Higher baseline HCV viral load and CD4 percentage predict response to hepatitis C treatment in HIV/HCV co-infected patients

Higher baseline HCV RNA levels predicted better sustained response to hepatitis C therapy in HIV-positive patients with HCV genotype 1 co-infection in the APRICOT trial, and pre-treatment CD4 cell percentage had a slight effect, according to two posters presented on Saturday at the Forty-Sixth Interscience Conference on Antiretroviral Agents and Chemotherapy in San Francisco.

APRICOT was an international trial in which 860 HIV/HCV co-infected participants who had not previously received interferon-based therapy were randomly assigned to receive either three million IU conventional interferon-alfa-2a three times weekly plus 800mg daily ribavirin; 180mg pegylated interferon-alfa-2a (Pegasys) monotherapy; or the same doses of pegylated interferon plus ribavirin, all for 48 weeks.

Baseline characteristics were similar across all three arms. About 81% of participants were men, with a mean age of about 40 years; about 79% were white and about 11% were black. About 61% had HCV genotype 1, 5% had genotype 2, 27% had genotype 3 and 7% had genotype 4. All had detectable HCV RNA (> 600 IU/ml) and elevated alanine aminotransferase levels at baseline. Participants overall had stable HIV disease; the mean CD4 cell count was about 530 cells/mm³, about 85% were on antiretroviral therapy and 60% had HIV viral loads below 50 copies/ml.

Final results from APRICOT were published in the July 29, 2004 edition of the New England Journal of Medicine. In an intent-to-treat analysis at 48 weeks, 40% of patients treated with pegylated interferon plus ribavirin achieved sustained virological response (SVR, defined as continued undetectable HCV RNA 24 weeks after the end of treatment), compared with 20% in the pegylated interferon monotherapy arm and 12% in the conventional interferon plus ribavirin arm. Amongst patients with HCV genotype 2 or 3, the corresponding SVR rates were 62%, 36%, and 20%, whilst in genotype 1 patients, SVR was observed in 29%, 14%, and 7%, respectively.

Baseline HCV viral load

In the present analyses, researchers looked in more detail at factors that predicted sustained response. The APRICOT trial found that amongst patients with HCV viral loads below 800,000 IU/mL, SVR rates were lower in participants with higher baseline HCV RNA. To assist in the management of HIV/HCV co-infected patients by defining “easier” and “difficult-to-cure” subgroups, Maribel Rodriguez-Torres and colleagues sought to determine which baseline HCV RNA values best predicted who was most and least likely to achieve SVR.

This analysis included 271 participants in the pegylated interferon plus ribavirin arm (176 with genotype 1; 95 with genotype 2 or 3); baseline characteristics were similar to those of the trial population as a whole.

SVR rates were consistently above 70% in participants with baseline HCV RNA below 100,000 IU/mL, but declined to less than 20% in those with more than 2,000,000 IU/mL. The researchers determined that the HIV RNA cut-off that most effectively identified patients likely to achieve SVR was 400,000 IU/mL, or 5.6 log₁₀. Amongst patients with HCV viral load levels below 400,000 IU/mL, sustained response rates were high regardless of genotype.

Amongst participants with HCV genotype 1, the SVR rate was “markedly lower” in those with baseline HCV RNA levels of 400,000 IU/mL or more compared to those with lower HCV viral loads (20% vs 71%). Amongst patients with genotype 2 or 3 patients, a similar pattern was observed, but the difference was “slight” (SVR rates of 59% vs 74%, respectively).

The researchers concluded that, “If baseline HCV RNA is to be used in clinical decisions, these analyses suggest the most appropriate HCV RNA cut-point with clinical relevance is 400 000 IU/ml.” They added that, “Use of this cut-point may allow further optimization” of therapy with pegylated interferon plus ribavirin in co-infected patients.

They emphasized, however, that for any specific individual, the outcome of hepatitis C treatment cannot be predicted in advance based on HCV RNA levels. Thus, “all patients should be treated and evaluated at weeks 4 and 12 of therapy.”

Baseline CD4 percentage

In APRICOT, a higher absolute CD4 cell count was associated with a higher rate of SVR amongst participants with HCV genotype 1, but not in those with genotypes 2 or 3; however, the number of patients with CD4 counts below 200 cells/mm³ was small.

In the second analysis presented at ICAAC, Douglas Dieterich and colleagues explored the effect of baseline CD4 cell percentage on sustained response. CD4 percentage refers to the proportion of T-lymphocytes that carry the CD4 surface marker. Data on CD4 percentage were available for 705 patients. The median baseline CD4 percentage was about 25.0%, with a range of 2.5% to 69.3%.

Across all CD4 percentage quartiles, SVR rates were higher in the group that received pegylated interferon plus ribavirin than in either of the other two treatment arms. Analysis of SVR rates according to CD4 percentage showed a “trend” towards greater virological response as baseline CD4 percentage increased. Looking only at patients in the two arms that received ribavirin, the researchers found that SVR rates “tended to improve” as baseline CD4 percentage rose, although the relationship was not consistent across genotypes or treatment regimens (see table).

When broken down by genotype, the effect of CD4 percentage was most pronounced amongst patients with genotype 1, with the lowest rate of HCV clearance observed in the lowest quartile of CD4 percentage scores. Amongst patients genotypes 2 or 3, in contrast, sustained response rates showed “no obvious trend” in relation to CD4 percentage.

Overall safety and tolerability of therapy did not appear to vary according to baseline CD4 cell count or CD4 percentage, though some adverse events and laboratory abnormalities were more common amongst patients with the lowest CD4 counts (below 200 cells/mm³).

During therapy, patients experienced a “slight” (less than 10%) increase in CD4 percentage relative to the total number of T-lymphocytes, which returned to baseline after completion of treatment. Decreased white blood cell count is a known side effect of interferon, but typically various types of cells decline by similar amounts, leaving percentages relatively stable.

The researchers concluded that amongst patients treated with conventional or pegylated interferon plus ribavirin, SVR rates improved with higher baseline CD4 percentage in genotype 1 patients, but not in those with genotype 2 or 3.

“Although analysis by baseline CD4 percentage quartiles did not reveal any strong influence on virological response rates from baseline, a slight trend toward an earlier and possibly a slightly more sustained response was seen in those with higher baseline CD4 percentage,” the investigators wrote.

“Although prospective studies in a larger number of severely immunocompromised patients are awaited, our findings suggest that the benefits of treating HCV among immunocompromised patients with HIV infection outweigh the potential risks.”