Patients and methods

Results

Median HIV load and CD4 counts, performed in 21 patients three months before starting interferon and ribavirin therapy, were 2.8 (2.3–5.9) log10 copies/ml and 293 (45–655) cells/ml, respectively. At the beginning of ribavirin and interferon therapy, CD4 counts were not different and HIV RNA plasma levels were significantly lower than three months earlier (p=0.3 and p=0.05, respectively).

There was no statistically significant change in HIV viral load or CD4 cell counts after three or six months of ribavirin therapy compared with baseline values (table 2, fig 1). However, an increase of more than 0.5 log copies/ml of plasma HIV-RNA (1.3, 0.6, and 0.6, respectively) was observed in three patients (14%) after 3–6 months of ribavirin. Two of these three patients had undetectable HIV viraemia prior to ribavirin. After three months of ribavirin plus interferon therapy, a median decrease of 68 (23–97) CD4 lymphocytes/ml was observed in 11 of 21 patients (52.4%; 95% CI 29.7–74.3%). After six months of anti-HCV therapy, the median decrease in CD4 was 57 (18–206) cells/ml in 10 of 18 tested patients (55.9%; 95% CI 30.7–78.5%). A decrease in haemoglobinaemia was observed after three and six months of ribavirin (p=0.0002 and p=0.0003, respectively). Ribavirin plus interferon were stopped in one case because of severe anaemia and in another case anaemia led to dose reduction of ribavirin and transfusion; in one other case, discontinuation of ribavirin was necessary because of both increased HIV viral load and decreased CD4 cell counts. In the latter, withdrawal of therapy was associated with a decrease in HIV viral load (8000 to 1800 copies/ml). For the two other patients who experienced an increase in HIV viral load during anti-HCV therapy, HIV viral load was not modified after completion of therapy. No other serious side effects were observed.

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Figure 1

Human immunodeficiency virus (HIV) viral load three months before, at the start of ribavirin therapy, and three and six months after ribavirin therapy in individual patients (n=21).

Eleven of 21 (52.4%) patients had initial negative HCV viraemia at three (n=10) or six (n=1) months but only six were PCR negative at the end of therapy, leading to rates of primary response and breakthrough of 23.8% and 28.5%, respectively. Six months after completion of therapy, three patients relapsed (14.3%) and three (14.3%) had sustained virological response.

Three months after completion of therapy, haemoglobinaemia and CD4 cell counts increased significantly (p<0.003 and p<0.03, respectively) while HIV viral load was not modified (p>0.05).

Discussion

Our results suggest that the ribavirin-interferon combination had a low in vivo impact, if any, on phosphorylation of nucleoside analogues and had a limited antiviral sustained efficacy in HCV-HIV coinfected patients who were previous non-responders to interferon therapy.

Ribavirin (1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) is a guanoside nucleoside analogue which shows marked antiviral activity against different RNA and DNA viruses, including HCV, but has no anti-HIV activity.11 ,12 In vitro studies have demonstrated that ribavirin inhibits intracellular phosphorylation of AZT, D4T, and zalcitabine, suggesting a decrease in their anti-HIV efficacy.8-10 The underlying molecular basis of such inhibition is under investigation and probably involves inhibition of thymidine kinase activity.10

The association of ribavirin and interferon with AZT or D4T for 3–6 months did not induce a significant change in HIV viral load or CD4 lymphocyte counts. This finding suggests that interactions between ribavirin and AZT or D4T may not influence HIV replication in vivo. However, three patients had an increase in HIV load of more than 0.5 log which could be related to impairment of AZT or D4T efficacy due to inhibition of phosphorylation and which led to discontinuation of ribavirin in one patient. It is noteworthy that an increase in HIV-1 RNA plasma levels cannot be related definitively to ribavirin but may be related to HIV resistance to antiretroviral therapy or to poor compliance with therapy. Similarly, as previously reported, the decrease in CD4 cell counts observed in 50% of patients was probably related to α interferon1 rather than to ribavirin. Indeed, a decrease in CD4 cell counts was not observed in large trials in which HIV infected patients received only ribavirin.11 ,12

Analysis of efficacy of anti-HCV combination therapy in coinfected subjects showed 23.8% and 14.3% primary (HCV-RNA clearance at the end of therapy) and sustained virological response rates, respectively, in patients who were previous non-responders to interferon therapy. This very low sustained rate of response in non-responders parallels those obtained in the general population.13 Eleven of 21 (52%) patients had initial negative HCV viraemia during therapy. We believe that the discrepancies between an anti-HCV antiviral effect, at least initially, and the fact that many of these patients were interferon relapsers or non-responders could be explained, at least in part, by better immune status at the time of the combination therapy than at the start of interferon monotherapy (data not shown). Indeed, it is noteworthy that most patients (80%) received interferon therapy before HAART was available; most patients had a poorer immune status at the time of the first anti-HCV therapy. Moreover, among patients with initial negative HCV viraemia, nearly half experienced a breakthrough. Interferon and ribavirin therapy was well tolerated, except for ribavirin related haemolysis which requires monitoring of haemoglobin concentration and perhaps a decrease in initial dose to 600–800 mg/24 hours.

In conclusion, our preliminary data suggest that short term treatment with ribavirin is feasible with no major clinical impact on HIV disease in patients receiving zidovudine and zalcitabine but requires close monitoring of HIV viral load. Therapeutic trials with longer follow up and in vitro evaluation are warranted to confirm the safety and efficacy of anti-HCV combination therapy in coinfected subjects.