XI CROI, Stage for Results of Three Large HCV Treatment Trials
By Tracy Swan
Still No Head-to-Head
Eagerly awaited results from three pivotal safety and efficacy studies of HCV treatment in HIV/HCV coinfected individuals were presented at the 11th Conference on Retroviruses and Opportunistic Infections. Tracy Swan prepared this short summary for TAGline.
Three large clinical trials, ACTG’s A5071, Roche’s APRICOT and ANRS HC02 (RIBAVIC), reported that combination therapy with pegylated interferon plus ribavirin was more effective than standard interferon plus ribavirin. Despite the superior efficacy of pegylated interferon, HCV treatment is less effective in coinfected people than in those with HCV alone. In HCV monoinfection treatment trials, sustained virologic response rates (SVR; no detectable HCV in the bloodstream six months after completion of HCV therapy) have ranged from approximately 40% in genotype 1 to >70% in genotypes 2 and 3. Direct comparison across studies is complicated by differences in sample size, baseline characteristics of their participants, brand of interferon used, dose of ribavirin and use of hematological growth factors.
Several factors contributed to differences in response rates in these studies. Although APRICOT was far larger than the other two trials, its results are not generalizable for several reasons. APRICOT used a higher dose of ribavirin (800 mg/day) than A5071’s initial dose (600 mg/day, escalated gradually), and a different type of pegylated interferon (alfa-2a; Roche’s Pegasys) than ANRS HC02 (alfa-2b; Schering’s Peg-Intron). Study populations differed; a majority of APRICOT’s participants had favorable prognostic factors: well-controlled HIV disease, high CD4 cell counts, low body weight and mild-to-moderate liver damage. A much larger proportion of ANRS HC02 participants had bridging fibrosis or cirrhosis. Blacks — in whom HCV treatment is less effective — constituted only 10% of APRICOT while approximately 30% of A5071’s participants were African-American.
The usual interferon-associated side effects — flu-like symptoms, fatigue and depression — were reported in all three trials. Laboratory abnormalities included thrombocytopenia, neutropenia, and anemia. Both ACTG A5071 and APRICOT allowed investigators to use growth factors for management of treatment-induced anemia and neutropenia; none were used in ANRS HC02, which may have contributed to its high discontinuation rate. During APRICOT, two deaths considered possibly or probably related to study drugs occurred; one from cardiac arrest and one suicide during hospitalization for depression. High dropout rates, serious adverse events and deaths underscore the need for less toxic treatments, multidisciplinary care and support during HCV treatment.
Sustained Virologic Responses in ACTG A5071, APRICOT and ANRS HC02 (RIBAVIC) by Trial, Regimen and HCV Genotype
ANRS HC02 (RIBAVIC)
|Number of Participants||133||868||412|
|Black and/or African-American||30% (AA)||10% (“Black”)1||N/A|
|Treatment (Peg-IFN + RBV)||Peg-IFN alfa-2a (Pegasys) 180 µg once weekly plus RBV 600 mg/day, gradually escalated to 1,000 mg/day for 48 weeks||Peg-IFN alfa-2a (Pegasys) 180 µg once weekly plus RBV 800 mg/day for 48 weeks||Peg-IFN alfa-2b (Peg-Intron) 1.5 µg/kg once weekly plus RBV 800 mg/day for 48 weeks|
|% SVR,2 Overall IFN + RBV||12%||12%||19%|
|% SVR, Overall Peg-IFN + RBV||27%||40%||27%|
|% SVR, Genotype 1 Peg-IFN + RBV||14%||29%||15%|
|% SVR, Non-1 Genotypes Peg-IFN + RBV||73%||62%||44%|
|Discontinuations From Peg-IFN + RBV arm||12%||25%||38%|
|Growth Factors Permitted||Yes||Yes||No|
|1. As APRICOT (the AIDS Pegasys Ribavirin International Co-Infection Trial) was an international study, not all Black participants were African-Americans.
2. SVR= Sustained Virologic Response (HCV RNA <50 IU/mL for >24 weeks after discontinuation of treatment).
Until more effective and less toxic treatments for hepatitis C are available, strategies for optimizing the efficacy and tolerability of pegylated interferon and ribavirin are needed. The 24-week course of treatment for HCV monoinfected individuals (standard of care for monoinfected individuals with genotypes 2 and 3) may not be adequate for coinfected people; high relapse rates after the end of treatment have been reported in previous studies. In APRICOT and A5071, relapse rates in genotypes 2 and 3 were low (from 64% to 62% at week 72; from 80% to 73%, respectively). Extending treatment from 48 weeks to 72 weeks in genotype 1 merits further investigation.
In the meantime, it may be necessary to revisit the treatment paradigm for hepatitis C. Slowing HCV disease progression and improving liver health may be a more realistic outcome for many coinfected people than eliminating hepatitis C. Improvement in the condition of liver tissue may occur in the absence of a sustained virologic response. In A5071, histologic improvement occurred among 9/26 (35%) of virologic non-responders. Maintenance therapy with low-dose pegylated interferon may be an option for virologic non-responders with advanced liver disease.
Some of the lessons learned from these trials are:
- Treatment with the full dose (800 mg/day) of ribavirin appears to be more successful than dose-escalation.
- The likelihood of achieving a sustained virologic response is extremely low unless HCV RNA is either undetectable or decreases by 2 logs at week 12.
- Growth factors ought to be used for management of anemia and neutropenia during HCV treatment rather than dose reductions.
Although Roche’s Pegasys appears to be the therapy of choice for coinfected people, in the absence of a head-to-head study comparing efficacy and tolerability of both products, we cannot be sure. Selecting the type of pegylated interferon may not be the most crucial element in an HCV treatment decision. These studies have led to other pressing questions. Schering and Roche could compare the efficacy and tolerability of their products, or use their resources to sponsor trials that answer questions such as:
- What are the most effective side effect management strategies?
- Should interferon-induced depression be treated pre-emptively, or on an as-needed basis?
- In HCV monoinfection, those with high HCV RNA (>800,000 IU/mL) are less likely to achieve sustained virologic response. Since HCV RNA levels are significantly higher in coinfected people, 800,000 IU/mL may not be an accurate threshold in coinfection. Is there a prognostic threshold in coinfection, given the higher viral loads? If so, what is it?
- Extending treatment for an additional 24 weeks may lower the relapse rate in genotype 1. How can clinicians identify individuals who are most likely to benefit from additional treatment?
- There have been a few reports of sustained virologic response among people who did not have undetectable HCV RNA or a 2 log decrease at week 12. Is there any way to identify people who may to achieve sustained virologic response although they did not have an early virologic response?
- How can we identify those who will have histologic improvement in the absence of a virologic response?