HIV/HCV coinfection update

HIV-HCV Coinfection Update

Sheila Lahijani, BS, RPh
Brown Medical School

Lynn E. Taylor, MD
Assistant Professor of Medicine, Brown Medical School

(condensed and excerpted from a posting in HCV Advocate, Medical Writers Circle)

Link: Coinfection update

Background
Human Immunodeficiency Virus (HIV) and chronic hepatitis C virus (HCV) coinfection is a growing public health concern, with an estimated 4-5 million persons coinfected worldwide.  In the United States, of the approximately one million people living with HIV/AIDS (PLWHA), 30% are also infected with HCV. 

In the late 1990s, with the introduction of potent medication combinations against HIV (highly active antiretroviral therapy, HAART) death rates due to AIDS declined dramatically.  Other medical problems emerged, namely liver disease due to chronic HCV.  … HIV affects the natural course of HCV by accelerating the rate of fibrosis (scarring) progression.  Coinfected persons may develop cirrhosis and end-stage liver disease more quickly.  Liver disease has become a leading cause of death and illness [in] PLWHA with well-controlled HIV.  It is important to acknowledge coinfection as a distinct condition.

DiagnosisAll PLWHA should be screened for HCV. HIV-seropositive persons can have a negative HCV antibody but still be infected with HCV (false negative test). 

There is controversy regarding the role of liver biopsy in HIV-HCV coinfection.  Liver biopsy is not a perfect test.  It is associated with risks, can give inaccurate results, and is not always accessible.  Lack of a liver biopsy should not prevent treatment.  Some experts agree that if a person has a high likelihood of achieving a sustained virologic response (SVR) and/or is a candidate for pegylated interferon/ribavirin therapy, th[ey] should receive HCV treatment without a liver biopsy.  If a coinfected person shows signs of cirrhosis, a liver biopsy is not necessary.

 

When should a repeat biopsy be performed?  Two to three years in the setting of HIV.  It is important to note that ALT levels in the blood do not always reliably indicate the extent of liver disease in HIV-HCV coinfected individuals.  Therefore, ALT should not be used to guide decisions on biopsy or treatment.

 

Evaluation and Treatment
Every HIV-HCV coinfected person with compensated chronic HCV (which means no history of ascites/fluid in the belly, encephalopathy/toxins in the bloodstream due to the liver’s inability to filter, or variceal bleeding/bleeding from swollen veins around the liver) should be considered for HCV antiviral therapy.

 

There is more data available now about the use of pegylated interferon and ribavirin combination therapy in coinfection.  Studies indicated that the optimal first-line treatment for chronic HCV in HIV-seropositive individuals never before treated for HCV is pegylated interferon plus ribavirin.  Even when SVR does not occur, fibrosis in the liver can improve or stabilize.  [The] studies showed that adherence to pegylated interferon and ribavirin is critical to successful therapy; coinfected individuals need to take at least 80% of their ribavirin and 80% of their pegylated interferon doses for at least 80% of the course of therapy in order to get the maximum benefit. 

As most coinfected persons in the U.S. have genotype 1 infection and high HCV viral loads, investigators are considering strategies to boost treatment efficacy.  The best dose of ribavirin and optimal length of treatment are not yet established.  Most large studies have used lower doses (e.g. 800 mg daily) of ribavirin rather than the weight-based higher doses due to concerns about side effects, especially anemia (a drop in red blood cells that carry oxygen). 

The present understanding is that many individuals contending with drug addiction and/or mental health problems can be treated for HCV with multidisciplinary care and appropriate supports.  

Current Recommendations

The only contraindication specific to HIV-seropositive persons is an active opportunistic infection.  Liver enzymes should be monitored after starting HIV medications.  Individuals should be screened for hepatitis A and B and given vaccines for these liver viruses if they are susceptible.  Counseling and education is an important part of care to reduce transmission to others and diminish further liver damage.  All coinfected individuals should be advised to avoid alcohol since it is known to worsen liver disease.  Alcohol also can have a negative influence on treatment response.  Condom use is recommended.  Of recent concern are reports of outbreaks of acute (new) HCV among HIV-positive men who have sex with men, likely due to unprotected anal sex, potentially facilitated by co-occurring sexually transmitted infections. 

Future Directions
Over the last few years much progress has been made in understanding coinfection.  An enormous need for further research remains.  Studies are in progress to evaluate new agents (potential medications) to target the HCV virus.  As the population of coinfected individuals ages, there will be a greater prevalence of advanced liver disease over time.

Drug dependence is among the main reasons that coinfected persons are not being treated for HCV infection.  This does not need to be the case and makes little sense given that the reservoir of HCV infection in the U.S. is among persons who inject drugs.

Finally, prevention efforts are vital to stem the overlapping epidemics of HIV, HCV and opioid addiction, and to limit the burden of liver disease among PLWHA.  These include expanded access to: HCV and HIV testing and care; sterile syringes via needle exchange programs and over-the-counter syringe sales; substance abuse treatment; and integrated, cross-disciplinary HIV, HCV and addiction care.  This can only occur with additional resources.  It is a public health imperative to prevent further coinfection and to expand access to high quality HCV care for PLWHA.

Future of HCV treatment

Future hepatitis C virus treatment: interferon-sparing combinations

Liver International - Excerpted. 
Special Issue: Proceedings of the 4th Paris Hepatitis Conference. The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.Volume 31, Issue Supplement s1, pages 62–67, January 2011

Edward Gane - New Zealand Liver Transplant Unit, Auckland, New Zealand

Link -  Future of HCV treatment

(Excerpts)

An estimated million people have chronic hepatitis C virus (HCV) infection. By 2030, more than 40% will be cirrhotic and the number of cases with end-stage liver disease is projected to triple. Current standard-of-care (SOC) is the combination of pegylated interferon plus ribavirin for 24–48 weeks. Unfortunately this is associated with poor efficacy and tolerability. It is hoped that the development of direct acting antiviral agents (DAAs) will address this  unmet medical need. The addition of a protease inhibitor to pegylated interferon plus ribavirin is associated with increase in efficacy and shortened duration of therapy in patients with HCV GT1 (Geno-Type 1) and is likely to become the new standard-of-care. It is hoped that the combination of multiple DAAs which target different steps of HCV replication should provide interferon-free treatment regimen.
 
The incidence of HCV infection has decreased by more than 50% over the last decade, reflecting reduced exposure risk. Although the size of the population with chronic HCV infection has been stable since 2000, this is an aging cohort and the proportion with cirrhosis will double over the next decade from 16 to over 35%. As a result, the annual rate of both HCV-related hepatocellular carcinoma and HCV-related-mortality is projected to triple again by 2030. The only way to prevent this projected health burden is to reduce the pool of infected patients through successful antiviral therapy. However, <10% of the infected population has been treated, and less than half of these have been cured. It is estimated that these numbers would need to increase almost 10-fold to prevent the projected increase in HCV-related complications.

Adherence to therapy is an important determinant of outcome. Both PEG-IFN (pegylated interferon) and ribavirin are associated with significant adverse effects, from flu-like symptoms, fever, rash, anorexia, thyroid dysfunction, to dose-related life-threatening cytopenias and mood disorders. Side effects result in a dose reduction in 60–80% of patients and treatment withdrawal in 5–10%. Many patients never start SOC because of real or perceived medical or psychosocial contraindications to either IFN or ribavirin. Many more defer therapy because of anecdotal stories about severe adverse effects.  Finally, there is a growing pool of largely GT1 patients who have not previously responded to PEG-IFN-a and ribavirin treatment, in whom retreatment no alternative treatment options are currently available.

Over the last 5 years, [Many]  protease and polymerase inhibitors have entered clinical development, of which several have halted because of toxicity.  The DAAs closest to being marketed are the protease inhibitors, boceprevir and telaprevir. Phase 3 global registration studies of both will be completed this year and are expected to be the first DAAs to gain regulatory approval as add-on therapy to current SOC PEG-IFN plus ribavirin. The benefits in terms of efficacy will be significant – 48 weeks of boceprevir plus SOC increased the SVR rates in treatment-naïve GT1 patients from 38 to 66%, while twelve weeks of telaprevir plus 24 weeks SOC increased the SVR rates from 43 to 75%. Triple therapy may also offer hope in treatment-experienced patients, especially previous responder relapsers and partial responders. However, both have specific toxicities (notably anemia and (taste perversion – read as nausea) with boceprevir and anemia and rash with telaprevir), which increased the rate of treatment withdrawal in the DAA combination arms.   Triple therapy, (adding telaprevir or boceprivir to SOC), is likely to become the new SOC in late 2011, this will not be suitable for patients either intolerant of or with contraindications to IFN or ribavirin, including patients with decompensated cirrhosis or following solid organ transplantation. Also, the efficacy of this triple therapy will probably be reduced in treatment-experienced patients, especially those who were non-responders to a previous treatment with SOC. All current protease inhibitors and most non-nucleoside polymerase inhibitors in development are active primarily against HCV GT1.  

The successful development of an all-oral, IFN-free regimen of multiple DAAs should address this current extensive unmet medical need and potentially become the standard of care for all patients with chronic HCV infection. The rationale for this approach is based on the current human immunodeficiency virus (HIV) treatment paradigm, in which a combination of different DAA agents, which target different steps of viral replication, has been shown to increase viral suppression as well as delay or prevent the emergence of antiviral resistance. There is a rapidly increasing list of potential candidates for such a combination including NS3 helicase inhibitors, NS3/4A protease inhibitors, cyclophyllin B inhibitors, NS5A inhibitors, NS5B nucleoside inhibitors and NS5B non-nucleoside inhibitors.

The primary goal of combination DAA therapy in HCV infection will be to provide a safe and effective substitute for IFN regimens in all treatment-naïve and -experienced patients.Although the new treatment paradigm for HCV is based on HIV, the goals are very different. In HIV infection, a cure is not achievable because it is impossible to eradicate infection from lymphocytes and macrophage reservoirs and from nuclear integration. Therefore, lifelong combination DAA therapy is needed to maintain viral suppression and prevent disease progression.  Viral eradication should be possible with short-course combination DAA.
 
An additional requirement before embarking on combination DAA studies in patients should be data from preclinical and human clinical studies for each candidate DAA, confirming lack of cross-resistance, lack of overlapping toxicities and a low likelihood of any drug–drug interactions, which could affect antiviral activity, bioavailability or clearance. [Current research] fulfilled all of these requirements but was performed in Australia and New Zealand, because the conservative regulatory environment of the FDA and EMEA did not allow this study to be performed in either Europe or the US at that time. The success of this proof-of-concept, and widespread enthusiasm in the HCV field over these results, will push the regulatory authorities to modify their previously conservative position.