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Highlights of Treatment for HBV or HCV Coinfection
Written for NATAP by Raymond Chung, MD, Director of Liver Transplantation Program, Massachusetts General Hospital
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HBV Coinfection
A number of studies examined the efficacy to date of the use of nucleotide analogues against lamivudine-resistant HBV in coinfected subjects.
Adefovir for HBV in HIV Coinfected Patients with 3TC Resistance (abstract 123). This French study reported interim data from a planned 96 week study of adefovir dipivoxil (ADV) 10 mg daily added to existing antiretroviral therapy, including lamivudine. 35 patients were enrolled. All had detectable HBV DNA and documented lamivudine-resistant (YMDD mutant) HBV. HIV was well controlled. Mean drop in HBV DNA was -3.4 logs at week 24, -4.07 logs at week 48, and -4.77 logs at week 72. 4 pts became HBV DNA undetectable (<1000 copies/mL) at week 72, and 12% of the HbeAg+ pts became HbeAg-. Serum ALT also fell. In the 14 pts with paired liver biopsies at 1 year, median inflammatory scores and fibrosis scores dropped, the former significantly. HIV control was unchangesd. ADV was well-tolerated.
Tenofovir for HBV in HIV-Coinfected Patients (abstract 124). Tenofovir Disoproxil Fumarate (TDF) is another nucleotide analogue with demonstrated excellent activity against wild type and nucleoside-resistant HBV. This study was reported as part of the global Tenofovir HIV (Gilead 907) trial, in which 550 patients were randomized to receive either TDF 300 mg/d vs. placebo for 24 wks added to the preexisting antiretroviral regimen. 94% had HIV NRTI mutations at baseline. Of this group 14 (12 treatment, 2 placebo) were HBV coinfected, with HBV log10 DNA > 6 million. All were Lam (3TC)-experienced, 6 continued LAM. 7 had YMDD (3TC) mutations at baseline. Mean drop in HBV DNA was -4.63 logs in the treatment group, +1.23 in the placebo group (p=0.04) at 24 weeks. HbeAg seroconversion occurred in 1 patient. The drug was well-tolerated, and HIV reductions were similar to those with HIV monoinfection. No new HBV mutations were seen in followup testing.
Tenofovir (abstract 675). This study from France treated 10 patients on LAM (3TC) with TDF 300 mg daily added to their regimens. 12-week interim data were presented. All had YMDD (3TC) mutant HBV, 9 were HBeAg+. Median drop in HBV DNA was -3.34 log at week 12. The drug was well-tolerated. One patient with baseline elevated Creatinine (2.6) had drug stopped at week 12 because of an increase to 4.3.
FTC for HBV in monoinfected (abstract 674). Emtricitabine (FTC) is an NRTI with dual activity against HIV and HBV. 98 coinfected pts were randomized to receive 25, 100, and 200 mg/d FTC. At 1 year, 37%, 42%, and 61% in each group had undetectable HBV DNA, and 32%, 38%, and 50% lost HBeAg. The incidence of HBV mutants at one year was 12% in the two lower-dose groups and 6% in the higher-dose group. (editorial: the authors characterized this as a low incidence of mutations, particularly at the 200 mg dose). 3 patients discontinued due to adverse reaction, one in each dose group.
Comment
Taken together, these data mark the leading edge of promising new treatment options for HBV coinfection. Given the likelihood that combinations of nucleoside or nucleotide analogues will produce even greater suppression of HBV replication, we can anticipate that the era of combination chemotherapy for naive patients with coinfection is upon us. As we await the results of clinical trials for NRTI-naive coinfected patients, we can take some measure of comfort knowing that adefovir and tenofovir demonstrate efficacy in control of nucleoside-resistant HBV. The data for FTC seroconversion are quite encouraging, and suggest that combination trials in NRTI-naive patients employing this agent will be of interest as well. We can also expect to see clinical trials of other promising nucleoside or nucleotide analogues in the near-future that have demonstrated activity against wildtype HBV, mutant HBV, or both.
HCV Coinfection
Treatment
Several studies reporting outcomes of interferon (IFN) based-treatments in HCV coinfection were presented.
Pegasys (pegylated interferon) + Ribavirin in HIV Coinfected (abstract LB-15). This report, an analysis of interim week 24 data from the ACTG A5071 Protocol, compared the safety, tolerability and efficacy of IFN-alfa-2a + ribavirin versus PEG-IFN-alfa-2a + ribavirin in the treatment of HCV/HIV coinfection. 133 patients were randomized to the two arms, which included subjects either with moderately well-controlled HIV on ART (CD4 > 100, HIV RNA < 10K) or off ART (CD4 > 300). Subjects were also required to have detectable HCV RNA and an abnormal liver histology. The IFN arm received an induction regimen of 6MU tiw for 12 wks followed by 36 wks of 3MU tiw. The PEGIFN arm received 180 mcg weekly. Both arms underwent dose escalation of ribavirin (RBV), beginning at 600 mg/d and escalating by 200 mg/d every four weeks to a ceiling dose of 1000 mg/d. Because of concerns about toxicity of these regimens, virologic nonresponders (VNR) were required to discontinue study drug at week 24 unless a liver biopsy revealed histologic response (HR), defined as a 2 point or greater improvement in the histologic activity index.
Baseline HIV and HCV characteristics were comparable. 85% were on ART, 60% with HIV undetectable. HCV RNA log 6.2 million, genotype 1 78%, cirrhosis 10%. At week 24, the PEG was associated with a 44% virologic response compared with 15% for IFN. When VNRs who underwent Week 24 liver biopsies were analyzed, 40% in the IFN arm and 26% in the PEG arm experienced histologic response. Both treatments were well-tolerated, with permanent premature discontinuation rates of 12% in each arm. PEG was associated with more grade 4 events, many of which were neutropenia managed by dose reduction with or without G-CSF. Absolute CD4 fell in both arms, more so with PEG, but CD% actually increased at week 24. HIV RNA control was maintained, and a slightly higher number of subjects had undetectable HIV RNA at week 24 than at baseline. Multivariate analysis after adjustment for stratification variables (HCV genotype, ART use) showed that PEG-IFN treatment, white race, good performance status, and low fibrosis score were independently associated with week 24 VR. End of treatment and sustained virologic response data will be presented with study completion.
Daily vs 3 Times Per week Interferon in HIV/HCV Coinfected (abstract 651). An interim analysis was presented for HRN-002, a multicenter U.S. randomized study of IFN-alfa-2b with RBV in coinfection. This study compared IFN-alfa-2b 3MU tiw + RBV 800 mg/d vs. IFN-alfa-2b 3MU daily + RBV 800 mg/d. Stable ART > 4 weeks was included, CD4 > 100, HCV RNA+ with compensated liver disease. 180 patients were randomized to the 2 arms. Baseline characteristics were similar (80% genotype 1). Week 12 virologic response was 25% in the daily group and 10% in the tiw group. A large number (37; 23%) of subjects discontinued before week 12; 20 were due to adverse effects (10 in each group). The majority were due to psychiatric (n=10)or lab abnormalities (n=60. One of 16 (6%) patients who received ddI-based ARTdeveloped pancreatitis/lactic acidosis. No increase in HIV RNA was seen in patients receivin d4T or AZT with RBV.
Reduced Dose PegIntron in HCV/HIV Coinfected (abstract 652). This study from Spain examined PEG-IFN-alfa-2b + RBV therapy in 65 IFN-naive, coinfected subjects. This was an immunologically more preserved group, with CD4 > 300 and HIV RNA < 5,000 the entry criteria. PEG-IFN apfa-2b 150 mcg weekly (not given as weight based, but as highest flat dose) + RBV 800 were given for 6-12 months. As with other European studies, this cohort had a high frequency of genotype 3 infection (30%). End of treatment virologic response was 50% (10% genotype 1 or 4, 59% genotype 3), with sustained virologic response 33%. Adverse events led to permanent discontinuation in 14%. One patient on a ddI-containing regimen developed pancreatitis. RBV dose reductions were necessary in only 3% of patients. No adverse effects on HIV RNA were reported. Author noted weight loss of >10% was recorded in 70% of patients. One patient taking ddI developed pancreatitis. No increases in HIV viral load were seen
6 Months IFN+RBV Therapy in HCV/HIV Coinfected, Daily IFN vs 3 Times Weekly (abstract 653). Another study from Spain, the Spanish HIV Interferon Ribavirin Trial (SHIRT), a multicenter randomized trial, examined two dose schedules of IFN-alfa-2b with ribavirin. 111 subjects were randomized to receive either IFN-alfa-2b in standard fashion (3MU tiw) or given as a daily induction at 6MU for 6 wks followed by 3MU tiw for a total of 6 months. Both arms received RBV at 800 mg/d. 38% of the cohort harbored genotype 3, the rest genotype 1 (47%) or 4 (15%). Mean HCV RNA was 3.3 million, 66% had >2 million. End of treatment VR was 29% and SVR 22% (genotype 3 38%, genotype 1 or 4 12%); therefore, relapse rate was 23% in the 6 months after treatment was stopped. 70% of the responders had genotype 3. There was no difference seen between the two treatment groups. Treatment discontinuation occurred in 12%. No increases in HIV RNA or significant decreases in CD4 count were seen. The authors noted that the low response rates might be improved with 12 months therapy instead of 6 and increased RBV dose; and the discontinuation rate was low.
HCV Kinetics
Two presentations addressed the issue of the kinetics of HCV RNA clearance immediately after antiviral therapy in coinfected subjects. The first, performed in subjects receiving PEG-IFN-alfa-2a with or without ribavirin, suggested that HCV RNA clearance is slower than that observed in those with HCV monoinfection receiving daily conventional IFN-alfa-2a. However, a control monoinfection group receiving PEG-IFN-alfa-2a was not included. The second, a substudy of ACTG A5071, compared the kinetics of HCV RNA in subjects receiving either PEG-IFN-alfa-2a + RBV or IFN-alfa-2a + RBV. It found that PEG + RBV is associated with more rapid phase I and phase II kinetics than conventional IFN + RBV. Moreover, the predicted time to clearance projected by kinetic behavior correlated with observed clearance for all subjects studied, so perhaps whether or not clearance will occur may be predictable. Further data are forthcoming with respect to comparison of the coinfected group with monoinfected subjects receiving comparable regimens. (abstracts 121 and 122).
Comment
Taken together, these data show that combination regimens can be administered safely in HCV/HIV coinfection. PEG-IFN and ribavirin regimens will therefore likely emerge as standard of care among coinfected persons. Overall, response rates are lower than those seen in HCV monoinfection; the contribution of the generally reduced doses of ribavirin given in these studies may in part explain the lower rates, but do not fully explain the picture. When the diminished SVR rates are coupled with the finding of histologic improvement among a substantial portion of virologic nonresponders seen in ACTG A5071, a theoretical justification for trials of maintenance IFN therapy in coinfection is provided. Caution should be exercised in treating patients on ddI-containing regimens, as pancreatitis continues to be reported in a number of studies using IFN and RBV-based treatment arms. This may reflect the effect of RBV on the intracellular metabolism of ddI (enhances its phosphorylation). Finally, the suggestion that kinetics of HCV RNA clearance are slower in coinfection, which requires confirmation, could provide theoretical justification to examine more prolonged courses of treatment in this population.
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