Viral suppression protects against long-term liver damage caused by older HIV drugs

A history of treatment with some older antiretroviral drugs can have a lasting negative impact on liver health, German researchers report in PLOS One. They found that although co-infection with hepatitis C virus (HCV) was the strongest risk factor for liver damage, treatment with didanosine (ddI) and zidovudine (AZT) was also associated with significant liver fibrosis or cirrhosis. Neither of these drugs is now used in routine HIV care, and the study found strong evidence that viral suppression with antiretroviral therapy halved the risk of liver fibrosis in those previously exposed to the drugs.

“This study demonstrates that history of ddI intake and AZT intake are independently associated with the presence of significant fibrosis and cirrhosis,” the authors comment. “Importantly, sufficient suppression of HIV replication protected from significant liver fibrosis…for the wide range of mono-infected patients, the strongest protection against development of liver fibrosis seems to be sufficient HIV-replication control, which outweighs the damage of previous cART [combination antiretroviral therapy] regimens with drugs such as ddI and AZT.”

Most people living with HIV now have a normal life expectancy as a consequence of effective antiretroviral treatment, and viral suppression with modern therapies has been shown to have a beneficial effect on liver health. Nevertheless, liver disease remains a leading cause of serious illness and death in people with HIV. Much of this can be attributed to co-infection with HCV and/or hepatitis B virus (HBV), or problematic alcohol use. It is well known that older, and now little used, antiretrovirals can cause liver toxicities. The drugs especially associated with liver damage include unboosted protease inhibitors and certain nucleoside reverse transcriptase inhibitors (NRTIs), including didanosine, zidovudine and stavudine (d4T).



Thickening and scarring of connective tissue. Often refers to fibrosis of the liver, which can be caused by an inflammatory reaction to long-term hepatitis infection. See also ‘cirrhosis’, which is more severe scarring.


Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

adjusted odds ratio (AOR)

Comparing one group with another, expresses differences in the odds of something happening. An odds ratio above 1 means something is more likely to happen in the group of interest; an odds ratio below 1 means it is less likely to happen. Similar to ‘relative risk’. 


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.

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.

Investigators at the HIV outpatient clinic at the University of Bonn wanted to assess the impact of therapy with these older drugs on the risk of significant fibrosis and cirrhosis.

They designed a cross-sectional study involving 333 HIV-positive adults who received care between 2009 and 2011.

Fibrosis and cirrhosis were assessed using transient elastography (FibroScan). Blood samples obtained during routine follow-up were examined to determine current CD4 count and viral load and viral hepatitis co-infection status. Patient records were reviewed for information on current and previous use of HIV therapy.

Patients had a median age of 45 years and 83% were male. Just over a quarter were infected with HIV by infected blood products or injecting drug use. The median time since HIV diagnosis was ten years. Most people (89%) were taking antiretrovirals and the median duration of treatment was five years. A third of people had co-infection with HCV and 7% with HBV. As regards the use of potentially liver-toxic drugs, a third of individuals had a history of zidovudine therapy, a quarter had a history of stavudine exposure and 12% had taken didanosine.

Overall, 18% of people had significant fibrosis and 8% had cirrhosis. Prevalence of both was significantly higher among people with HCV co-infection compared to HIV-mono-infected individuals.

After controlling for potential confounders, co-infection with HCV was by far the most important risk factor for the presence of serious fibrosis or cirrhosis (aOR = 5.3; 95% CI, 3.1-91, p < 0.001). A history of therapy with didanosine was also significant (aOR = 2.7; 95% CI, 1.3-5.6, p = 0.008). However, current viral load below 40 copies/ml was strongly protective against the presence of liver damage (aOR = 0.5; 95% CI, 0.3-0.9, p = 0.024). A separate analysis of people with HCV co-infection showed that a history of zidovudine therapy was also a significant risk factor for serious fibrosis or cirrhosis (aOR = 4.1; 95% CI, 1.2-13, p = 0.021).

“Our study demonstrates that a history of ddI and AZT treatment still bears an unfavourable influence on the presence of liver disease,” conclude the authors. “Control of HIV replication seems to be the master switch in hampering development of liver fibrosis in HIV patients.”


Anadol E et al. Exposure to previous cART is associated with significant liver fibrosis and cirrhosis in human immunodeficiency virus-infected patients. PLOS One, 13(1): e0191118, (2018)