Introduction

Ritonavir is an antiretroviral protease inhibitor that is widely used in combination with other protease inhibitors in the therapy and prevention of human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). Ritonavir can cause transient and usually asymptomatic elevations in serum aminotransferase levels and, rarely, can lead to clinically apparent acute liver injury. In HBV or HCV coinfected patients, highly active antiretroviral therapy with ritonavir may result of an exacerbation of the underlying chronic hepatitis B or C.

Background

Ritonavir (ri toe' na vir) is peptidomimetic HIV protease inhibitor that acts by binding to the catalytic site of the viral protease, thereby preventing the cleavage of viral polyprotein precursors into mature, functional proteins that are necessary for viral replication. Ritonavir was approved for use in the United States in 1996 and is still widely used in combination with other antiretroviral agents for the prevention and treatment of HIV infection. Ritonavir is available under the brand name Norvir in capsules of 100 mg and as an oral solution (for pediatric use). Ritonavir (50 mg) is also available in a fixed combination with lopinavir (200 mg) under the brand name Kaletra. While originally evaluated and approved to be used in full doses (600 mg twice daily) in combination with nucleoside or nonnucleoside reverse transcriptase inhibitors, ritonavir is now used mostly in a low or “booster” dose (50 to 100 mg twice daily) in combination with other protease inhibitors such as atazanavir, fosamprenavir, indinavir, lopinavir, nelfinavir, and saquinavir. Ritonavir is a potent inhibitor of CYP 3A4 activity in the liver, and in low doses causes a prolongation of the half-life of other protease inhibitors that are metabolized by this pathway. The most common side effects of ritonavir are nausea, diarrhea, gastrointestinal upset, change in taste, fatigue, rash and, with long term use, hyperlipidemia and lipodystrophy.

Hepatotoxicity

Some degree of serum aminotransferase elevations occurs in a high proportion of patients taking ritonavir containing antiretroviral regimens. Moderate-to severe elevations in serum aminotransferase levels (>5 times the upper limit of normal) are found in up to 15% of patients treated with full doses of ritonavir and are more common in patients with HIV-HCV coinfection. With low “booster” doses, ritonavir does not appear to increase the frequency or severity of serum enzyme elevations, and those that occur are usually asymptomatic and self-limited, resolving even with continuation of ritonavir. Clinically apparent liver injury from full doses of ritonavir has been reported, but hepatotoxicity from low dose ritonavir has not been clearly linked to acute liver injury. In many situations, the liver injury is difficult to attribute to ritonavir because it is used in combination with higher doses of other protease inhibitors. HIV protease inhibitors have been associated with acute liver injury arising 1 to 8 weeks after onset, with variable patterns of liver enzyme elevation, from hepatocellular to cholestatic. Immunoallergic features (rash, fever, eosinophilia) are uncommon as is autoantibody formation. Ritonavir in combination with saquinavir has also been associated with a rapid onset (1 to 4 days) acute hepatic injury in patients who are taking rifampin and perhaps other agents that affect CYP 450 activity, such as phenobarbital. Finally, initiation of ritonavir based highly active antiretroviral therapy can lead to exacerbation of an underlying chronic hepatitis B or C in coinfected individuals, typically arising 2 to 12 months after starting therapy and associated with a hepatocellular pattern of serum enzyme elevations and increases followed by falls in serum levels of hepatitis B virus (HBV) DNA or hepatitis C virus (HCV) RNA. Ritonavir therapy has not been clearly linked to lactic acidosis and acute fatty liver that is reported in association with several nucleoside analogue reverse transcriptase inhibitors.

Likelihood score: C (probable rare cause of clinically apparent liver injury).

Mechanism of Injury

The cause of liver enzyme elevations during ritonavir therapy is not entirely known. Ritonavir is extensively metabolized by the liver via the cytochrome P450 system (CYP 3A4), which it also inhibits. Thus, production of a toxic intermediate of ritonavir or other agents that are metabolized by CPY 3A4 may underlie liver injury. In patients with HIV and HCV or HBV coinfection, initiation of highly active antiretroviral therapy may be associated with flares of the underlying chronic hepatitis, which may be the result of reconstitution of the immune system, viral interactions or direct effects of the agents on the hepatitis virus.

Outcome and Management

The rare cases of clinically apparent liver injury attributed to ritonavir have been self-limited, and chronic hepatitis and vanishing bile duct syndrome have yet to be linked to its use. Rechallenge leads to recurrence of liver injury and should be avoided. There is little evidence of cross reactivity among the various protease inhibitors and other agents can usually be safely substituted. The exacerbation of hepatitis B or C that can occur with ritonavir based antiretroviral therapies can be severe and lead to acute liver failure or progressive, end stage liver disease. Patients with HCV or HBV coinfection should be monitored prospectively for viral and serum aminotransferase levels and appropriate therapy instituted if possible.

References to ritonavir are included with references to all the HIV protease inhibitors in the overview section of Protease Inhibitors (updated September 2017). Most of the HIV protease inhibitors in clinical use are proteinomimetic drugs and are structurally unrelated.

Drug Class: Antiviral Agents, Antiretroviral Agents

Other Drugs in the Subclass, Protease Inhibitors: Amprenavir, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinavir, Nelfinavir, Saquinavir, Tipranavir

Case 1. Precipitation of hepatic steatosis and lactic acidosis by addition of ritonavir to long-term stavudine therapy.

[Modified from: Picard O, Rosmorduc O, Cabane J. Hepatotoxicity associated with ritonavir (letter). Ann Intern Med 1998; 129: 670-1. PubMed Citation]

A 28 year old woman with HIV infection and AIDS developed serum aminotransferase elevations (133 U/L) five weeks after starting an antiretroviral regimen of ritonavir (1200 mg/day), stavudine and lamivudine. She had been on multiple nucleoside reverse transcriptase inhibitors in the past, including zidovudine, didanosine, zalcitabine and lamivudine and had normal serum aminotransferase levels on several occasions. She did not drink alcohol and tests for hepatitis A, B and C were negative. Despite the ALT elevations, she was asymptomatic and the abnormalities rapidly resolved with stopping antiretroviral therapy. Five weeks after restarting this regimen, however, she developed abdominal pain, nausea and jaundice. She was found to have weight loss, an enlarged and tender liver, and ascites. Serum ALT was 327 U/L, bilirubin 18.0 mg/dL and prothrombin index was 22%. Tests for viral hepatitis were negative. She developed lactic acidosis and encephalopathy. A liver biopsy showed microvesicular steatosis, cholestasis and fibrosis with minimal inflammation. The antiretroviral agents were stopped, and she improved slowly, liver tests being normal 8 weeks later. Lamivudine and stavudine without ritonavir were reintroduced and she remained without evidence of recurrence of liver injury over the next 9 months.

Case 2. Exacerbation of chronic hepatitis C during antiretroviral therapy in a patient with HIV-HCV coinfection.

[Modified from: John M, Flexman J, French MA. Hepatitis C virus-associated hepatitis following treatment of HIV-infected patients with HIV protease inhibitors: an immune restoration disease? AIDS 1998; 12: 2289-93. PubMed Citation]

A 36 year old man with HIV infection developed rise in ALT levels followed by symptoms and jaundice 8 weeks after starting antiretroviral therapy with lamivudine (300 mg/day), stavudine (80 mg/day) and ritonavir (1200 mg/day) (Table). His levels of HIV RNA had fallen (5.5 to <2.6 log10 copies/mL) and CD4 counts had risen (32 to 138 per μL) on antiretroviral therapy. He had no recent risk factors for viral hepatitis and ultrasound showed no evidence of biliary obstruction. A liver biopsy showed chronic hepatitis. He tested negative for hepatitis A and B, but for the first time, was reactive for anti-HCV. Testing of stored serum specimens demonstrated that HCV RNA was present at moderately high levels (5.8 log10 copies/mL) for at least two years before initiation of antiretroviral therapy. Treatment was stopped and serum aminotransferase levels improved slowly and incompletely. Restarting therapy using stavudine, didanosine and indinavir was followed by a further worsening of serum aminotransferase levels, which also did not improve with alpha interferon or with prednisolone therapy, but which eventually fell to baseline after stopping HIV therapy whereupon HIV RNA levels rose to baseline.

Case 3. Exacerbation of chronic hepatitis B during antiretroviral therapy in a patient with HIV-HBV coinfection.

[Modified from: Carr A, Cooper DA. Restoration of immunity to chronic hepatitis B infection in HIV-infected patient on protease inhibitor. Lancet 1997; 349: 995-6. PubMed Citation]

A 34 year old man with HIV-HBV coinfection developed an abrupt rise in ALT levels (Table) 5 weeks after initiation of antiretroviral therapy with ritonavir (500 mg twice daily). Ritonavir was stopped, but ALT levels remained high. He was known to have serum HBsAg and HBeAg for several years, but serum aminotransferases had always been normal or “near normal.” Serological tests for hepatitis A, C and D (delta) were negative and ultrasound of the abdomen showed no evidence of biliary obstruction. A liver biopsy showed chronic hepatitis with an acute lobular component. He slowly improved and 6 months later was found to have become HBeAg-negative and anti-HBe-positive, with a marked decrease in HBV DNA levels and fall of ALT to near normal levels.