Abacavir/Lamivudine Could Be Driving Liver Damage in People with HIV/HCV Coinfection


Progression of liver fibrosis among ART-treated patients with HIV/HCV coinfection is associated with the type of nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) "backbone," Canadian research published in the September 23 online edition of Clinical Infectious Diseases suggests.

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The study was designed to see if fibrosis progression -- assessed by measuring changes in APRI scores over 5 years -- was associated with protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) treatment. However, the findings showed that progression was actually linked to the NRTIs abacavir/lamivudine (Epzicom or Kivexa).

"[Abacavir/lamivudine] use with either a PI or NNRTI was associated with changes in APRI score over time regardless of anchor class [PI or NNRTI]," commented the authors. No significant association was found between fibrosis progression and treatment with the NRTI backbone tenofovir/emtricitabine (Truvada). The authors do not regard their findings as definitive and are calling for further research.

A large number of HIV-positive people are coinfected with hepatitis C virus (HCV). Coinfected patients experience faster progression of liver fibrosis compared with HIV-monoinfected patients. Some antiretroviral drugs have been associated with liver toxicities. However, no long-term study has evaluated the association between antiretroviral class and progression of liver disease in coinfected individuals.

Investigators with the Canadian Co-infection Cohort therefore designed a study to assess the progression of liver disease in coinfected people treated with modern antiretroviral regimens based -- or anchored -- on either a PI or NNRTI. The NRTI backbone was also taken into account.

Fibrosis was assessed by measuring changes in APRI score -- a biomarker index calculated using aspartate transaminase (AST)lavel and platelet count. The authors’ statistical analysis took into account other factors potentially associated with liver damage, including age, sex, duration of HCV infection, drug and alcohol use, HIV viral load, and CD4 cell count.

The study population included 628 patients. They were equally divided between PI and NNRTI users. Efavirenz (Sustiva) was by far the most commonly used NNRTI (92%). The most frequently used PI was ritonavir-boosted atazanavir (Reyataz; 47%), followed by lopinavir/ritonavir (Kaletra; 29%), ritonavir-boosted darunavir (Prezista; 15%), and atazanavir alone (9%). Approximately two-thirds of patients received the Truvada backbone (PI = 67%; NNRTI = 69%).

The authors' first analysis showed that PI therapy was associated with an 11% increase in APRI score over 5 years. This compared to a 5-year increase of 7% with NNRTI therapy. The median APRI score was 32% higher among Truvada users when compared to people treated with Epzicom.

Despite this, changes in APRI score appeared to be driven by use of the Epzicom backbone. The median 5-year increase was 16% when combined with a PI and 11% when used with a NNRTI.

The investigators believe that the association between Epzicom and liver damage is biologically plausible. "[Abacavir] can reduce hepatocyte proliferation and increase intracellular lipids and lactate levels," they explained. "[Abacavir] is extensively metabolized by the liver."

In contrast, Truvada users did not experience a significant increase in APRI score during follow-up when used with either a PI (8% increase over 5 years) or NNRTI (3% increase over 5 years).

"This study was designed to investigate the role of the class of anchor agent on progression of liver fibrosis, not the backbone," concluded the authors. "Therefore further investigation is required to better understand how different backbone/anchor drug combinations can affect the liver of HIV-HCV coinfected persons in the long-term."



L Brunet, EE Moodie, J Young, et al. (Canadian Co-infection Cohort Study). Progression of liver fibrosis and modern combination antiretroviral therapy regimens in HIV-hepatitis C co-infected persons. Clinical Infectious Diseases. September 23, 2015 (online ahead of print).