Increase ribavirin dose for better HCV treatment response in coinfected individuals, experts argue

In order to improve response to hepatitis C virus (HCV) treatment, individuals coinfected with HIV and HCV should increase their dose of ribavirin (Copegus / Rebetol / Virazole), according to two presentations to the Second International Workshop on HIV and Hepatitis Coinfection, held in Amsterdam last week. Interim results from the ongoing Spanish PRESCO study suggest that ribavirin should be dosed by body weight, rather than the standard 800mg/day recommended in current guidelines, and a small pilot study from France suggests that therapeutic drug monitoring (TDM) of ribavirin levels may also improve treatment response and reduce side-effects.

Vincent Soriano of Madrid's Hospital Carlos III, the principal investigator of the ongoing multisite PRESCO (Pegasys Plus Ribavirin for HCV Treatment in HIV/HCV Coinfection) study, used data from his team's poster (by Ramos et al.) to compare results at week 4 and week 12 in two studies that combined pegylated interferon (pegIFN-alfa2a or Pegasys) with ribavirin to treat HIV/HCV coinfected individuals - PRESCO and APRICOT - as well the registrational study for Pegasys with ribavirin from Fried and colleagues that was conducted in HCV monoinfected individuals.

Soriano picked week 4 and 12 data because, he argued, HCV viral load at week 4 has the strongest positive predictive value of a sustained virological response (SVR) to anti-HCV treatment, and HCV viral load at week 12 has the best negative predictive value i.e. those individual who do not achieve at least a two log drop after 12 weeks are unlikely to achieve an SVR.

PRESCO, interim results of which were first presented at the 44th ICAAC in November 2004, will eventually include data from around 350 individuals with a CD4 cell count above 300 cells/mm³, most of whom are on stable anti-HIV therapy. Exclusion criteria include psychiatric illness, alcohol abuse, ddI (didanosine, Videx / VidexEC) use, and cirrhosis. Around 50% of the circa 200 individuals enrolled so far are infected with HCV genotype 1 and 10% have genotype 4 - the two genotypes most difficult to treat - and another 40% have genotypes 2 or 3. Participants receive pegIFN-alfa2a (Pegasys) 180 µg/week plus ribavirin dosed between 800-1200 mg/day, according to weight. 800mg/day for those who weight less than 65kg; 1000mg/day for those who weigh between 65-85kg; and 1200mg/day for those who weigh over 85kg. The median baseline weight is around 68kg, resulting in most participants using 1000mg/day.

APRICOT (AIDS Pegasys Ribavirin International Coinfection Trial) was the largest study of its kind, and included 860 HIV/HCV-coinfected participants from 19 countries who were receiving anti-HCV treatment for the first time. Final results, which were published in the New England Journal of Medicine in 2004, found that overall, 40% of HIV/HCV coinfected patients treated with 180 µg/week pegIFN-alfa2a in combination with 800mg/day ribavirin achieved an SVR after the completion of therapy, although the SVR was only 29% in those infected with HCV genotype 1.

In the Fried study, participants received either standard interferon or Pegasys plus 1000 or 1200mg of ribavirin, based on weight.

On-Treatment Week 4 Comparison

On-Treatment Week 12 Comparison

Measuring ribavirin levels

In the PRESCO study, higher ribavirin plasma levels were found to be independent predictors of early virological response at weeks 4 and 12 (p=0.007). At a second presentation earlier in the day, investigators from Paris reported data from their prospective pilot study on the relationship between ribavirin concentrations in both plasma and red blood cells (erythrocytes) and whether there was a correlation between these ribavirin concentrations and both treatment response and side-effects.

Results were available from fourteen individuals coinfected with HIV and HCV initiating standard anti-HCV treatment (i.e. 800mg/day ribavirin). Genotype distribution was as follows: G1 (n=5), G2 (n=1), G3 (n=6) and G4 (n=2), and xix of the 14 (43%) had cirrhosis. Ribavirin levels (measured only as Cmin, twelve hours after last dosing of ribavirin) in plasma and erythrocytes were determined at weeks 4 and 12.

At week 4, a wide variability between individuals was seen. Although the median Cmin was 1.27µg/mL for plasma, the range was 1.12µg/mL-2.17µg/mL. Similarly median Cmin for erythrocytes, corrected for haematocrit, was 229µg/mL, although the range varied between 58µg/mL-573µg/mL. No correlation was seen between ribavirin Cmin and BMI or weight.

The investigators found that there was a correlation between ribavirin plasma and erythrocyte levels (p=0.05), and that there was a significant relationship between ribavirin plasma levels and drop in levels of haemoglobin, the part of the red blood cells that carries oxygen (p

Similarly, the investigators found that the ribavirin Cmin in erythrocytes above 170µg/mL at week 4 was significantly correlated with HCV virological response at week 12 (p

Concern over side-effects

The comparison between the three studies presented by Soriano and Ramos only included individuals who tolerated the treatment, and intention-to-treat analyses were not provided. In the subsequent discussion, it was pointed out that higher doses of ribavirin may lead to side-effects that cause patients to stop treatment, in particular, haemolytic anaemia, or loss of red blood cells. In fact, interim results of PRESCO presented in November 2004 found a high rate of treatment discontinuation due to adverse events, with 23% of patients withdrawing from the study before completing even 24 weeks of treatment. In addition, around one third of participants required ribavirin dose reductions.

Data from HCV monoinfected individuals presented at the American Association for the Study of Liver Diseases (AASLD) annual meeting, held last November in San Francisco, suggests that erythropoietin (EPO, Eprex, NeoRecormon,Procrit, Epogen), a hormone that stimulates red blood cell production, may enable individuals to tolerate higher doses of ribavirin. EPO was not used in the PRESCO study, and although members of the audience commented that EPO may indeed help individuals tolerate higher doses of ribavirin, the cost of EPO, in the UK at least, is currently an issue.

Whilst the optimal dose varies between patients according to response, a year's EPO costs around £2,750. Although this doesn't appear excessive compared with anti-HIV drugs, some funders in NHS have refused to pay for EPO to treat the side-effects of cancer treatments, citing lack of cost-effectiveness compared with blood transfusions. However, at least one study has found that this was associated with increased risk of death in HIV patients with anaemia, even after adjusting for antiretroviral use, AIDS status, CD4 cell count, viral load and haemoglobin level. In contrast, EPO was not linked to an increased risk of death. A report last year by NICE (The National Institute for Health and Clinical Excellence), which can authorise its use throughout the UK, concluded that "erythropoietin is not recommended for the treatment of anaemia induced by cancer treatment except in the context of research studies". NICE have not evaluated EPO for the treatment of ribavirin-induced haemolytic anaemia.

Dr Marion Peters, from the University of California in San Francisco, and a member of the on-stage panel that discussed the Soriano/Ramos data, summed up the feeling of the conference towards increased ribavirin dosing when she said: "This study is very valuable. But this data says, 'let's give weight-based appropriate dosing', and not just as much as possible. Perhaps 800mg a day of ribavirin is not adequate and going to weight-based daily 1000mg to 1200mg is the way to go," side-effects notwithstanding.