Hepatitis C virus RNA dynamics during antiretroviral therapy

We thank Drs Bruno, Sacchi, and Filice for their comments regarding our paper on immunologic dynamics during antiretroviral therapy in HIV-HCV–coinfected hemophiliac patients. In the paper, we suggested that treatment for HIV-HCV patients should begin with highly active antiretroviral therapy (HAART) for HIV prior to interferon (IFN) therapy for HCV because HAART improves the host immune function in the host by increasing the CD4⁺ cell count and often results in decreasing HCV viral load, which is thought to be advantageous for patients starting IFN therapy. Bruno et al raise the following issues regarding starting HAART before starting IFN: (a) HAART is not necessarily associated with HCV viral load, (b) anti-HIV drugs are more often toxic for hepatocytes in HCV-coinfected individuals, (c) severe side effects of IFN treatment may affect the patients' adherence to HAART, and (d) IFN therapy combined with ribavirin could affect the response to HAART because of a drug interaction.

Whether HAART reduces HCV load in HIV-HCV patients is still controversial. Although Samaniego et al initially reported no association between HAART and HCV load,1-1 after a longer observation period they did find such an association.1-2 The influence of HAART on HCV load may be delayed in relation to CD4⁺ cell count recovery. It also may be that the response varies between patient races1-3 or between patient populations (hemophilia patients have no repeated transmission mode, such is seen in drug abusers or homosexual men). The duration of infection and pretreatment CD4⁺ cell count of patients may also be involved. Our hemophiliac patients had been infected with HIV before the establishment of screening for clotting factors and, thus, may have been infected longer and had a lower CD4⁺ cell count than HIV-HCV patients described in other studies.

Anti-HIV-drug–induced hepatotoxicity is considered more common among HCV-coinfected patients, but this may be due to underlying HCV-related liver disease. Even among those patients experiencing toxic effects, the elevated transaminase level was transient and no irreversible outcomes were observed.1-4 HAART can be administered safely to HIV-HCV–infected patients, though the patients' transaminase levels should be monitored.

Our hemophiliac patients who are suffering from both diseases are earnest in seeking treatment. They gave informed consent for the IFN therapy and were prepared for the side effects. To date, none of our patients treated by HAART and IFN therapy have ceased treatment due to side effects. Careful attention to the patient's outlook and careful serum monitoring by the physician is very important, however.

Once a patient starts HAART, it is continued even after the start of IFN therapy. In vitro study has suggested that ribavirin inhibits action of anti-HIV drugs.1-5 Certainly cotreatment with ribavirin may strengthen the IFN effect but may weaken the underlying effect of HAART. A recent report, however, demonstrated the safety and effectiveness of this combination during HAART: as many as 50% of the study patients were sustained responders to treatment with IFN plus ribavirin.1-6 

HCV-related disease has become a more significant issue than HIV disease that is well controlled by the establishment of HAART. Due to the fact that HIV accelerates the progression of HCV disease, a successful outcome with IFN therapy is critical. IFN therapy for HCV infection aims at complete elimination of the virus and is short-term, whereas the aim and duration of HAART for HIV infection are quite different. Because the outcome of IFN therapy, alternatively successful viral elimination or not, depends greatly on the initial host and virus conditions,1-7 the starting point for IFN therapy must be optimally advantageous for the host.

Approximately 85% of acutely HCV-infected persons develop chronic, persistent viremia, suggesting the difficulty of viral clearance even under normal immune conditions. The remaining persons who fortunately recover from hepatitis with eradication of HCV show a dominant Th1-response among CD4⁺ cells,1-8 inducing specific CTL activity.1-9 Thus CD4⁺ cells are central to the cytotoxic immune system, playing an important role in the eradication of viruses. Actually, in HIV-HCV–infected patients, a sustained IFN response has been associated with a pretreatment CD4⁺ cell count.1-10 Thus IFN therapy should be performed under as near- normal immune conditions as possible.

Finally, a standard therapy for HIV-HCV–coinfected patients has not been established. Which therapy should precede: HAART or IFN? The answer may depend on the pretreatment host and viral factors such as the CD4⁺ cell count and the HCV viral load. More information or a large study addressing this question is urgently needed.