Treatment of Hepatitis C in HIV-coinfected Patients: Towards an Individualized Approach

By Marina Nunez, MD, PhD

New research studies continue to highlight the issue of a poor response to anti-HCV therapy among HIV-HCV-coinfected patients. In a multicenter study reported on at the 13th CROI in Denver, Spanish investigators analyzed 145 patients treated with pegylated interferon (IFN) and ribavirin (RBV) outside clinical trials [1].

The researchers reported sustained virological response (SVR) in 19% of patients with HCV genotypes 1 or 4, and in 53% of patients with HCV-2 or -3. In line with previous reports, 25% of subjects prematurely discontinued therapy due to side effects or were lost from follow-up.

Similar efficacy was observed with both types of pegIFN, a-2a (Pegasys) and a-2b (PegIntron). Four factors were identified as independent predictors of SVR in multivariate analysis: adherence to treatment >80%, genotypes 2/3, and HCV RNA levels <600,000 IU/mL and CD4 counts over 300 cells/mm3 at baseline. However, in another study, different cut-offs of nadir CD4 counts were not able to discriminate responders to anti-HCV therapy [2].

In a cohort of US Veterans in a retrospective study, factors influencing early virological response (EVR) were investigated [3]. Patients who had initiated pegIFN and RBV treatment outside clinical trials before March 31, 2005 having received at least 9 weeks of treatment, and for whom HCV RNA data between 8-16 weeks were available, were identified. Out of 208 patients evaluated, 116 experienced EVR as defined by undetectable HCV RNA levels or a decline of at least 2 log10 from baseline levels.

Factors found to independently predict EVR to anti-HCV therapy in backwards stepwise multivariate analysis were baseline CD4 count ³ 350 cells/mm3 (OR 2.90, 95% CI 1.26-6.63; p=0.01), HCV viral load < 500,000 IU/ml (OR 2.87, 95% CI 1.23-6.66; p=0.01), HCV genotype 2/3 (OR12.54, 95% CI 3.57-43.98; p<0.0001), and treatment with pegIFN-a2a (OR 2.99, 95% CI 1.43-6.26; p=0.004).

Ethnicity and RBV dose, measured as recommended or higher (defined as 1,000 mg/day if £ 75 Kg and 1,200 mg/day if > 75 Kg for genotypes 1/4, and 800 mg/day for genotypes 2/3) versus under-dosage, lost their statistical significance as predictor factors of early virologic response (EVR) in the multivariate analysis.

While the findings are very interesting, they require caution in their interpretation since the study is not randomized. In addition, it is uncertain if the way in which the data were adjusted by RBV dosage was completely efficient. Thus, if IFN-a-2a was more often given with recommended or higher doses of RBV, the type of IFN might have acted as a confounding factor.

The important role of EVR to achieve SVR was underlined once more in a Spanish study presented at this conference [4]. The authors analyzed, within a study comparing standard IFN-a-2b (Intron A) and pegIFN-a-2b (PegIntron), those patients coinfected by HCV genotypes 2 or 3, all of whom had been treated for 24 weeks and received 800 mg/day of RBV.

Out of 42 patients, 36 had HCV RNA levels measured at week 4. Both end-of-treatment and sustained virological responses were more common among patients with undetectable HCV RNA (<100 IU/ml) at week 4 (95% vs. 69% and 90% vs. 37.5%, respectively). While 48 weeks of anti-HCV therapy in HIV-HCV-coinfected patients with genotypes 2/3 may increase the overall response, these results highlight that there is a subset of rapid responders for whom 24 weeks of treatment seem enough. These data suggest that an individual adjustment of the duration of therapy based on EVR is the most appropriate approach.

One of the determinant factors for achieving EVR in HIV positive patients coinfected by HCV genotypes 1 or 4 is the plasma concentration of RBV, according to an Italian study that supports published data [5,6]. In a further analysis of their previous work, Spanish investigators analyzed inter-individual and intra-individual over time variations in RBV plasma levels among 98 HIV-HCV-coinfected patients receiving pegIFN+RBV combined treatment [7].

Mean RBV concentrations throughout the course of treatment were 2.88 mg/mL. While wide inter-individual variability was found, RBV plasma levels were relatively stable in every individual during the first 12 weeks of treatment. However, at 24, 36 and 48 weeks significant increases in median RBV plasma concentrations were observed over values obtained at week 4: +0.32 mg/mL, p=0.02; +0.55 mg/mL, p<0.001; and +0.55 mg/mL, p=0.003, respectively (Figure 1).

Figure 1. Mean RBV concentrations throughout the course of anti-HCV treatment.

At week 24 this intra-individual increase significantly correlated with a loss in body weight (p=0.03). If that is the reason for the observed elevation in RBV plasma levels over time, then the clinical consequences of these variations remain to be seen.

Access to care and to anti-HCV treatment of HIV-HCV-coinfected patients needs further improvement, especially in certain populations. This issue was evaluated in the national cohort of US Veterans infected by HCV [8]. Years 1999 to 2003 were included in the analysis. History of IFN-based therapy was searched in 120,507 subjects with HCV infection, of whom 6,502 were coinfected with HIV. Coinfected patients were younger and more often black and male.

Treatment for HCV was prescribed significantly less often to HCV-infected (11.8%) than to HIV-HCV-coinfected patients (7.2%) (p<0.0001). Factors found to predict no prescription of HCV therapy included older age, Hispanic and black race, drug use, anemia, and psychiatric disorders (bipolar disorder, and major and mild depression).

Efforts need to be made to overcome the barriers to benefiting from treatment for HCV infection. In that regard, criteria for selecting candidates to therapy should be used with flexibility, and in such a way that treatment decisions are made on an individual basis.

The use of hematological growth factors for the management of anemia and to a lesser extent of neutropenia derived from the treatment with IFN and RBV is still under debate. While there is quite abundant literature on anemia and its treatment with erythropoetin, little information on the issue of decreased neutrophils secondary to the use of IFN is available. The occurrence of infectious complications following IFN-based HCV therapy in HIV-HCV-coinfected patients was investigated by Canadian investigators [9].

The rate of infectious complications among 28 HIV-HCV-coinfected patients (1.2 infections/100 person-weeks of therapy) was similar to that in 186 non-HIV patients (1.0 infections/100 person-weeks of therapy). Figure 2 displays the distribution of type of infectious complications developed during the course of IFN therapy, which was comparable in HIV-coinfected and non-HIV patients.

Nadir or baseline neutrophil counts did not correlate with incidence of infectious complications (neither bacterial nor fungal), irrespective of HIV status. In their conclusions, the authors stated that IFN dose reduction or use of G-CSF, in those patients experiencing neutropenia, are not supported by this analysis. Nevertheless, larger studies are needed before giving recommendations on the matter.

Figure 2. Distribution of infectious complications during the course of interferon-based anti-HCV treatment.

02/17/06

References

1. J Mira and others. Efficacy of pegylated interferon + ribavirin in HIV/HCV coinfection outside of well-circumscribed clinical trials: the Andalusian multicenter study. 13th Conference on Retroviruses and Opportunistic Infections. 5-8 February 2006, Denver, CO [Abstract 861].

2. S Hopkins and others. Nadir CD4 count does not predict response to pegylated interferon and ribavirin in HIV/HCV coinfected patients. 13th Conference on Retroviruses and Opportunistic Infections. 5-8 February 2006, Denver, CO [Abstract 860].

3. LI Backus and others. Early virological response to pegylated interferon and ribavirin in a large cohort of HIV/HCV-coinfected veterans. 13th Conference on Retroviruses and Opportunistic Infections. 5-8 February 2006, Denver, CO [Abstract 858].

4. M Crespo and others. Utility of the early viral response to individually adjust the duration of treatment for chronic hepatitis C, genotype 2 or 3, in HIV-coinfected patients. 13th Conference on Retroviruses and Opportunistic Infections. 5-8 February 2006, Denver, CO [Abstract 81].

5. D Gonzalez-Requena and others. Effect of ribavirin trough concentration on early virological response according to HCV genotype and on early hemoglobin decrease in HCV/HIV coinfected patients treated with RBV + pegIFN. 13th Conference on Retroviruses and Opportunistic Infections. 5-8 February 2006, Denver, CO [Abstract 857].

6. A Rendon and others. Early monitoring of ribavirin plasma concentrations may predict anemia and early virologic response in HIV/hepatitis C virus-coinfected patients.  J Acquir Immune Defic Syndr 2005; 39:401-05.

7. AL Rendon and others. Ribavirin plasma levels throughout the course of HCV therapy in HCV/HIV-coinfected patients: clinical implications. 13th Conference on Retroviruses and Opportunistic Infections. 5-8 February 2006, Denver, CO [Abstract 581].

8. A Butt and others. Rate and predictors of treatment for hepatitis C. 13th Conference on Retroviruses and Opportunistic Infections. 5-8 February 2006, Denver, CO [Abstract 862].

9. C Cooper and others. Infection rates in HIV/HCV and HCV patients treated with interferon are similar and not related to neutropenia. 13th Conference on Retroviruses and Opportunistic Infections. 5-8 February 2006, Denver, CO [Abstract 864].