Antiretroviral therapy (ART) may delay liver disease progression in people coinfected with viral hepatitis by preserving immune function. Conversely, viral hepatitis coinfection complicates HIV treatment, because it increases the risk for treatment-associated hepatotoxicity (liver injury) and discontinuation of antiretroviral therapy.

Despite concerns about hepatotoxicity, the benefits of antiretroviral therapy clearly outweigh the risks for coinfected people. In fact, ART may be a life-saving intervention for some coinfected people, since serious HCV-related liver damage is most likely to occur in people with less than 200 CD4 cells. The majority of coinfected people do not experience serious antiretroviral-induced hepatotoxicity. Clearly, HIV treatment should not be withheld from people coinfected with viral hepatitis, although careful monitoring for signs and symptoms of hepatotoxicity is warranted.

What Is Hepatotoxicity?

Some medications can cause liver injury, ranging from mild to life threatening. Drug-induced liver injury may be asymptomatic, but it usually can be identified by laboratory tests. Injury to liver cells is indicated by abnormally high levels of two liver enzymes, alanine aminotransferase (ALT) and aspartate amino transferase (AST). Some drugs cause bile duct blockage, referred to as cholestatic injury, which is indicated by elevated gamma-glutamyl transferase and alkaline phosphatase levels. Although cholestatic injury usually resolves after discontinuing medication, in rare cases, liver failure may occur.

Antiretroviral-induced hepatotoxicity is characterized by elevated liver enzyme levels with or without the following additional symptoms of liver inflammation: jaundice, fatigue, loss of appetite, abdominal pain, nausea, vomiting, diarrhea, light-colored stools, and dark urine. In addition to these symptoms, rash may precede or accompany nevirapine-induced hepatotoxicity syndrome.

Hepatotoxicity often occurs within weeks of starting a new antiretroviral regimen or agent, but may also develop with continued drug exposure over a longer period of time. In many cases, providers can closely monitor and "treat through" hepatotoxicity. However, experts recommend that all medications be discontinued when liver enzyme levels reach ten times the upper limit of normal within the first four weeks of starting a new ART regimen. Continued use of a hepatotoxic drug or regimen may be life threatening.

Several drugs from the three major classes of antiretroviral agents, NRTIs, NNRTIs, and PIs, have been associated with hepatotoxicity, and, in 2005, severe liver toxicity was responsible for Glaxo SmithKline stopping all clinical trials of its experimental CCR5 antagonist aplaviroc.

Mechanism of Hepatotoxicity

While coinfection with viral hepatitis significantly increases risk for antiretroviral-associated hepatotoxicity, several additional factors can also cause or contribute to liver toxicity. These can include alcohol use, direct toxicity of a specific drug, and interactions between ARV agents and medications used to treat a range of HIV-related comorbidities, namely opportunistic infections and psychiatric conditions. Genetic differences in drug metabolizing enzymes and related host factors may also affect an individual's risk for hepatotoxicity.

In coinfected people, ART-related immune restoration may result in flares of symptomatic hepatitis, and certain antiretroviral agents may exacerbate hepatic steatosis (the accumulation of fat in the liver), a condition associated with more serious liver damage in persons with hepatitis C.

The liver is involved in the metabolism of several antiretroviral agents, and serious liver damage may alter the liver's metabolic or excretory capacity. Yet the extent of liver damage can vary widely among coinfected individuals, ranging from mild fibrosis to serious liver scarring, known as cirrhosis. Coinfected people with more serious liver damage (defined as Metavir biopsy score of F3 or F4) are more likely to develop antiretroviral-associated hepatotoxicity than those with lower Metavir scores (F1 or F2) and less liver damage.¹

For vulnerable persons with more advanced liver disease, metabolic alterations may lead to increased or decreased drug exposure, resulting in either the accumulation of toxic drug levels -- with accompanying increased risk for side effects and toxicity -- or a decline to subtherapeutic levels and an increased risk for developing drug resistance. Metabolic alterations may also increase the potential for drug-drug interactions.

Antiretroviral Drug Levels and Hepatotoxicity

Antiretroviral drug levels must be high enough for a drug to achieve its effect without causing toxicity; the range between a minimally effective dose and a toxic dose is known as the therapeutic window. Doses above the therapeutic window may aggravate side effects and increase toxicity, leading to discontinuation, or worse. It is reasonable to assume that some cases of hepatotoxicity result from chronic dosing above the therapeutic window. Furthermore, the different therapeutic window may vary in each individual depending on coadministered prescription drugs and genetic, immunologic, or environmental factors.

Pharmacokinetic (PK) studies assess what happens to a drug in the body: how it is absorbed, distributed, metabolized and eliminated. Pharmacodynamic (PD) studies evaluate drug activity, or what a drug does to the body. Data from both types of studies are needed to characterize the hepatic safety and proper dosing of antiretroviral agents in coinfected people. It is important that coinfected people are included and closely observed in Phase II and Phase III studies of new drugs so that longer-term data on hepatic safety and tolerability of antiretroviral agents may be collected.

Some data on drug levels in people with serious liver damage are available. In 2003, FDA issued guidance to industry for conducting pharmacokinetic (PK) studies in persons with hepatic impairment (defined as mild-to-moderate cirrhosis according to the Child-Pugh scoring system). FDA recommends, rather than requires, these studies when hepatic metabolism and/or excretion accounts for a substantial portion (>20 percent) of the absorbed drug or elimination of a parent drug or active metabolite. In addition, even when the drug or active metabolite is eliminated to a lesser extent than 20%, FDA strongly recommends that industry conduct these studies whenever labeling, literature, or available information suggests that the drug has a narrow therapeutic range.²

Although hepatic impairment studies performed to date have yielded useful information, their results do not apply to all coinfected people -- only those who have developed cirrhosis. Antiretroviral drug levels are not studied in coinfected people with mild to moderate liver damage, and not all approved antiretroviral agents have been studied in cirrhotics.

Prior to approval, FDA should require that PK studies of antiretroviral agents are conducted in coinfected people with varying degrees of liver damage, particularly those with more advanced liver damage such as bridging fibrosis and cirrhosis. Ideally, barring any significant concerns about drug safety, PK studies in coinfected persons should be underway before Phase III trials and Expanded Access Programs are launched.

PK studies are only the first step towards optimizing antiretroviral therapy for coinfected persons. Additional data are needed, particularly longer-term assessment of antiretroviral drug levels, side effects, safety, efficacy, tolerability and liver disease progression in coinfected persons.

Biopsy Alternative Needed

However the major challenge in designing such studies is the lack of a non-invasive and inexpensive method to assess liver damage in research and clinical practice. Liver biopsy is the best way to determine what is happening to liver tissue, but it is expensive, invasive, can be painful, and carries a small risk of complications; rarely, these have been life-threatening. Ongoing research is evaluating several alternatives to liver biopsy, but none have replaced the gold standard.

One potential solution involves using a combination of blood tests, known as serum biomarker panels, to assess the extent of liver damage in clinical practice. Although many experts do not believe that serum biomarker panels are a viable substitute for liver biopsy, these panels are likely be used in the clinic. One way to understand the value of these panels would be to recruit coinfected people who had been biopsied into PK studies, then compare results from serum biomarker testing to biopsy. If a good correlation between biopsy and serum biomarker panel results were found, this would mean that valuable and clinically relevant data could be collected.

Drug Levels Matter

More research on ARV drug levels in coinfected persons is also warranted, particularly since conflicting data have emerged from many scattered, small PK studies of single drugs. For example, Dominguez and colleagues reported that coinfected participants had significantly lower levels of lopinavir/r vs. those with HIV alone in Hepadose, a recent PK study measuring PI and NNRTI levels in 132 HIV-positive people, 70 of whom were coinfected. Hepadose measured trough PI and NNRTI plasma concentrations in 132 people (the trough is the lowest level of a drug present in the bloodstream immediately prior to the next dose). But a different study from Dickinson and colleagues did not find significant differences in plasma levels of lopinavir/r according to HCV status, or even among cirrhotics.^3,4

Hepadose also detected significantly higher trough concentrations of efavirenz, nevirapine and nelfinavir in coinfected people compared to people with HIV alone. In particular, the study saw trough concentrations of efavirenz and nevirapine that were significantly above therapeutic range in 56% of coinfected patients with fibrosis scores of F0 to F3, and a whopping 86% of those with F4 (vs. 24% for those with HIV alone).³

Other studies have reported similar findings. Jeantils and colleagues detected above-the-range trough concentrations of efavirenz in six of twelve coinfected individuals. Accordingly, the investigators successfully reduced daily efavirenz doses from 600mg to 400 mg.⁵

Until more data are available on ARV drug levels in coinfection, therapeutic drug monitoring (TDM) may be useful for coinfected individuals, particularly those with advanced liver damage, and persons experiencing elevated liver enzyme levels, side effects, or virologic failure. TDM studies provide individualized plasma levels of protease and/or non-nucleoside reverse transcriptase inhibitors (nucleoside analogue drugs, which become active only inside of cells, require intracellular assays to measure drug concentrations). Dosing is adjusted accordingly, as needed. Unfortunately, TDM is an individualized measurement, and not applicable to anyone other than the person being studied. TDM is more commonly used in Europe than the United States, where it is costly and difficult to obtain outside of a clinical trial.

Tracy Swan is with Treatment Action Group.

References

1. Aranzabal L, Casado J, Quereda C, et al. HAART-associated hepatotoxicity in HIV/HCV co-infected patients with advanced chronic liver disease or cirrhosis. Abstract TuPe1.1C38. 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, Brazil. July 2005.

2. Food and Drug Administration. Guidance for Industry. Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling. May 2003. (Accessed on 7th October 2005.)

3. Dominguez S, Peytavin G, Guiguet M, et al. The HEPADOSE Study: evaluation of protease inhibitors and non nucleoside analogue plasma concentrations in HIV/HCV and HIV infected patients. Abstract WePp0305. 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, Brazil. July 2005.

4. Dickinson L, Micheli V, Meraviglia P, et al. The impact of co-infection with Hepatitis C or Hepatitis B on lopinavir pharmacokinetics in patients infected with HIV. Abstract WePe3.2C06. 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, Brazil. July 2005.

5. Jeantils V, Wade A, Touitou H, et al. Therapeutic drug monitoring of efavirenz (EFV) in HIV-1 infected patients treated with efavirenz containing regimen. Abstract H-1995. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, Illinois. 2003.