Diagnosis and management

Diagnosing drug-related hepatotoxicity can be challenging because some of the laboratory abnormalities and early symptoms resemble those of other types of liver disease. Furthermore, HIV-positive patients often take multiple drugs and it can be difficult to determine which is causing the problem.

Liver function tests, including measurements of liver enzymes, should be done before starting a new antiretroviral drug. Regular monitoring should be done during treatment, more frequently if a drug is known to cause hepatotoxicity. While any high reading is cause for concern, generally a pattern of increasing levels over time is more important than a single elevated reading. Examination of a small sample of liver tissue is not routinely done to diagnose hepatotoxicity.

The most important clue to drug-induced toxicity is laboratory abnormalities or symptoms that appear after a new medication is started. However, while liver toxicity often begins within several weeks, and a majority happens within six months, it can also develop later. In one study, the nevirapine hepatotoxicity rate increased from 4% at three months to 10% at six months to 20% at one year.ref]

Monitoring is most important during the weeks and months after starting a drug, but should continue throughout treatment. In 2001, the manufacturer of nevirapine advised that patients should have their liver function closely monitored for twelve months after starting the drug, but in a 2004 advisory, the company increased this to 18 months.

Management of liver toxicity must be done on a case-by-case basis, balancing risks and benefits and the availability of substitute therapies. The most straightforward approach is to stop the offending drug. This should be done promptly in cases of serious hypersensitivity reactions or clinical signs of liver failure. If a drug is stopped due to severe hypersensitivity, it should not be restarted.

In the case of mild or moderate liver enzyme elevations, drug discontinuation may not be necessary. The liver is often able to adapt and laboratory abnormalities can spontaneously resolve. There is some debate about whether to automatically discontinue drugs in the case of severe liver enzyme elevation, with some experts preferring frequent, careful monitoring.

Most liver enzyme elevations return to normal without any apparent long-term consequences once the offending drug is discontinued. However, this may take weeks or even months. In a South African study, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels improved to moderate or lower levels after a median of 19 days in patients with severe hepatotoxicity with nevirapine (Viramune) treatment.¹

For HIV/HCV co-infected patients, treatment for hepatitis C may increase the liver’s ability to tolerate anti-HIV drugs, since people with more advanced liver disease are more susceptible to hepatotoxicity.^{2 3} For this reason, a panel of co-infection experts recommended that anti-HCV therapy be completed before starting antiretroviral therapy in patients who do not require immediate treatment for HIV.⁴

Beyond drug discontinuation, management depends on which drug is responsible for the toxicity. Antihistamines and corticosteroids may be used to control hypersensitivity reactions, while rare cases of anaphylactic shock require emergency intensive care. The same is true for lactic acidosis. In the case of paracetamol, an amino acid called N-acetylcysteine (NAC) works as an antidote if taken soon enough.

Fortunately, the liver can regenerate and even serious injury is likely to improve once the cause is removed. However, in cases of fulminant liver failure, or with some types of drug-related toxicity that cause permanent damage, a liver transplant may be the only option.

Studies have shown that with improved antiretroviral therapy, HIV-positive patients with well-controlled disease now have a post-transplant success rate similar to that of HIV-negative people.^{5 6} Most of these patients do not experience accelerated HIV disease progression when using immunosuppressive medications to prevent organ rejection and can resume antiretroviral therapy once their condition stabilises after the operation.