Starting HIV therapy associated with improvements in liver function, especially when viral load is suppressed

Starting antiretroviral therapy is associated with improvements in liver function in HIV-positive men with and without viral hepatitis co-infection, investigators from the United States report in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

Patients enrolled in the Multicenter AIDS Cohort Study (MACS) had their liver function monitored using aspartate aminotransferase to platelet ratio index (APRI) before and after starting HIV therapy. Liver function declined significantly in both mono- and co-infected men in the period before therapy was started. Initiating antiretrovirals was associated with an improvement in APRI, and this was associated with viral load. The beneficial effects of antiretroviral therapy waned after two years for the mono-infected men, possibly because of the toxicities associated with older anti-HIV drugs.

“We demonstrated that HAART [highly active antiretroviral therapy] is associated with improvement in APRI in HIV-infected men with and without viral hepatitis,” comment the researchers. “Our observation that men with undetectable HIV RNA had the largest decreases in APRI and that the effect was reduced progressively with increasing HIV RNA supports the hypothesis that the beneficial hepatic effects of HAART are mediated via suppression of HIV replication.”

Glossary

virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.

ribonucleic acid (RNA)

The chemical structure that carries genetic instructions for protein synthesis. Although DNA is the primary genetic material of cells, RNA is the genetic material for some viruses like HIV.

 

hepatitis B virus (HBV)

The hepatitis B virus can be spread through sexual contact, sharing of contaminated needles and syringes, needlestick injuries and during childbirth. Hepatitis B infection may be either short-lived and rapidly cleared in less than six months by the immune system (acute infection) or lifelong (chronic). The infection can lead to serious illnesses such as cirrhosis and liver cancer. A vaccine is available to prevent the infection.

replication

The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

prospective study

A type of longitudinal study in which people join the study and information is then collected on them for several weeks, months or years. 

Liver disease is a major cause of serious illness and death in HIV-positive patients who are co-infected with HBV and/or HCV. Declines in liver function have also been observed in men with HIV mono-infection. Immune suppression has been postulated as a cause of liver dysfunction in the context of untreated HIV infection. Antiretrovirals may improve liver health, but several anti-HIV drugs are known to have liver toxicities.

To obtain a clear understanding of the effects of antiretroviral therapy on liver function, investigators from MACS designed a prospective study involving HIV-positive men with and without hepatitis co-infection. APRI – an accepted marker of liver function – was monitored before and after the initiation of treatment.

The study population comprised 494 men, of whom 53 had viral hepatitis co-infection (24 HIV/HCV, 27 HIV/HBV, 2 HIV/HBV/HCV).

Liver function was measured four years and one year prior to HIV therapy being started. Analysis was repeated two and five years after treatment initiation.

Over three-quarters of patients (79%) started antiretroviral treatment before 2001 and 87% received therapy with toxic NRTIs such as didanosine and stavudine.  

Initial analysis showed significant increases in APRI in the pre-treatment era for both the mono- and co-infected patients (0.49 to 0.55, p < 0.01; 1.26 to 1.62, p = 0.02, respectively). In contrast, in the first two years following the initiation of HIV therapy, mean APRI declined in both the mono-infected (0.55 to 0.53, p = 0.01) and co-infected (1.62 to 1.31, p = 0.07) groups.

After adjusting for factors such as age, race and CD4 cell count, in mono-infected men APRI increased by 17% in the period before therapy was started. Changes in liver function in the first two years after initiating treatment were related to viral load. APRI decreased by 16% for men with viral suppression, by 2% for patients with a viral load between 500 and 75,000 copies/ml and increased by 47% for individuals with a viral load above 75,000 copies/ml. Analysis through to five years after treatment initiation showed overall increases in APRI, but APRI did not return to pre-treatment levels..

Among co-infected men, multivariate analysis showed an average increase of 34% in APRI in the pre-treatment period. Similar to mono-infected patients, changes in APRI in the two years after therapy initiation were associated with viral load. Patients with viral suppression had a 22% decrease, while those with a viral load between 500 and 75,000 copies/ml had a 13% decrease. There were too few patients with a very high viral load to rigorously analyse the impact of treatment on liver function.

Unlike the mono-infected patients, APRI continued to decline among co-infected men with viral suppression (p = 0.03) through to the five-year follow-up point (mean 8% decrease).

Cumulative exposure to older, more toxic NRTIs was associated with higher APRI after treatment initiation. After taking this into account, liver function five-years after starting antiretrovirals among mono-infected men with viral suppression was significantly better than that observed in the period before treatment was initiated.

“APRI improves with suppression of HIV RNA replication in HIV-mono-infected and HIV-viral hepatitis co-infected men in the first two years after [treatment initiation],” conclude the authors. “This improvement is greatest in those who achieve an undetectable HIV RNA.” They call for further research to elucidate the mechanisms for this improvement and to see if the benefits persist into the long-term with newer HIV treatment combinations.

References

Price JC et al. Highly active antiretroviral therapy mitigates liver disease in HIV infection. J Acquir Immune Defic Syndr, online edition. DOI: 10.1097/QAI.0000000000000981, 2016.