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Peg/RBV treatment, liver transplants, RBV/nuke interaction study, HCV & HAART response
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Reported by Nancy Shulman, MD, Stanford University
TOPICS
-- Treating coinfection with pegylated interferon plus ribavirin: final 72-week results from 3 major studies
-- Ribavirin interactions with nucleosides
-- Does HCV impair immune reconstitution after HAART?
-- Transplants in HIV+ patients
Treatment of HCV in HIV-infected patients: Final results from 3 randomized trials including pegylated interferons
HCV is an ever increasing problem in people with HIV and many are being treated or thinking about treatment for their HCV. Although we predict that HIV-infected patients would respond less than patients who are HIV negative, we have had sparse data on treatment responses in the HIV-infected patients. Finally, the results from 3 large randomized studies enrolling over 1300 patients in total were presented at the CROI: ACTG 5071, APRICOT, ANRS-RIBAVIC trials.
ACTG 5071 was an NIH sponsored study that enrolled 133 HIV/HCV patients in the US. Half received regular interferon alfa-2a 6 million units 3 times a week for 12 weeks, then 3 million units 3 times a weeks for 36 more weeks, all with ribavirin starting at 600mg per day and increasing to 1000mg as tolerated over 6 weeks. Half received Pegylated interferon alfa-2a (Pegasys, Roche) 180ug per week with the same escalating dose of ribavirin as the first group for 48 weeks. Patients had to be HIV+, HCV RNA +, CD4>100 and HIV VL>10,000 if they were on treatment, and any viral load, but CD4 >350 if they were off treatment. Abnormal ALT was not required. The patients overall had median CD4 counts of 444 and 492 in IFN and Peg arms respectively, and most patients were on HAART. 78% were genotype I (the more difficult to treat) and 66% had abnormal ALT levels. The median level of fibrosis (scarring) on a 0-6 scale was 2 in both and overall only 10% had substantial amounts of scarring (5-6). One-third were African-American and 12% Latinos, both groups who have historically been less responsive to HCV treatment.
Sustained virologic response rates were 27% overall in the Peg arm vs. 12% in the regular interferon arm. In genotype 1 the rates were a dismal 14% vs. 6%. Of note over 50% of patients with genotype 1 on Peg relapsed after treatment was discontinued which may be due to the lower, escalating dose of ribavirin. Ribavirin has been shown to reduce relapse rates associated with interferon and the per kg dose of ribavirin has been shown in multiple trials to be important. Had they started with higher doses of ribavirin (1000mg or 1200mg), the results might have been better. For genotypes 2/3 the rates were 73% (similar to HCV-mono-infected) in the Peg arm and 33% in the non-peg arm. 54% of responders and 36% of non-responders had substantial histologic improvement of their liver biopsies with the treatment which was similar in both arms. Only 12% overall discontinued and this was even across both arms. CD4 counts went down with interferon, but came back to baseline after stopping interferon.
The APRICOT study was a large multicenter international Roche-sponsored trial that had 3 arms, IFN alfa-2a 3 million units 3 times a week with Ribavirin 800mg/day, Pegylated IFN alfa-2a (Pegasys) 180ug per week plus placebo, or Peg 180ug per week plus Ribavirin 800mg/day, all for 48 weeks. There were 860 patients who received at least one dose of treatment. Patients had to have CD4 >100, elevated ALT, HIV+, and be HCV RNA+. 78% were white, 15% had cirrhosis, 60% were genotype 1, mean CD4 counts were over 500 in each arm and 2/3 had undetectable HIV RNA levels.
The sustained response rate overall was 40% in the Peg + Ribavirin group, 20% in the Peg + placebo group and 12% in the regular interferon + ribavirin group. For genotype I the results were 29%, 14% and 7% respectively. For genotypes 2/3 the results were 62%, 36% and 20%. Drop out rates were high with 25% in the Peg + Ribavirin group and 40% in the standard interferon + ribavirin group, mainly due to ineffectiveness and the drop outs due to side affects were about 12% across all arms. CD4 counts decreased but the CD4% increased during interferon therapy. In those patients with detectable HIV RNAs, the HIV RNA decreased by nearly a log due to the interferon anti-HIV affects.
The RIBAVIC Study (ANRS HCO2) was a French government sponsored trial that randomized 205 patients to receive Peg-alfa interferon-2b (Peg-Intron, Schering) 1.5ug/kg + Ribavirin 800mg/d and 207 patients to receive interferon alfa-2b 3 million units 3 times a week for 48 weeks. Patients had to have CD4>200, stable HIV RNA levels, detectable HCV RNA. Two-thirds had undetectable HIV RNAs, most were on HAART, 80% had a history of IV drug use, 58% were Genotype 1, and 40% had bridging fibrosis or cirrhosis (more advanced disease than the first 2 trials).
The sustained response rate was 27% in the the Peg group vs. 15% in the regular IFN group, the genotype 1 results were 15% and 5% respectively. Genotype 2/3 46% and 40%. Dropout rates were high (42% of the patients overall divided equally among the two arms, 31% for adverse events. Virologic responders had an improvement in their imflammation on biopsy, while the non-responders had little improvement overall when looking at the median scores before and after. The presenter did not mention if any and how many patients improved their biopsy appearance.
The three studies showed that Pegylated interferons are superior to standard interferon therapy in HIV+ patients with HCV. The results for genotype 1 are poorer than in HCV monoinfected. In contrast, HIV+ patients who have Genotype 2 or 3 do nearly as well as mono-infected patients. All of the studies used lower doses of ribavirin which may have reduced the sustained response rates. In addition, all the studies showed that like in HCV mono-infected studies, if by 12 weeks there is not a 2-log reduction in HCV viral load from baseline, there will not be a sustained virologic response. This is the case nearly 100% of the time. The largest trial, the APRICOT study had the best results. In the ACTG study, there was a high % of African Americans and Latinos who generally respond poorer to interferon treatment. In addition, the ribavirin was initiated at a low 600mg per day and titrated upward which may have decreased the response rates. We learned that early doses of ribavirin are important from the HALT-C trial in mono-infected patients. The RIBAVIC study enrolled patients with more advanced liver disease, more IV drug users, and had very high drop out rates, all of which could have decreased the response rates. RIBAVIC also used Peg-Intron which has a less optimal pharmacokinetic profile than Pegasys which was used in the other trials.
Histologic benefits were seen in responders and non-responders in the ACTG, in responders in the RIBAVIC, and in both in a poster presentation (4) of Peg + Ribavirin vs. Peg retreatment of prior interferon non-responders. This is seen also in mono-infected patients and is the rationale for using low-dose maintenance interferon in patients with advanced fibrosis who are non-responders to Peg + Ribavirin. Trials to assess the benefits of maintenance interferon in HIV+HCV+ are underway.
References:
- Chung, et al. Abstract 110, 11th CROI.
- Torriani, et al. Abstract 112, 11th CROI.
- Perrone, et al. Abstract 117LB, 11th CROI.
- Rodriguez-Torres, et al. Abstract 821, 11th CROI.
NATAP's Jules Levin reports on the 3 studies:
ACTG 5071: http://www.natap.org/2004/CROI/croi_14.htm
APRICOT Study: http://www.natap.org/2004/CROI/croi_5.htm
RIBAVIS Study: http://www.natap.org/2004/CROI/croi_15.htm
Ribavirin interactions with nucleosides
In vitro, ribavirin decreases the HIV activity of AZT, D4T, 3TC and DDC by competing for phosphorylating enzymes. Remember that the nucleosides must have 3 phosphate groups attached when they are inside the cell in order to be active against HIV. Ribavirin increases the DDI and Abacavir activity and has been associated with increased DDI related toxicities such as pancreatitis and lactic acidosis. The antagonism seen with AZT, D4T, and 3TC has been a potential concern in using these nucleosides with ribavirin to treat HCV in HIV-infected patients. Two studies were presented addressing the pharmacokinetics of intracellular nucleoside-triphosphate concentrations with ribavirin.
In an oral presentation, a substudy from the APRICOT study addressed this question. Patients beginning treatment with 800mg ribavirin or placebo with Peg Interferon had pharmacokinetic sampling at 0, 2, 4, 6, 8, and 12 hours after their morning nucleoside dose before starting ribavirin or placebo and 8-12 weeks after starting ribavirin or placebo. The ratios of intracellular drug-TP vs. the naturally occurring substrate were measured as 12 hour AUC (area under the curve concentration) ratios. The AZT-TP ratio decreased slightly, from 0.25-0.23 in 8 patients receiving AZT and Ribavirin. The AZT-TP ratio increased slightly in the 12 receiving AZT and placebo from 0.25-0.31. This was not statistically significant. 3TC-TP ratios D4T-TP ratios were also not significantly changed with ribavirin or placebo.
Another smaller study looked at pharmacokinetics in patients before and after starting 1000mg or 1200mg ribavirin. The same measurements in the above study were done at 3 and 14 days post treatment. Five patients on AZT had a reduction of intracellular AZT-TP: dTTP (the natural substrate concentration) ratio of 44% at day 3 and 14 after ribavirin was started, which was statistically significant. The D4T-TP ratios were not significantly changed. The 3TC-TP ratio increased at day 3 and went back to baseline at day 14. The difference in the two studies could have been the higher dose of ribavirin, but the oral presenter did not propose such a conclusion. In any rate, the interaction does not seem to impair HIV RNA control in any of the studies seen. This may be because the anti HIV activity of interferon trumps any loss of AZT activity.
References:
- Gries, et al. Abstract 136LB, 11th CROI.
- Hennessy, et al. Abstract 822, 11th CROI.
Does HCV impair immune reconstitution after HAART?
The Swiss cohort study initially found lower CD4 count increases after initiating HAART in HIV+ patients who had HCV vs. those who were HCV-. Subsequent studies have revealed conflicting data when they factor in HIV viral load suppression. Again, two posters had conflicting results.
The EuroSIDA cohort includes data from patients all over Europe and includes Argentina. About 5000 patients had a known HCV status and were used in the analysis. HCV+ were more likely have liver-related morbidity and mortality, but had no increased risk for AIDS or death after controlling for other things like CD4 count upon entry into the cohort study, HAART, prior AIDS diagnosis, and several other demographic variables. In addition, if an immune response was defined as >50% increase in CD4 count, no difference in proportion of immune responders to HAART was seen in HCV+ vs. HCV-. They did not analyze absolute number of T-cell increases in each group.
Another small study from Buenos Aires evaluated a database of clinical trials performed and assessed the CD4 increase in antiretroviral naïve patients who had HIV RNA <400 copies on study. The 33 HCV+ patients had a lower overall absolute increase in CD4 counts (median 230 increased to 300 at 48 weeks) vs. the 180 HCV- (median 269 increased to 440 at 48 weeks).
One group from NY attempted to see what happens to CD4 after HCV is cleared with interferon or Peg interferon + ribavirin. Sixteen sustained responders were compared with 23 non-responders. They reportedly had similar baseline characteristics (number undetectable HIV VL, baseline CD4 counts, etc.) The responders had a mean 61 CD4 cell increase from baseline prior to IFN treatment vs. a mean 79 cell loss in the non-responder group. It was not clear to me on the poster how they selected the 39 subjects from their larger treatment cohort group of 85 patients which may have biased the results of the analysis, but it was an intriguing observation. It will be interesting to see a larger analyses like this one from the 3 larger trials reported above.
References:
- Rockstroh, et al. Abstract 799, 11th CROI.
- Zala, et al. Abstract 817, 11th CROI.
- Uriel, et al. Abstract 825, 11th CROI.
Transplants in HIV+ patients
There were 3 posters on transplants in HIV+ patients. The USCF group reported their experience with 14 kidneys, 9 livers (4 with HCV, 5 with HBV), one patient had both kidney-liver transplant. 8 of 9 liver transplanted patients survived and 13/14 kidney transplanted patients survived a median follow up period of 480 days (8-1234days range). The death in the liver transplant was from recurrent HCV/graft failure at 15 months post transplant. The death in the kidney transplant was from congestive heart failure. They had a high rate (70%) of acute rejection in the kidneys that warranted increased immunosuppression. The website for their multicenter transplant study is spitfire.emmes.com/study/htr/ for more information.
Twenty-one HIV+ patients have received liver transplants in Spain, 17 for HCV, 2 for HBV, and 2 for HCV+HBV. Nineteen were from cadavers and two received a portion of a liver living related donors. 19 are alive at a median of 8 months of follow up (range 1-24 months). One died of sepsis at 3 months after transplant and one died at 14 months from HCV relapse/graft failure. They had 8 cases of acute rejection. Fifteen patients had recurrence of HCV in the graft between 1 and 12 months after transplant. Seven started peg+ribavirin.
A group from Paris reported results of 11 liver transplants, all HIV/HCV+. Three patients died, two of recurrent HCV/graft failure at 22mo and 4 mo, and one died of cancer of the pancreas 11 months after transplant. HCV recurred in all patients.
The data looks pretty good for liver transplant survival when compared to HIV-. The main issue is recurrent HCV and many institutions who are transplanting patients now are putting them on Peg + Ribavirin at the first sign of recurrence to protect the graft. The groups all reported difficulty in managing the complexity of drug interactions between the antiretrovirals and the immunosuppressants.
References:
- Roland, et al. Abstract 836, 11th CROI.
- Rufi, et al. Abstract 837, 11th CROI.
- Teicher, et al. Abstract 828, 11th CROI.
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