Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

  • Anti-viral drugs with activity against HIV (Human Immunodeficiency Virus)

    • HIV-1 Pathophysiology/Pathogenesis:  HIV Disease Presentations

      Hepatobiliary Dysfunction in HIV (continued)

      • Effects of Anti-Retroviral Medications (continued)⁶

        • Administration of some nucleoside analogues which inhibit reverse transcriptase may result in fatal hepatomegaly with associated stenosis and lactic acidosis.⁶ 

           

          • Liver Biopsy Showing Macrovacuolar Steatosis¹¹

            "Liver biopsy from an HIV-infected patients who presented with zidovudine-related lactic acidosis (x500). "Marked macrovaculolar steatosis with rare lipid microvacuoles can be seen." Figure above corresponds to figure 2 of reference 11. Ogedegbe A-E O Thomas DL Diehl AM Hypertactataemia syndromes associated with HIV therapy (Review) Lancet Infectious Disease 3:  329-337, 2003.

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            "Micrograph of Non-alcoholic fatty liver disease (NAFLD)."¹⁰

            Nephron  "Micrograph of non-alcoholic fatty liver disease (NAFLD). Masson's trichrome & Verhoeff stain" "The liver has a prominent (centrilobular) macrovesicular steatosis (white/clear round/oval spaces) and mild fibrosis (green). "The hepatocytes stain red. "Macrovesicular steatosis is lipid accumulation so large it distors the cell's nucleus. "Differential diagnosis of centrolobular (zone III) macrovescular hepatic steatosis: Diabetes Obesity Alcohol" http://en.wikipedia.org/wiki/Fatty_liver http://commons.wikimedia.org/wiki/File:Non-alcoholic_fatty_liver_disease1.jpg

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            Computed Tomography (CT) image:  Liver steatosis (fatty liver)⁹ 

            Heilman J Liver steatosis (fatty liver):  CT image http://commons.wikimedia.org/wiki/File:Liversteatosis.png http://en.wikipedia.org/wiki/Fatty_liver

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            Hepatic Steatosis (Fatty Liver)⁸

            Hepatic Steatosis "Mechanism behind lipid accumulation in liver cells. "TNF:  tumor necrosis factor alpha NF:  nuclear factor IRS:  insulin receptor substrate apoB:  apolipoprotein M MTTP:  microsomal triglyceride transfer protein" http://en.wikipedia.org/wiki/Fatty_liver http://en.wikipedia.org/wiki/File:Steatosis.jpg

          • Examples of such drugs include zidovudine (AZT) and stavudine.

          • The association between lactic acidosis steatosis has been documented in clinical studies.⁷ 

            • One example study considered for clinical cases in which patients taking stavudine exhibited lactic acidosis, hepatic steatosis and myopathy.⁷ 

              • This was a small clinical study consisting of two men and two women, both HIV positive.

                • These individuals presented with lactic acidosis and elevated aminotransferase serum levels.

                  • Some patients underwent liver biopsy and muscle biopsy.

                    • Histologic findings from biopsy not only suggested that hepatic/muscle abnormality but also suggested mitochondrial injury.

              • For example, one patient, a 63-year-old obese HIV-infected woman presented with a 1-month history including nausea, abdominal pain with vomiting.⁷ 

                • The medical workup found severe metabolic acidosis with an arterial blood pH of 7.12, along with notably elevated serum lactate levels with hepatic steatosis and pancreatitis.

                  • The patient had been using stavudine and lamivudine for the prior six months.

                  • These agents were discontinued with the patient eventually recovering and new antiretroviral therapy consisting of nelfinavir, saquinavir and nevirapine substituting for previous antiretrovirals.

                    • The above described illness did not recur. The other patients followed a generally similar pattern.

              • The authors note that this type of life-threatening hepatic steatosis and lactic acidosis presentation, albeit uncommon, was identified in the early 1990s.⁷ 

                • By 1994, 40 cases had been reported to regulatory agencies.

                • In those instances zidovudine and didanosine were considered likely causative with the underlying mechanism proposed to be involving dysfunction of mitochondrial DNA replication.⁷

                 

          • "Algorithm for the management of hyperlactaemia in HIV-infected patients taking NRTIs."¹¹

            "Algorithm for the management of hyperlactaemia in HIV-infected patients taking NRTIs." Ogedegbe A-E O Thomas DL Diehl AM Hypertactataemia syndromes associated with HIV therapy (Review) Lancet Infectious Disease 3:  329-337, 2003.