Dose modification associated with poorer response to HCV therapy in HIV/HCV coinfected patients

HIV-positive individuals coinfected with hepatitis C virus who modify their dose of anti-hepatitis C therapy reduce their chances of achieving a sustained response to hepatitis C therapy, according to the results of a US study published in the May 15^th edition of Clinical Infectious Diseases.

Although the investigators did not find that modifying hepatitis C therapy due to haematological disorders was associated with a poorer treatment outcome, they believe that this could be because of the small number of individuals in the study, and, for this reason, the low number of treatment changes. They recommend that further, larger analyses are carried out to “more accurately assess the effect of haematologic toxicities”.

HIV, hepatitis C, and blood disorders

Significant numbers of HIV-positive individuals are coinfected with hepatitis C virus, and in the era of potent antiretroviral therapy, hepatitis C-related complications are becoming an increasingly important cause of illness and death in coinfected patients. It is well established that in coinfected patients, hepatitis C viral load is higher and progression to fibrosis, cirrhosis and liver cancer is faster, leading to increased mortality compared to patients who are only infected with hepatitis C.

Treatment for hepatitis C virus is available. The currently recommended standard of care consists of pegylated interferon plus ribavirin. The efficacy of this therapy is somewhat lower in coinfected patients than hepatitis C-monoinfected individuals.

Blood disorders, such as leukopenia (a reduced number of white blood cells), anaemia (reduced red blood cells), thrombocytopenia (reduced platelet count), and cytopenia (reduced cell count in the blood) can all be complications of HIV or hepatitis C virus infection. It is also known that anti-hepatitis C therapy can cause blood disorders, with ribavirin associated with anaemia, and interferon with thrombocytopenia and neutropenia (low neutrophil count – neutrophils are a type of white blood cell). Such blood disorders have been associated with the discontinuation of hepatitis C therapy, dose reduction, or the use of supporting therapies such as erythropoietin (EPO) and granulocyte-colony-stimulating factor (G-CSF).

The study

The ACTG A5071 study was designed as a prospective randomised trial to determine the safety and efficacy of two anti-hepatitis C treatment regimens in HIV-positive individuals. These regimens were interferon-alfa-2a plus ribavirin, or pegylated interferon-alfa-2a plus ribavirin.

Because of concerns about the overlapping haematologic toxicities of HIV and hepatitis C, and the side-effects associated with anti-hepatitis C therapy, the investigators conducted an analysis of their results to determine if the modification of anti-hepatitis C treatment, particularly for blood problems, influenced treatment outcome.

A total of 133 coinfected patients were randomised. All were aged 18 or over, had chronic HIV and hepatitis C infection, with a hepatitis C viral load above 600 IU/ml, and a CD4 cell count of 100 cells/mm³ if they were on antiretroviral therapy, or 300 cells/mm³ if they were not taking HIV therapy.

Screening for haematological disorders was undertaken prior to randomisation, and to enter the study patients were required to have a neutrophil count above 1000 cells/mm³, a haemoglobin concentration of 10g/dl or above, and a platelet count of 70,000 platelets/mm³ or greater.

The study lasted for 48 weeks and patients were monitored at regular intervals throughout.

Doses of the study medication were altered if a patient experienced side-effects, including blood disorders. At the discretion of an individual’s doctor, supportive therapy could be prescribed.

Results

Patients treated with pegylated interferon-alfa-2a were significantly more likely to reduce the dose of either pegylated interferon (p = 0.03), or ribavirin (p = 0.013), than individuals who were randomised to the interferon-alfa-2a arm. This difference was clear from week twelve of the study onwards.

However, the investigators found that reasons for treatment modifications did not differ significantly between patients in the two arms of the study. Neutropenia led to the majority of dose reductions (but no treatment discontinuations) in both the pegylated interferon and interferon arms. Anaemia was the cause of the majority of ribavirin dose reductions, and only one patient, stopped the drug because of this side-effect.

The risk of side-effects was not affected by an individual’s use of antiretroviral therapy, the particular HIV drugs taken, the use of AZT, CD4 cell count, hepatitis C genotype, or hepatic activity index.

No significant difference was observed between the two study arms in the number of patients who initiated supportive therapy with EPO. However, significantly more patients in the pegylated interferon arm commended treatment with G-CSF (p = 0.008).

Dose modification as a factor affecting the success of anti-hepatitis C therapy

Analysis showed that patients who modified their anti-hepatitis C therapy for any reason were significantly less likely to experience a successful response to hepatitis C therapy than patients who remained on unaltered therapy (p = 0.01).

Taking either EPO or G-CSF supportive therapy was significantly associated with a response to treatment (p = 0.04).

However, the investigators were unable to show if a treatment modification for blood disorders was significantly associated with a poorer treatment response. They observe that this finding was “limited by the fact that our clinical trial was not specifically designed to answer this question.”

They conclude “dose modification is associated with a lower response to therapy”, adding that it is important to study the outcome of individuals who modify doses for haematologic reasons “in larger clinical cohorts, to more accurately assess the effect of haematologic toxicities and the use of growth factors on the outcome of HCV therapy.”