Risk factors

A variety of factors can increase the likelihood that a person will develop drug-related liver toxicity. There are specific, and sometimes contradictory, factors associated with specific drugs. While a CD4 cell count above 250 cells/mm3 increases the risk of liver toxicity amongst women taking nevirapine (Viramune), mitochondrial toxicity has been linked to lower CD4 cell counts.1 Similarly, whilst obesity has been linked to nucleoside reverse transcriptase inhibitor-related steatosis, women with low body weight are at higher risk for nevirapine-related liver toxicity.2

Other risk factors can be generalised across the various drug classes. These include older age, female sex, malnutrition, and heavy alcohol use. For some drugs, certain inherited genetic variations increase susceptibility to drug-related liver toxicity.3 For example, the HLA-DRB1*0101 gene pattern is linked to a higher risk for nevirapine hypersensitivity in Caucasians.4

Use of more than one hepatotoxic drug or other substance at the same time increases the risk of liver damage.

Perhaps the strongest risk factor for drug-related hepatotoxicity is pre-existing liver disease, including chronic hepatitis B or C (particularly genotype 3), non-alcoholic fatty liver disease, or alcohol-related cirrhosis.5 6 7 One study even suggests that pre-existing liver disease, not CD4 count, is the most important risk factor for nevirapine-related liver toxicity in women.8 A damaged liver is more susceptible to the toxic effects of drugs; liver impairment may reduce the ability to process drugs. 

Pregnancy, pre-existing liver abnormality, and hepatitis co-infection, but not nevirapine use, were risk factors for liver toxicity in one study of women in and outside the US.9

Co-infection with hepatitis B or C increases the risk of liver toxicity associated with NRTIs such as ddI (didanosine, Videx/VidexEC) and d4T (stavudine, Zerit), non-nucleoside reverse transcriptase inhibitors such as nevirapine, and protease inhibitors.10 11 12 In the HEPATOX study of various PI- and NNRTI-based regimens, hepatitis C co-infection was the only factor associated with an increased risk of hepatotoxicity. Of those who developed liver toxicity, 89% had hepatitis C.13 In another study, twice as many hepatitis B or C co-infected individuals starting an initial NNRTI-based regimen developed serious hepatotoxicity than did HIV mono-infected patients; that rose to 3.5 times as many for those starting a protease inhibitor-based regimen.[ref] Though percentage varies by country, an estimated 25% of HIV-positive people are co-infected with the hepatitis C virus.

In an analysis of records from more than 11,600 HIV-positive United States veterans, individuals co-infected with hepatitis C were more likely to develop fulminant hepatic failure on antiretroviral therapy as compared with HIV mono-infected patients.14 Another study suggested that people with hepatitis B or C co-infection taking nevirapine experience faster progression of liver fibrosis.15 Finally, 40% of HIV/HCV co-infected patients had steatosis, most of whom had taken d4T (stavudine, Zerit).16

Still, serious liver toxicity remains uncommon even in people with hepatitis B or C, and most co-infected patients are able to take protease inhibitor-based regimens safely.17

Although not toxicity per se, people with pre-existing viral hepatitis can experience ‘flares’ of liver enzyme elevations and clinical symptoms when antiretroviral therapy improves their immune function.10 This is known as immune reconstitution syndrome. In addition, people with hepatitis B may develop liver flares when they stop taking anti-hepatitis B drugs such as 3TC (lamivudine, Epivir) or adefovir (Hepsera).

References

  1. Lichtenstein KA et al. Significant correlation between low CD4 nadie and the incidence of peripheral neuropathy, pancreatitis, and lactic acidosis. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 731, 2003
  2. Sanne I et al. Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis 191: 825-829, 2005
  3. Navarro VJ et al. Drug-related hepatotoxicity. N Engl J Med 354: 731-739, 2006
  4. Martin AM et al. Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proc Natl Acad Sci U S A 101: 4180-4185, 2004
  5. Aranzabal L et al. Hepatotoxicity in HIV-infected patients starting HAART. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, abstract H-1485, 2005
  6. Aranzabal L et al. Risk of HAART-associated hepatotoxicity in HIV / HCV coinfected patients with cirrhosis. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, abstract H-1489, 2005
  7. Torti C et al. The influence of genotype 3 hepatitis C coinfection on liver enzyme elevations in HIV-infected patients after commencement of a new HAART: results from the MASTER EPOKA cohort. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, abstract H-1484, 2005
  8. Peters PJ et al. Nevirapine-associated hepatotoxicity was not predicted by CD4 count ≥250 cells/µL among women in Zambia, Thailand and Kenya. HIV Medicine. doi:10.1111/j.1468-1293.2010.00873.x, 2010
  9. Ouyang DW et al. Increased risk of hepatotoxicity in HIV-infected pregnant women receiving antiretroviral therapy independent of nevirapine exposure. AIDS 23: 2425-30, 2009
  10. Puoti M et al. Severe hepatotoxicity during combination antiretroviral treatment: incidence, liver histology, and outcome. J Acquir Immune Defic Syndr 32: 259-267, 2003
  11. Guitton E et al. Influence of HCV or HBV coinfection on adverse drug reactions to antiretroviral drugs in HIV patients. Eur J Clin Pharmacol 62: 243-249, 2006
  12. McGovern BH et al. Hepatic steatosis is associated with fibrosis, nucleoside analogue use, and hepatitis C virus genotype 3 infection in HIV-seropositive patients. Clin Infect Dis 43: 365-372, 2006
  13. Aranzabal L et al. Low risk of hepatotoxicity in patients currently starting HAART: the HEPATOX study. Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract TuPe2.3C25, 2005
  14. Kramer J et al. Hepatitis C coinfection increases the risk of fulminant hepatic failure in patients with HIV in the HAART era. J Hepatol 42: 309-314, 2005
  15. Macias J et al. Effect of antiretroviral drugs on liver fibrosis in HIV-infected patients with chronic hepatitis C: harmful impact of nevirapine. AIDS 18: 767-774, 2004
  16. Sulkowski M et al. Hepatic steatosis and antiretroviral drug use among adults coinfected with HIV and hepatitis C virus. AIDS 19: 585-592, 2005
  17. Sulkowski MS et al. Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir. AIDS 18: 2277-2284, 2004
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap
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This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member of your healthcare team for advice tailored to your situation.