Abacavir/lamivudine could be driving liver damage in ART-treated patients with HIV/HCV co-infection

Progression of liver fibrosis among ART-treated patients with HIV/HCV co-infection is associated with the type of nucleoside reverse transcriptase inhibitor (NRTI) “backbone”, Canadian research published in the online edition of Clinical Infectious Diseases suggests. The study was designed to see if fibrosis progression was associated with protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) treatment. However, the findings showed that progression of liver disease was actually associated with the NRTIs abacavir/lamividune (Kivexa; ABC/3TC).

Fibrosis progression was assessed by measuring changes in APRI score over five years.

“ABC/3TC use with either a PI or NNRTI was associated with changes in APRI score over time regardless of anchor class [PI or NNRTI],” comment the authors. No significant association between fibrosis progression and treatment with the NRTI backbone tenofovir/emtricitabine (Truvada; TDF/FTC) was found. The authors do not regard their findings as definitive and are calling for further research.

Glossary

protease inhibitor (PI)

Family of antiretrovirals which target the protease enzyme. Includes amprenavir, indinavir, lopinavir, ritonavir, saquinavir, nelfinavir, and atazanavir.

fibrosis

Scarring of the liver – the development of hard, fibrous tissue. See also ‘cirrhosis’, which is more severe scarring.

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 

lactate

Another name for lactic acid.

A large number of HIV-positive patients are co-infected with HCV. Co-infected patients experience faster progression of liver fibrosis compared with HIV-mono-infected 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 co-infected individuals.

Investigators from the Canadian Co-infection Cohort study therefore designed a study to assess the progression of liver disease in co-infected patients 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 – AST 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 count.

The study population comprised 628 patients. They were equally divided between PI and NNRTI users.

Efavirenz was by far the most commonly used NNRTI (92%).

The most frequently used PI was atazanavir/ritonavir (47%), followed by lopinavir/ritonavir (29%), darunavir/ritonavir (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 five years. This compared to a five-year increase of 7% with NNRTI therapy. The median APRI score was 32% higher among Truvada users when compared to patients treated with Kivexa.

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

The investigators believe that the association between Kivexa and liver damage is biologically plausible. “ABC can reduce hepatocyte proliferation and increase intracellular lipids and lactate levels,” they explain. “ABC is extensively metabolised 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 five years) or NNRTI (3% increase over five years).

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

References

Brunet L et al. Progression of liver fibrosis and modern combination antiretroviral therapy agents in HIV-hepatitis C co-infected patients. Clin Infect Dis, online edition, 2015.