC, Dec 2005.
Authors: I. MAIDA1, V. SORIANO 2, J. GONZALEZ-LAHOZ 2, M. NUÑEZ 2; 1Univ. of Sassari, Sassari, Italy, 2Hosp. Carlos III, Madrid, Spain.
Poster H-1483
About 30% of HCV monoinfected patients have ALT levels within normal limits (WNL), and 11-19% of them show significant histologic liver damage. Therefore it has been suggested that patients with normal ALT should be evaluated for HCV treatment. We have examined the proportion of HIV/HCV-coinfected subjects with normal ALT and assessed the degree of fibrosis.
From an HIV/HCV-cohort we identified patients never treated for HCV and with detectable plasma HCV RNA and persistently normal ALT levels throughout the prior 12 months of follow-up (≥ 4 determinations). Presence and grade of fibrosis was evaluated by FibroScan.
Out of 279 HCV RNA+ patients, 25 (8.9%) had persistently ALT WNL.
Chraracteristics: 19 (76%) male, 24 (96%) IDUs), 21 (84%) on HAART, median (Md) age 40, Md CD4 638 cel/mm3 (29%), Md HIV RNA <50 cops/mL, Md HCV RNA 519,000 IU/mL, Md ALT 35 IU/mL, Md AST 37 IU/mL. HCV genotypes: HCV-1, 13 (56.5%); HCV-2, 1 (4.3%); HCV-3 1(4.3%); HCV-4, 8 (34.8%).
FibroScan results were as follows: F1 8 (47.1%), F2 4 (23.5%), F3 2 (11.8%), F4 3 (17.6%).
A trend among patients with HCV-4 genotype (50%) to have more often severe fibrosis (F3-F4) was observed compared to genotype HCV-1 (11.1%) (p= 0.07).
The authors concluded that: 9% per cent of HIV-infected subjects with detectable HCV RNA present persistently normal transaminase levels, being HCV-1/4 genotypes more frequent than HCV-2/3.
Nearly one third of HIV-infected patients with chronic HCV infection and persistently normal ALT have advanced degrees of liver fibrosis. HCV-4 genotype shows a trend to have higher degrees of fibrosis.
Incidence and Risk Factors for Weight Loss During Dual HIV/Hepatitis C Virus (HCV) Therapy: coinfected patients are more likely to lose weight on peginterferon/ribavirin therapy than HCV monoinfected and lose more weight
ICAAC, Dec 2005.
V. LO RE, J. KOSTMAN, R. GROSS, R. REDDY, K. MOUNZER, M. PUTT, I. FRANK, B. STROM;
Univ. of Pennsylvania, Philadelphia, PA.
Poster V-612
Background: Case reports suggest that HIV/HCV patients lose weight during dual therapy. Mitochondrial toxicity from nucleoside analogues used for HIV/HCV therapy may explain such weight loss. We compared the incidence and degree of weight loss among HIV/HCV patients receiving antiretroviral therapy (ART) and pegylated (PEG)-interferon + ribavirin (RBV) to: 1) HCV-monoinfected patients receiving PEG-interferon + RBV, and 2) HIV-monoinfected patients receiving ART. Hypothesized risk factors for weight loss included the type and number of nucleoside analogues and RBV dose.
Body weights in HIV/HCV and HCV subjects were checked up to 6 months prior to and up to 12 months after initiation of HCV therapy, and weights for HIV-monoinfected subjects were checked over 18 months on ART, all retrospectively. The primary outcome was clinically significant weight loss (≥ 5% of baseline weight).
Of 192 subjects, 63 had HIV/HCV, 64 had HCV alone, and 65 had HIV alone.
Clinically significant weight loss occurred in 48 (76%; 95% CI, 65-87%) HIV/HCV subjects compared to 25 (39%; 95% CI, 27-51%) HCV subjects (p<0.001) and 2 (3%; 95% CI, 0-7%) HIV subjects (p<0.001).
The RR (95% CI) for clinically significant weight loss in HIV/HCV subjects was 1.95 (1.39, 2.73) compared to HCV subjects and 24.8 (6.3, 97.6) compared to HIV subjects.
The degree of weight loss over 3-month intervals was greater in dually treated HIV/HCV subjects vs. treated HCV (-5.14 kg vs. -2.95 kg at 6 months, p=0.03; -6.92 kg vs. -2.57 kg at 12 months, p=0.07) and treated HIV subjects (-5.14 kg vs. +0.90 kg at 6 months, p<0.001; -6.92 kg vs. +1.48 kg at 12 months, p<0.001).
The type and number of nucleoside analogues and RBV dose were not significant risk factors for weight loss.
The authors concluded: The incidence and degree of weight loss are greater in dually treated HIV/HCV patients vs. treated HCV or HIV patients. Future studies should evaluate changes in body.
PSI-6130 is a Potent and Specific Inhibitor of Hepatitis C Virus in Huh-7 Cells
ICAAC, Dec 2005
M. J. OTTO1;
1Pharmasset, Inc., Tucker, GA, 2Emory Univ. & VA Med. Ctr., Decatur, GA.
Poster F-481
Nearly 2% of the U.S. population and an estimated 170 million people worldwide are HCV carriers. The current standard of care is a combination of pegylated interferon and ribavirin that has limited efficacy. We have identified a pyrimidine nucleoside analog, E-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine (PSI-6130), which is a specific, potent and non-cytotoxic inhibitor of HCV in the HCV-subgenomic replicon assay.
Anti-HCV activity was measured using subgenomic-HCV replicon cells (Clone A cells, Apath, LLC) and a real-time PCR assay previously described by Stuyver et al. (AAC, 2003). Antiviral activity against bovine viral diarrhea virus (BVDV) was also determined. Cytotoxicity was assessed by the MTS assay method in human HepG2, Huh-7, CEM and PBM cells. Mitochondrial toxicity was evaluated in a 14-day assay with HepG2 cells by assessing the levels of mitochondrial DNA and RNA.
An EC90 (concentration producing 1 log10 reduction in viral RNA) value of 4.6 ± 2.0 E M was determined for PSI-6130 in the HCV replicon assay and compared to 2'-C-methylcytidine, 2'-C-methyladenosine and Eo-interferon with EC90's of 21.9 ± 4.3 E M, 2.1 ± 0.27 E M, and 4.5 IU/ml, respectively. Unlike 2'-C-methylcytidine and 2'-C-methyladenosine, PSI-6130 was essentially inactive against BVDV. No cytotoxicity was observed with PSI-6130 in any of the cell lines tested (CC50 >100 E M) compared to 2'-C-methyladenosine (CC50 ~ 37 E M). No mitochondrial toxicity was observed with PSI-6130.
PSI-6130 demonstrated potent and specific anti-HCV activity in cell-based assays. The nucleoside was approximately 5-fold more potent than 2'-C-methylcytidine and 2-fold less potent than 2'-C-methyladenosine in our hands. Our findings support the further development of PSI-6130 as a specific treatment for HCV infection.
HIV ART Drug Levels were Higher in Cirrhotic Coinfected Patients Compared to Non-cirrhotis Coinfected Patients: TDM og ART in Coinfected Patients May Be Useful
"Influence of Liver Fibrosis on Plasma Levels of Non-Nucleoside Analogs and Protease Inhibitors in HIV+ Patients"
ICAAC Dec 2005
Author: P. M. BARREIRO, Hosp. Carlos III, Madrid, Spain.
Poster A-217
Background from authors: All PIs and NNRTIs are metabolized in the liver, so that lower doses should be provided in patients with hepatic insufficiency. Little is known on the impact of liver fibrosis on the levels of PIs or NNRTIs.
Plasma drug levels were analyzed by HPLC in subjects receiving nevirapine (NVP), efavirenz (EFV), lopinavir/r (LPV) or atazanavir (ATZ) for longer than 12 weeks. Liver fibrosis was estimated by transient elastography (FibroScan), an imaging method recently validated in comparison with liver biopsy.
Results: A total of 82 HIV/HCV-coinfected patients without prior liver decompensation were analyzed: 7 on NVP, 9 on EFV, 40 on LPV and 26 on ATZ.
Mean Cmin was: NVP 4.7±2.2 ug/ml; EFV 3.0±3.1 ug/ml; LPV 5.7±3.0 ug/ml; ATZ 0.6±0.7 ug/ml.
Mean liver stiffness at elastography was 8.2 (IQR, 5.9-12.1) KPa.
The distribution of patients according to elastographic estimation of the Metavir score was: F0-F1 (<7.1 KPa) 40%; F2 (7.1-9.4 KPa) 25%; F3 (9.5-12.5 KPa) 12%; F4 (>12.5 KPa) 23%.
Mean drug levels were higher in cirrhotic patients (>12.5 KPa at liver elastography) as compared with non-cirrhotics, both for EFV (7.1 vs 1.8 ug/ml, p<0.01) and ATZ (1.2 vs 0.5 ug/ml, p<0.01).
Mean liver stiffness was higher in subjects with drug levels above the therapeutic range as compared with those with lower values: 19.6±9.7 vs 6.7±5.0 KPa for EFV > vs <4 ug/ml (p<0.01); and of 23.6±24.7 vs 9.7±3.5 KPa for ATZ > vs <0.8 E g/ml (p<0.01). Plasma levels of NVP or LPV did not differ when comparing cirrhotic and non-cirrhotic patients. (note from Jules Levin: the reliability and predictability of the liver stiffness test is NOT well established.)
Conclusions: Liver clearance of EFV and ATZ seems to be reduced in asymptomatic cirrhotic patients, what translates into higher plasma drug levels. They might benefit from pharmacokinetic monitoring to avoid drug overexposure. Liver fibrosis assessment by non-invasive tools may permit to identify HCV/HIV-coinfected patients that warrant antiretroviral dose adjustment in order to minimize toxicities.
|
|
| |
| |
|
|
|
|
|
