Treatment and Management of HCV-HIV Coinfection: Recommendations from an International Panel of Experts

The Journal of Hepatology has published in its current online issue (May 2005) the "short statement" of the expert panel of the First European Consensus Conference on Treatment of HBV and HCV in HIV-coinfected Patients. It is available in the online journal free to non subscribers, who must register to gain access to the document. The short summary of the panel's consensus statement also appears in the May 2005 hardbound issue of the journal.

HIV and Hepatitis.com will be showcasing highlights from the short version of the recommendations over the coming week. Following is the text of the recommendations from the panel of experts on HCV-HIV Coinfection issues:

Screening for HCV

All HIV-infected patients should be screened for HCV. Screening for HCV in HIV-infected patients should be done using a third generation anti-HCV antibody test (AII).

A positive result should be followed by evaluation for the presence of HCV-RNA (AII). Detection of HCV-RNA indicates active disease.

A negative anti-HCV antibody test excludes HCV infection—except if the patient has acute HCV (diagnostic window) or has a blunted immune response, in which case HCV-RNA should be measured to document the infection (AIII).

Use of Antiretroviral Therapy

Initiation of treatment with nevirapine (Viramune) is associated with a risk of hepatic toxicity, which manifests as significant increases in ALT. This is more frequent in women who commence therapy with a higher CD4 cell count (see labelling for nevirapine). Most events are sub-clinical and usually reverse spontaneously. In HCV/HIV co-infected patients, nevirapine should be used with caution (AII).

Initiation of antiretroviral therapy in HIV/HCV co-infected patients should follow the current recommendation for initiation of antiretroviral in HIV mono-infected patients (BII). However, for patients with CD4 cell count levels that are just above the recommended threshold for initiation of ART, commencement of ART should be considered before the start of HCV therapy because of the risk of a decrease in CD4 cell count during IFN-based anti-HCV therapy (BIII).

Liver Biopsy and Other Evaluations

Liver biopsy provides information on histological disease, extent of inflammation (grading), extent of fibrosis (staging) and also about co-morbidities. The decision to perform a liver biopsy should be individualized as the resulting information about grading and staging will influence the decision to treat (AIII). This is particularly important in patients who are less likely to achieve a sustained virological response (SVR), for example, patients infected with genotype-1, when the risk-benefit of treatment is doubtful (for example, when there is a high risk of adverse events), and when patients' motivation for treatment is low.

Several non-invasive methods to evaluate inflammation and fibrosis are currently under investigation (for example, serum fibrosis markers and tissue elastography) but their usefulness in HCV co-infected patients requires validation.

Treatment

The combination of peginterferon alfa (PEG-IFN-alfa) and ribavirin is the treatment of choice for HCV infection.

Goals of Therapy

The primary aim of anti-HCV treatment is sustained virological response (SVR) defined as undetectable serum HCV-RNA 24 weeks after the end of therapy—evaluated using sensitive molecular tests (AI). Long-term follow-up studies in HCV mono-infected patients indicate that SVR is clinically related to viral eradication in a vast majority of patients and improvement in histology, which is associated with decreased risk of disease progression (cirrhosis, decompensation and HCC).

When Should Treatment for HCV Start?

Acute hepatitis C: Treatment of acute hepatitis C may reduce the risk of chronicity. Therefore, if serum HCV-RNA is not eliminated spontaneously within 3 months of onset of disease (clinically and/or laboratory documented), treatment should be offered (CIII). Treatment with PEG-IFN is recommended for 6 months in HCV mono-infected patients. Data in co-infected patients are limited—use of monotherapy or combination therapy in this population remains undetermined.

Chronic hepatitis C: If chronic hepatitis C is detected early in the course of HIV infection (before initiation of HAART is necessary), treatment for chronic hepatitis C is advised (AIII). However, if a co-infected patient has severe immune deficiency (CD4 count <200 cells/mm3), the CD4 cell count should be improved using HAART before commencing anti-HCV treatment (AII).

Candidates for Treatment

Treatment for HCV offers the possibility of eradicating HCV within a defined treatment period. This is potentially advantageous for the subsequent management of the patient with HIV, and every patient should therefore be considered for treatment when the benefits of therapy will outweigh the risks.

There are several baseline parameters that can predict a greater likelihood of achieving a SVR:

Patients infected with genotypes 2 and 3.

A low viral load (<800,000IU/ml).

Absence of cirrhosis.

Age <40 years.

Higher ALT levels (>3× ULN).

Conversely, low CD4 cell count can reduce the chance of SVR. Several studies using standard IFN plus ribavirin suggest a lower SVR in patients with a low CD4 count (<200cells/mm3) at baseline. There is currently insufficient evidence to conclude that SVR to PEG-IFN plus ribavirin therapy is negatively affected by low baseline CD4 cell count.

We recommend treatment, without liver biopsy or other liver assessment, for patients infected with HCV genotypes 2 or 3, and patients infected with HCV genotype 1 if the HCV viral load is low, if there are no major contraindications present and patients are motivated to undergo therapy (AI). The SVR is in the order of 40–60% in these patient groups. In case of the availability of a liver biopsy demonstrating lower grades of liver fibrosis (F0-1), regardless of HCV genotype, treatment can be deferred (BIII). A liver biopsy is especially important to perform for patients with suspected low chance of SVR (either because of an a priori low chance of response and/or excess risk of severe adverse events.

In patients infected with HCV genotype 1 and with a high HCV viral load, recommendation for treatment should also take into account liver disease stage. In particular, patients with histological evidence of advanced liver disease (fibrous septa) should be considered for treatment (AII).

Because ALT levels do not necessarily reflect the stage of fibrosis—especially in HIV/HCV co-infected patients—a ‘normal’ ALT level alone should not be used as an argument to defer treatment (AII). A biopsy in this situation can help to make a more informed decision on whether to start or defer treatment.

Patients on opioid substitution therapy should not be deferred from treatment. Psychological and social support in a multidisciplinary team should be provided for these patients. Initiation of anti-HCV therapy in active drug users should be considered on a case-by-case basis (CIII).

Treatment with IFN can reveal and worsen depression. Treatment for hepatitis C should therefore be deferred in patients with moderate to severe depression until the condition improves (EII). In patients with mild psychiatric illness, treatment for hepatitis C should not be deferred and support for the psychiatric condition (counselling and/or antidepressant medication) should be offered (BIII).

IFN-based therapies are contraindicated in patients with decompensated liver cirrhosis (Child Pugh stage B or C) (EI). Liver transplantation, where feasible, should be the primary treatment option for these patients (CII).

Management and Therapeutic Options

The standard dose for PEG-IFN 2a is 180μg once weekly, and for PEG-IFN 2b it is 1.5μg/kg bodyweight, once weekly.

Although clinical trials in HIV/HCV co-infected patients used a fixed dose of 800mg ribavirin once daily for all genotypes, studies from HCV mono-infected patients support the use of 1000–1200mg ribavirin once daily for treatment of infections with genotypes 1 and 4, and 800mg ribavirin once daily for genotypes 2 and 3. We therefore recommend an initial ribavirin dose of 1000–1200mg once daily for HIV/HCV co-infected patients with a high HCV genotype 1 or 4 viral load (B III). For all other patients, a dose of 800mg once daily is recommended (A II).

Regardless of genotype, duration of treatment in co-infected patients should be 48 weeks (BI) [emphasis added—Ed]

Assessment of Response

If an early virological response (EVR) of at least 2 log10 reduction in viral load compared to baseline is not achieved at week 12, treatment should be stopped, because the negative predictive value to achieve SVR is 99–100% (A II).

In patients who achieve at least a 2 log10 reduction in viral load at week 12, treatment should be continued. In mono-infected patients testing for HCV-RNA at week 24 is recommended, and in patients who remain positive for serum HCV-RNA at week 24 (negative predictive value for achieving SVR is 100%), treatment should be discontinued. A similar algorithm applies for HIV/HCV co-infected patients (A II).

The population of non-responders is heterogeneous, non-response is observed with any therapy for HCV, and can range from ‘no viral decline during treatment’ to ‘end-of-treatment virological response and subsequent virological relapse’. The decision to retreat patients with PEG-IFN plus ribavirin should be considered based on the type of response/non-response and tolerability to the previous treatment, the extent of liver damage and the HCV genotype (C III).

If the therapeutic aim in patients with biopsy-proven advanced fibrosis/cirrhosis is to delay or prevent disease progression in non-responders at week 12 and/or week 24, continuation with PEG-IFN monotherapy can be considered (C III). Dose, duration and clinical benefits of such maintenance therapy should be confirmed in clinical trials in HIV/HCV co-infected patients (A III).

Concomitant Use of Antiretroviral Therapy

During PEG-IFN plus ribavirin combination therapy, didanosine is contraindicated in patients with cirrhosis (E I) and should be avoided in patients with less severe liver disease (E II). Stavudine, especially in combination with didanosine, is associated with an excess risk of lactic acidosis and should be avoided (E II). In addition, the use of zidovudine should be avoided due to an excess risk of anaemia and neutropenia (D II).

A potential negative impact of protease inhibitor (PI) use on SVR in patients with HIV/HCV co-infection treated with PEG-IFN plus ribavirin has been suggested in a subgroup analysis of one study—this requires clarification. The jury do not recommend against the use of PIs (CIII).

Monitoring and Follow-up

A full blood count and liver tests (transaminases and bilirubin) should be performed during the first month of therapy at weeks 1, 2 and 4, and thereafter on a monthly basis. CD4 cell count should be monitored monthly. Additional laboratory tests can then be carried out at the physician's discretion and should include assessment of thyroid stimulating hormone (TSH) at least every 3 months.

Virological response should be monitored by serum HCV-RNA quantification before initiation of treatment and 12 weeks after starting therapy using the same molecular test. Patients who achieve a 2 log10 drop but remain HCV-RNA-positive should be tested again at week 24 by a sensitive test with a lower limit of detection of 50U/ml. Assessment of SVR should be made 24 weeks after completion of the therapeutic course by a qualitative test.

Management of Adverse Events

Effort should be made to keep patients on the optimal dose of PEG-IFN plus ribavirin and to proactively manage side effects of therapy. Such management should include use of:

Paracetamol (possibly combined with non-steroidal anti-inflammatory drugs) for influenza-like syndrome (AII).

Erythropoietin for severe anaemia (BI).

Growth factors to correct severe neutropenia (CIII).

Selective serotonin reuptake inhibitor antidepressants for clinically-relevant depression (AII).

Thyroid hormone substitution in hypothyroidism (AII).

Beta-blockers to relieve symptoms of hyperthyroidism (CIII).

Jury Panel
Alfredo Alberti (Italy) (President), Nathan Clumeck (Belgium) (President), Simon Collins (UK), Wolfram Gerlich (Germany), Jens Lundgren (Denmark), Giorgio Palu (Italy), Peter Reiss (Netherlands), Rodolphe Thiebaut (France), Ola Weiland (Sweden), Yazdan Yazdanpanah (France), Stefan Zeuzem (Germany).

Link to full article "Short Statement of the First European Consensus Conference on the Treatment of Chronic Hepatitis C and B in HIV Co-infected Patients" (March 1-2, 2005, Paris, France).

Reference
A Alberti and others (Jury Panel). Short Statement of the First European Consensus Conference on the Treatment of Chronic Hepatitis C and B in HIV Co-infected Patients" (March 1-2, 2005, Paris, France). Journal of Hepatology 42(5): 615 - 624. May 2005.

Information Resources

HIV and Hepatitis.com Main Page for HIV-HCV Coinfection

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4/27/05