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

        • Liver injury has been associated with some anti-HIV retroviral drugs.² 

          •   Even fatal reactions have been described with nucleoside analogues, non-nucleoside analogues and protease inhibitors.

          • Nucleoside analogues inhibit DNA synthesis which can result in mitochondrial toxicity, thus interfering with normal oxidative metabolism.² 

            • Nucleoside reverse transcriptase inhibitors (NRTIs )-induced mitochondrial toxicity appears important in promoting lipoatrophic element of HIV-associated lipodystrophy syndrome.¹⁰ 

               

              • "Lipoatrophy:  Facial Fat Loss"¹²

                Chow DC Day LJ Shikuma CM Lipoatrophy: facial fat loss https://www.hiv.va.gov/provider/image-library/lipodystrophy.asp?post=1&slide=21

              •  

                "Lipoatrophy:  Fat Depletion of Leg"¹³

                Chow DC Day LJ Shikuma CM Lipoatrophy:  Fat Depletion of Leg http://www.hiv.va.gov/provider/image-library/lipodystrophy.asp?post=1&slide=22

            • NRTIs inhibit mitochondrial DNA polymerase-γ (mtDNA-γ), important for mtDNA replication.

              •  

                Human Mitochondrial Genome¹⁴

                Shanel Structure of the human mitochondrial genome http://commons.wikimedia.org/wiki/File:Mitochondrial_DNA_en.svg http://en.wikipedia.org/wiki/Mitochondrial_DNA

              •  

                "Mitochondrial Function:  Formation of Mitochondria DNA"¹⁵

                Spach DJ Case 5:  Antiviral Medications and Lactic Acidemia- HIV Web Study, University of Washington Figure 3 from reference 14, slightly modified. ("Formation of Mitochondrial DNA")

               

              • mtDNA encodes for many oxidative-phosphorylation chain proteins.

                •  

                  "Mitochondrial Function:  Oxidative Phosphorylation Complex Subunits"¹⁶

                  Spach DJ Case 5:  Antiviral Medications and Lactic Acidemia- HIV Web Study, University of Washington Figure 3 from reference 14, slightly modified. ("Oxidative Phosphorylation Complex")

                • Reduced mtDNA may inhibit aerobic respiration in addition other mitochondrial activities.¹⁰  

                  • Furthermore, mitochondrial toxicity associated with NRTIs may also be due detrimental actions on mitochondrial proteins and enzyme activity associated with oxidative phosphorylation.

                  • Reduced transcription of mitochondrial RNA absent appreciable mtDNA depletion has been noted about two weeks following beginning of dual-NRTI treatment (e.g. zidovudine/lamivudine or stavudine/lamivudine).

                    • These results have been interpreted as suggesting that NRTIs are responsible for mitochondrial dysfunction by mechanisms in addition to mtDNA polymerase-γ inhibition.¹⁰ 

          • Hepatotoxicity associated with some anti-HIV retroviral drugs or HIV-related agents has been described not only as a common cause of hepatic abnormalities but that toxicity of some drugs may be worsened in the presence of hepatitis C infection.⁹

            • Under these circumstances, individuals may exhibit elevated serum alanine transaminase (ALT) or aspartate aminotransferase (AST) serum levels.

            • With some agents including macrolide antibiotics, such as azithromycin, or trimethoprim-sulfamethoxazole other liver injury patterns may be observed.

              •  

                Macrolide Antibiotic Azithromycin (Zithromax and others):  Inhibits some Gram-positive/negative/and atypical bacteria

              •  

                Trimethoprim-Sulfamethoxazole [Co-trimoazole] (TMP-SMX, Septra, Bactrim, combination 1:5 trimethoprim to sulfamethoxazole

                Trimethoprim:  Dihydrofolate reductase inhibitor; Sulfamethoxazole:  Sulfonamide antibiotic

            • Since such liver injury may be asymptomatic, monitoring of serum liver enzymes becomes a prominent means of detection.

            • Within the HIV antiretroviral class, administration of HIV protease inhibitors such as tipranavir/ratonavir or with non-nucleoside reverse-transcriptase inhibitor such as nevirapine may result in severe hepatotoxicity.⁹ 

              • A clinical study evaluated the frequency of significant hepatotoxicity as described by grade 3 or grade 4 changes in alanine or aspartate transaminase levels, considering 568 patients receiving non-nucleoside reverse transcriptase inhibitors (NNRTIs) involving nevirapine (NVP) and efavirenz (EFV).¹¹ 

              • These agents have been identified is associated with severe hepatic pathologies.¹¹ 

                • 312 patients out of 568 were prescribed EFV; whereas, 256 individuals were prescribed NVP.

                  • A relatively large percentage of patients tested positive for hepatitis C virus (43%); furthermore, about 8% of patients tested positive for hepatitis B virus.

                  • About 16% of patients receiving NVP and 8% of patients receiving EFV exhibited severe hepatotoxicity.

                    • About 33% of NVP and about 50% of EFV-associated hepatotoxic events were noted during the first three months of treatment.

                    • The likelihood of toxicity was notably increased among individuals with chronic viral hepatitis (about 70% of cases) and also notably increased in patients receiving concurrent protease inhibitors (82% of cases).

                    • Most patients (84%) who had chronic HCV or HBV did not exhibit severe hepatotoxicity.¹¹ 

              •  

                Tripranavir (Aptivus)

              •  

                Ratonavir (Norvir)

              •  

                Nevirapine (NVP, Viramune)

              • This toxicity may be more likely when these agents are administered in the presence of chronic hepatitis B or hepatitis C viral infections.