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  DDW Liver Conference
San Francisco, May 19-22, 2002
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HCV/HIV Coinfection at DDW Liver Conference
Reported by Jules Levin
  There was not much on HCV/HIV coinfection treatment at DDW. Discussed below are the 3 treatment studies I found, and an additional study showing nonresponders can achieve improved disease progression despite no viral load response. I think these 3 clinical treatment studies have too many limitations to accurately reflect the response to therapy by coinfected patients. For one, the percent of genotype 1 patients in these studies is lower than the percent of genotype 1 patients in the USA. This has the effect of making the study results seem better than they would in the USA. Two of the 3 studies are too small. None of the 3 studies included African-Americans; in only one study were hispanics included, and this study had 5 hispanics. Since it appears as though African-Americans do not respond as well to HCV therapy, these study results do not reflect the community and overstate expected results. Only 1 of these 3 studies was conducted in the USA.
One of the lackings in research is that there is a need for quality study data in coinfected patients. The ACTG 5071 study is ongoing and interim results were reported at the annual Retrovirus Conference reporting preliminary 44% sustained responses at week 24 for patients receiving Pegasys+ribavirin compared to 15% for patients receiving standard interferon+ribavirin. Patients received a dose escalation of ribavirin at the start of therapy so this may have had an effect of reducing the response rate. This was done to limit the ribavirin side effects. Although the results are preliminary 44% was disappointing. We should wait for the final study results so we can better understand why these results were seen.
DDW Report
D Oliver et al (UCSD-San Diego) reported in a poster at DDW on 14 coinfected patients they treated with interferon alfa-2b plus ribavirin for 24 or 48 weeks. These patients were treated from 7/99 to 12/00. So this is a bit dated and the study is too small to draw conclusions. All patients had stable HIV disease with 8 of the patients receiving HAART. 50% of the patients had undetectable HIV. The mean CD4 count was 370, with 3 patients having CD4 counts <200. The patients were 12 men, 9 caucasians, 5 hispanics (no African-Americans), 7/14 IVDUs, 3 got HCV from blood products, and 4 from multiple sex partners.
8/14 were genotype 1 (56%). This is a small percentage of genotype 1 patients for the US, making the results seem perhaps better than would normally be seen in the US. . In the US 70% have genotype 1. 6/14 patients (43%) were sustained responders; 3 of the 6 responders were genotype 1. There were 2 relapsers (14%). 6 patients were nonresponders, and 4/6 (66%) of them were genotype 1. The nonresponders discontinued therapy at week 24. Two patients discontinued due to adverse events: myalgia/arthralgia; thrombocytopenis (low platelets).
4/14 patients had cirrhosis (35%) but the authors did not report on the response by stage of disease, And 2 patients had stage 1 disease. There were 4 interferon dose reductions: from 3 MU once daily to 3 MU 3x/week; from 5 MU once daily to 3 MU once daily; from 5 MU once daily to 3 MU once daily; from 5 MU once daily to 3 MU once daily. The authors did not make it clear in the poster what interferon doses all the patients were getting. Four patients reduced ribavirin doses from 800 to 600 mg per day due mostly to anemia.
This appears to me to be a poor study. The number of patients is too small to draw conclusions. The number of patients with genotype 1 is too small and that inflates the response rate. There were no African-Americans in the study therefore not reflecting the coinfected community.
V Cargnel from Italy reported on a study conducted at the University of Milan. She reported that in 1990 5% of HIV+ patients died of liver disease and in 2000 it was 38%. In this study, patients received one of 2 regimens: PegIntron 1.5 mcg/kg plus ribavirin 800 mg/day (n=59) or PegIntron 1.5 mcg/kg monotherapy(n=63) for 48 weeks with a 24 week followup period.
All patients had <400 HIV RNA and CD4s >300, and were HCV treatment-na´ve. About 120 patients are enrolled, mostly IVDUs. Mean CD4s are about 580, ALT 144, HCV-RNA 1 million. 40% of patients receiving Peg/RBV had genotype 1 while 50% of those receiving Peg monotherapy had genotype 1. Again, these percentages do not reflect the percentage of patients with genotype 1 in the US, which is 70%, and 80% in coinfection. So these study results may be higher than would be seen in the USA>
49 patients have completed at least 24 weeks of therapy. 17 patients (35%) have negative PCR: 14/25 receiving Peg/RBV and 3/24 receiving only PEG). 56% (14/25) were PCR negative at week 24 on Peg/RBV but this was an on-treatment analysis. In other words 30% (18/59) of patients receiving Peg/RBV discontinued therapy mostly in the first month, due mostly to side effects and they were not counted as failures. If they were counted as failures the 56% rate would be lower. Only 17% (4/23) with genotype 1 had negative PCR compared to 50% (13/26) with genotype 2/3, of patients receiving Peg/RBV. Intolerance or flulike symptoms were the most common cause for discontinuation (13%); 5.7% discontinued due to non-compliance; 1.6% for depression; 3.3% for hemotologic toxicity; 1.6% for rash.
Responders tended to have much steeper reduction in viral load in the first month than nonresponders. Cargnel reported that a HCV-RNA drop of > 2 log by month 2 is associated with a virologic response at month 6. Nonresponders had a viral load drop of 1.72 log or less by month 2. Nonresponders had a 1.63 viral load drop at month 6. Responders averaged a viral load drop of 3.18 log or more, and had a 3.94 or more viral load drop at month 6. Cd4s decreased from 581 to 452, but there was no change in HIV viral load. PegIntron was reduced to 0.75 mcg/kg in 12 patients; ribavirin to 600 mg in 2 patients. No lactic acidosis was observed, nor any life threatening adverse events.
Mannah et al from Germany reported on the efficacy, tolerance and safety of high dose induction interferon-2b plus ribavirin in HIV-coinfected patients in an open prospective study. 23 HIV/HCV-coinfected patients (median age: 41) 18 male and 5 female were treated for 2 weeks with ribavirin 1200mg/day alone to assess changes in endogenous IFN levels. All patients were naive for anti-HCV therapy. Subsequently, patients received IFN (5 MU/once per day) plus RBV (600 mg/bid) for the next 10 weeks. Thereafter patients received standard IFN (5 MU 3x/week) in combination with RBV (1200mg per day) up to week 48. 14 of the patients (61%) received concomitant highly active antiretroviral therapy.
At baseline median values were: HIV-RNA 990 copies/ml, CD4-count 536, CD4-percent 30%, and alanine aminotransferase (ALT) 70. Median HCV-RNA was 1 million copies/ml. 13 patients (57%) had a HCV-genotype 1 infection. Again, a lower percent of genotype 1 than seen in the USA.
Within the first two weeks of RBV monotherapy no significant change of endogenous IFN levels were observed. After 3 months of therapy 10/23 individuals (43%) showed an early virological response (defined as HCV-RNA < 500 IU/ml = limit of detection). End of treatment response at week 48 as well as sustained response at week 72 was 13% (3/23). 20/23 (87%) patients discontinued treatment before week 48. Reasons for treatment discontinuation were: virological non-response (n=10), severe interferon-related side-effects (n=2), anemia (n=2), pancreatitis (n=1), depression/aggressivity (n=3), severe CD4-count decrease (n=1) and active substance abuse (n=1). So, 50% of the discontinuations were due to adverse events.
The low response rate was associated with the high dropout rate adverse events. The authors suggested that dose intensification of interferon is associated with significant toxicity in HIV/HCV coinfected patients and thereby limits positive treatment success.
HCV /HIV Nonresponders Experience Improved Disease Progression
Maribel Rodriguez from Puerto Rico reported on the histologic response of 28 HCV/HIV coinfected patients receiving HCV therapy. This study found an important result. As we know, some patients with HCV or HCV/HIV will not achieve the desired viral load response (undetectable or a clear reduction in viral load). What this study found was that HCV/HIV coinfected patients who do not achieve a viral load response to HCV therapy (nonresponders) were able to achieve an improvement of liver disease. Both fibrosis and inflammation improved despite no response in viral load. These types of benefits have been seen in HCV moninfected patients. This is the first study I know of showing this benefit in HCV/HIV coinfected patients. The study looked at patients with biopsy before and after treatment. The study is small and the results preliminary but they found that:
(1) the fibrosis progression rate reversed in the patients receiving interferon but not in the patients who did not receive treatment;
(2) the study found liver disease activity (necroinflammatory score necroinflammatory progression rate) was reversed.
(3) The second biopsy was performed 1.5 years after therapy was stopped suggesting that the benefit can last that long.
This addresses the question --does maintenance therapy help when a patient does not achieve a viral load response? This is a controversial issue. There have been numerous studies that found interferon can improve liver disease and slow or prevent progression of disease and cancer. However, these studies have not conclusively proven that maintenance therapy actually slows or prevents disease progression and achieves clinical benefit. The HALT-C study is being conducted by the NIH to look at this question but results will not be available for several years. Smaller studies are ongoing or in planning stage to look at this question. In the meantime, patients have to make treatment decisions. A patient with cirrhosis who does not achieve a viral load response will have to consider maintenance therapy. The evidence so far accumulated suggests maintenance therapy is helpful. In treating patients, many doctors in fact use maintenace therapy for patients with advanced disease while waiting for more conclusive study results. Some doctors encourage monoinfected patients to enter the HALT-C Study.
Since the effect of INF in the liver histology is unknown, we evaluated 28 coinfected patients with pre and post interferon treatment liver biopsies. INF treatment was given for at least 6 months. Detailed history was assessed: age, gender, risk, alcohol , HIV treatment, and HCV duration. ALT, HIV RNA, HCV RNA, CD4 were also obtained. 23 patients (82%) received interferon Analysis of histology (fibrosis) using Ishak score was performed. Fibrosis score (0-5), necroinflammatory score (0-18), fibrosis progression rate and necroinflamatory progression rate were calculated. Mean duration of INF Tx was 11 Mo (6-22 Mo.).
Most patients were male (83%), with mean age 42.4 years, HCV Genotype 1 (86%), and no significant alcohol ingestion was documented pre and between both biopsies. Most patients (67%), were on HAART. Patients are immunocompetent with a mean CD4 of 473. The mean HIV RNA is 3.9 log (about 100,000 copies/ml) and 33% were HIV RNA non-detectable. Mean HCV PCR was 6.1 log (about 1 million) and mean duration HCV disease 18 years (9-42 years). Mean fibrosis score pre-treatment was 2.79 vs. 3.46 post treatment. The necroinflamatory score (NS1) was reduced from the first biopsy with a mean score of 7.96 vs. NS2 (post treatment) of 5.82; (p=0.013). In addition, necroinflamatory progression rate, NPR1 was reversed, between the two biopsies (NPR1) = 0.48 vs. NPR2 = - 0.59 (P=.03). ALT levels did not correlate with activity or fibrosis values at any point. In fact, ALT changes were inversely correlated to necroinflamatory scores at the post treatment biopsy (P=.04).
Rodriguez reported the INF treated vs. non-treated patients analysis show: FPR1 is .146 (N=18) vs .27 (N=5). The FPR2 is .172 and .24 respectively. The difference between the FPR2 and FPR1 is .4685 (N=5) vs -.6468 (N=18) for the IFN treated group. This difference is not significant In conclusion, INF Tx. in coinfected non-responders has a significant beneficial effect in activity. No conclusions can be reached in this population, regarding fibrosis progression, but the data suggests that fibrosis progression can be diminished with IFN Tx. Further follow up of liver histology and additional patients are needed to assess the long-term impact of treatment.