Ribavirin levels after four weeks of treatment predict which HIV/hepatitis C coinfected and re-treated patients will respond

Blood levels of ribavirin after four weeks of treatment may predict which HIV/hepatitis C coinfected patients receiving hepatitis C “rescue therapy” are likely to have a good response to such treatment, according to Spanish research presented to the Fourth International Workshop on HIV and Hepatitis Coinfection in Madrid on June 20^th. But in a separate study presented to the Workshop, the same team of researchers found that increasing the daily dose of ribavirin to 2000mg did not increase the chances of patients achieving a sustained response to hepatitis C therapy.

A significant number of coinfected patients have received hepatitis C therapy with what would now be considered “sub-optimal” treatment consisting of standard interferon (rather than the pegylated form of the drug) and/or a low dose of ribavirin (600mg daily rather than the now-recommended 1000mg or 1200mg daily depending on weight).

Investigators wished to see if it was possible to retreat these individuals with the now-recommended standard treatment and presented data from a pilot study involving 61 individuals, 50 of whom had completed treatment.

The patients had a mean age of 50 years, 82% were men, and 78% were infected with the harder to treat hepatitis C genotypes 1 and 4. HIV therapy was being taken by 90% of the patients with good results, mean CD4 cell count being 680 cells/mm³ and 90% of patients had an undetectable HIV viral load.

Hepatitis C therapy produced a sustained virological response in 32% of patients – a response rate comparable to that seen in chronically coinfected patients receiving current standard of care anti-hepatitis C treatment for the first time.

Many of the factors associated with a better chance of treatment success have been well established in earlier studies and include infection with hepatitis C genotype 2 or 3 (p = 0.002) and a baseline hepatitis C viral load below 500,000 copies iu/ml (p = 0.02).

But the investigators found that patients who had a successful response to hepatitis C therapy had significantly higher blood plasma concentrations of ribavirin after four weeks of treatment (2.57 ug/ml vs. 1.92 ug/ml, p = 0.02), and in multivariate analysis, higher concentrations of ribavirin at this time were an independent factor for successful anti-hepatitis C treatment (p = 0.01).

The investigators chose to monitor ribavirin levels at four weeks to ensure that levels of the drug had reached a “steady state.” But some delegates to the conference expressed concern that monitoring drug levels at this time may be too late as it is already possible to tell which patients have had a rapid response to hepatitis C therapy and will successfully respond to hepatitis C therapy. It was suggested that ribavirin levels can be adequately monitored as little as 24 hours after initiation of treatment with the drug. Measuring of drug levels at this point would give increased ribavirin doses the opportunity to affect outcomes.

The findings of the Spanish study involving previoiusly-treated patients were echoed by that of a French study presented as a poster to the Workshop. This study involved 68 coinfected individuals starting anti-hepatisis C therapy for the first time. Levels of ribavirin at week four were significantly associated with a subsequent sustained virological response to therapy.

But is there really any value in increasing ribavirin doses? Evidence from the same team of investigators suggests not. They designed a study involving 147 HIV/hepatitis C coinfected patients. These patients were randomised into two arms. The first received standard hepatitis C therapy of pegylated interferon plus a weight-based dose of ribavirin (1000mg per day for those below 75kg, 1200kg daily for those weighing above 75kg). The other arm of the study also received pegylated interferon, but for four weeks were given an increased dose of ribavirin – 2000mg daily. Anaemia can be a side-effect of ribavirin so these patients were provided with weekly erythropoietin (EPO) therapy to boost their red blood cell count.

After four weeks of treatment the investigators found that blood levels of ribavirin were identical in the two arms of the study. Furthermore, the rate of rapid virological response – a reliable indicator of subsequent sustained virological response – was also identical between the two study arms at 23%.

The factors associated with outcome have been well established in earlier studies: hepatitis C genotype, hepatitis C viral load, and stage of fibrosis.

But higher doses of ribavirin supported by EPO appeared to be safe – rates of anaemia or severe anaemia were comparable in the two study arms, and similar numbers of patients in both arms adjusted their ribavirin dose because of side-effects.