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Hepatitis C Report from the Retrovirus Conference: report 1
Reported by Jules Levin
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Several studies at Retrovirus reported HIV accelerates HCV progression, and coinfected patients get sick more often: they more often experience any grade 4 clinical event and grade 4 liver-related events, and quicker death (abstract 657-M, Reisler; abstract 658-M, Rimland). This is in part due to the populations infected with both HIV and HCV.
HIV May Impair Immune Response to HCV
Several basic science in vitro (test tube) studies reported at Retrovirus show HCV/HIV coinfected patients have an impaired immune response to HCV, even though they can respond well to HIV and have good CD4 counts and low HIV viral load (for example, abstract 640-M, Lauer, Mass General; abstract 121, Torriani, UCSD).
Women Coinfected
One study reported 20% of the 400 HCV/HIV coinfected patients at Virginia Commonwealth University and Medical College of Virginia were women. 86% were African-American, and 75% reported IVDU as the main risk factor for getting HCV (abstract 664-M, Tsogas).
HCV May be in Brain & Cervical Lavage (CVL)
Nine HCV/HIV positive women from the WIHS (Women Inter-Agency HIV Study) were tested for HCV RNA in plasma and cervical lavages (CVL). HCV RNA was detected in the blood and plasma of 5/9 women (abstract 648-M, Nowicki, USC). The authors suggest there may be a separate compartment for HCV in CVL and this may play a role in vertical (pregnant women-to-newborn) and sexual transmission.
HCV-infected patients have reported experiencing fatigue, depression, and emotional distress & anxiety. Several studies have suggested this is true and that HCV may be able to enter the brain. A study at Retrovirus reported that HCV RNA was found in autopsy brain tissue samples from 3 of 6 patients tested (one patient was HIV+). (abstract 649-M, Laskus, Mayo Clinic). The type of HCV strain found suggested that HCV could replicate in the brain. The findings suggested HCV could be carried across the blood-brain-barrier by HCV-infected lymphoid cells in a process similar to that in HIV.
Poor Care For Coinfected: 40% coinfected in SF care system
Marion Peters and a group from UCSF reported on 4000 HIV+ patients and hepatitis patterns in the San Francisco Community Health Network from June 1996 to July 2000. Hepatitis test results were available for 2900 patients (76%). 40% had HCV and 9% HBV. Many patients with hepatitis had normal ALT (liver enzymes). High rates of persistently elevated ALT levels among coinfected patients may predict advancing liver disease. Doctors were providing HIV HAART treatment less often to HCV-infected patients, regardless of their HIV disease status, lifestyle, and ALT levels (abstract 662-M).
HCV/HIV coinfected patients are not receiving hepatitis A vaccines and drink too much. The US Public Health service Guidelines recommend hepatitis A vaccine for coinfected patients, and advises they abstain from alcohol to avoid progression to liver failure. Teshale from the CDC (abstract 665-M) analyzed data from 14,000 patients from the Adult/Adolescent Spectrum of HIV Disease project (1998-2001). This is an ongoing observational database of HIV+ patients in 11 cities. 13% of patients were reported to be coinfected with HIV and HCV. I suggest this is an underestimate, when compared to the many other studies finding higher rates. The underestimate could perhaps be due to not adequately testing all HIV+ persons. 26% of coinfected persons were female. 45% were black, 28% were white, and 26% were Hispanic. 50% were IVDUs, 17% were men who have sex with men, and 34% were IVDU/MSM. Perhaps most important, only 6% of the coinfected and 7% of the HIV only-infected were vaccinated for hepatitis A. 36% of coinfected patients used alcohol before being tested for HCV and 20% reported drinking after learning they had HCV. The authors recommended education and awareness programs be provided to doctors regarding the need to vaccinate coinfected patients with the hepatitis A vaccine, and to help coinfected patients stop using alcohol.
Pegylated Interferon (Pegasys) plus Ribavirin Treatment in Coinfected Patients: 80% had high viral load & genotype 1
ACTG study 5071 compares the effectiveness & safety of Pegasys + ribavirin to standard interferon + ribavirin. Patients with compensated cirrhosis were permitted into the study. As well patients with CD4 >100 and HIV viral load <10,000 on stable ART were permitted to enter study. But for patients who were HIV treatment-naïve their CD4 count had to be >300. 133 patients were randomized to receive pegasys 180 ug once per week by subcutaneous injection or standard interferon 6 MIU 3 times per week for 12 weeks followed by 3 MIU 3 times per week, also by subcutaneous injection. All study patients started therapy with 600 mg of ribavirin per day and increased dose to 1000 per day. This was done to limit the side effects during the initial stages of therapy and to improve remaining on study drug. Study treatment is for 48 weeks with a 24 week followup period. The sustained virologic response is evaluated at the 72 week time-point.
80% of the study patients were men; 33% African-American; 14% Hispanic; 49% White;45 years old; median CD4 count was 450-500; 60% of patients had <500 copies/ml; 90% were on HIV therapy. The median Karnofsky score was 90.
The average HCV viral load was 6.2 million; 83% of patients had >6 million viral load. And 78% had genotype 1; 68% had abnormal ALT; median HAI score 5.0 (out of 18); median fibrosis score 2.5; 10% had cirrhosis (fibrosis score 5-6). So, the two patient groups were comparable.
RESULTS
By intent-to-treat analysis, 15% patients receiving standard interferon/ribavirin (10 of 67 evaluable patients) had <100 copies/ml HCV RNA; this compared to 44% of patients receiving Pegasys/ribavirin (29 of 68 evaluable patients) who had undetectable (<100 copies/ml) of HCV viral load (p=0.0003).
Patients with genotype 1: 33% (17/51) of patients receiving Pegasys/RBV had undetectable HCV RNA vs 7% receiving standard IFN/RBV (p=0.0014).
Non-genotype 1 patients: 80% (Pegasys/RBV) vs 40% (IFN/RBV) (p=0.06).
About 50% of patients were able to normalize their ALT.
About one-third to half of the viral nonresponders had a biopsy at week 24 and 26-40% had histologic improvement. This is very encouraging, suggesting that a viral response may not be necessary to see improvement in the liver of coinfected patients.
Adverse Events
There were 17 grade 4 AEs in the Pegasys group vs 4 in the interferon group, but the discontinuation rate was only 12% and it was the same for both groups. Leukopenia (low white blood cell count) was reported more often in the Pegasys arm but was successfully managed by dose reduction or GCSF or both. Both treatment groups reported about equal numbers of grade 2 and 3 adverse events.
Absolute CD4 counts declined by 80 (from 450 to 370) in the interferon group by week 24, and by 120 in the Pegasys group (500 to 380). But the CD4% did not decline.
There was no apparent effect on HIV viral load during therapy. Some patients who had undetectable HIV before starting HCV therapy became detectable (5%-10%), but some patients with detectable HIV viral load before HCV therapy became undetectable (10%-18%).
The predictors of viral response (by multivariate statistical analysis) were: receiving Pegasys (p=0.004); white race (p=0.016); Karnofsky score = 100 (p=0.046); fibrosis score 0-2 (out of 6) (p=0.021).
Dr Chung emphasized that it is important to identify patients with HCV early in their disease stage (early testing). This is underscored by the better response to therapy for patients in this study with low fibrosis scores.
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