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

      • Hepatobiliary disease remains an important health concern in HIV infected patients.² 

        • Perhaps 33% of HIV patient deaths may be related to hepatic disease.² 

          • Reasons for death due to hepatic disease in this patient subset is both due to hepatitis B or hepatitis C co-infection along with hepatic injury described by a range of dysfunction from hepatic steatosis, hypersensitivity reactions to immune reconstitution, seen following administration of cART (HAART) combined antiviral medications.

      • The likelihood of coinfection with HIV and hepatitis viruses appear dependent on geographic region.² 

        • Overview:  In the United States, about 90% of HIV-infected patients exhibit coinfections with HBV (hepatitis B virus).

          • About 10% of patients show chronic HBV infection. A range from 5%-50% of current/past patients describes coinfection with hepatitis C virus (HCV).

            • A higher rate of HCV infection, 70%-95%, appears associated with IV drug users who have HIV infection.

            • The consequence of HIV infection on the course of hepatitis appears profound. HIV + hepatitis coinfection exhibit a 300% increase in persistent hepatitis B surface antigenemia.

            • A 4 to 10 fold increases in liver-related deaths has been found in patients with HIV and active hepatitis B viral infection, when compared to patients with either infection alone.²

            • With respect to treatment, IFN-α may be less effective in treating HBV in those patients with HIV co-infection.² 

              • However, a number of other agents such as lamivudine, emtricitabine, adefovir/tenofovir/entecavir and telbivudine either alone or in combination are helpful in treating hepatitis B in those patients also infected with HIV.

                • These drugs exhibit activity against HIV and should not be used by themselves in HIV patients since such use may increase likelihood of emergence of HIV resistant strains.

                • Accordingly, treating hepatitis B infection in a patient with HIV infection constitutes a reason to treat HIV infection in that patient, independent of CD4⁺ T cell count.²

        • Hepatic dysfunction is common in patients with HIV and is reflected in increased serum alanine and aspartate aminotransferase enzymes (ALT and AST) as well as alkaline phosphatase levels.⁹ 

          • Hepatic disease may follow from viral hepatitis, HIV-related opportunistic infection or other means including:

            • Drug toxicities

            • Alcohol

            • Malignancies or

            • Nonalcoholic fatty liver disease.

          • Given related routes of transmission, hepatitis B viral (HBV) and/or hepatitis C viral (HCV) infection(s) often accompanies HIV disease.⁹  

            • Liver dysfunction as a result of these viruses represents a relatively common cause of death in HIV-infected patients despite cART (HAART) combination, highly active antiretroviral therapy.

              • A retrospective analysis carried out over 10 years following the introduction of cART evaluated proportion of deaths resulting from end-stage liver disease in HIV infected adults.¹⁰  

                • This study considered patients in France between 1995 and 2005.

                  • In 2005, approximately 24,000 patients HIV-infected individuals were evaluated.

                    • 287 deaths were noted in 2005 with 35% related to AIDS and 17% to end stage hepatic disease. ¹⁰  

                      • Most patients (75%) who died from hepatic disease had chronic hepatitis C.

                        • Excessive alcohol consumption was noted in about half of the patients.

                      • At death, most patients (62%) had undetectable HIV viral load with a median CD4⁺ T cell count of 237 cells/µL.

                      • During the study period, from 1995 to 2005, deaths due to end-stage liver disease increased from 2% to 17%; furthermore, deaths due to hepatocellular carcinoma increased from 5% (1995) to 25% (2005)¹⁰  

          • Hepatic disease in patients infected with HIV may be caused by a number of different viruses.⁹ 

            • These viruses include:

              • Hepatitis A

              • Hepatitis B

              • Hepatitis C

              • Hepatitis D (with hepatitis B)

              • Hepatitis E

              • Epstein-Barr (EBV)

              • Cytomegalovirus

              • Herpes simplex virus

              • Adenovirus

              • Varicella zoster (VZV)⁹

          • For hepatitis B virus: it is almost 4 times more likely that an individual positive for HIV, exhibiting acute HBV will transition a chronic HBV infection, compared to individuals without HIV infection.⁹ 

            • This fourfold difference corresponds to 5% versus 20%.

            • One important consequence of this co-infection is that co-infected patients exhibit increase risk of liver associated morbidity and mortality compared with individuals with chronic hepatitis B virus by itself.⁹

              • In a study specifically evaluating liver-disease mortality in individuals coinfected by HIV-1 and hepatitis B virus (HBV), a prospective cohort involving 5293 men with respect to their HIV-1 antibody status and hepatitis-B surface antigen status (HBsAg) were evaluated.¹¹ 

                • 6% of men were found HBsAg-positive. 6% corresponded to 326 individuals.

                  • Furthermore, 65% of these individuals, i.e. 213 were also HIV-1 positive.

                • Of the 4967 HBsAg negative individuals, about half were infected with HIV-1.

                • Overall, the study considered 55,123 "person-years".

                  • No deaths due to liver dysfunction were found in individuals infected neither with HIV-1 nor exhibiting the HBsAg antigen.

                    • One death was found in an individual who was HBsAg positive, while HIV-1-negative. 35 deaths (corresponding to 20,605 person-years) was associated with HIV-1-only infection [1.7 liver mortality per 1000 person-years].

                    • However, 26 deaths (corresponding to only 1834 person-years) was found in the group of individuals infected both with HIV-1 and hepatitis B virus [corresponding to a liver mortality per 1000 person-years of 14.2]. ¹¹ 

              • The study concluded in part that co-infection was associated with increased liver-related mortality, particularly in individuals with low CD4+ T cell counts.

                • The study also concluded that the increased risk for liver-related mortality in coinfected patients emphasized the importance of prevention, identification and effective management of hepatitis B in this group.¹¹ 

            •  Patients with HIV infection should be screened for hepatitis B infection.

              • Specifically, testing for HBsAg, hepatitis B core antibody and hepatitis B surface antibody is appropriate prior to HIV antiviral therapy administration.

                • Some anti-retroviral agents are also efficacious against HBV.

                • Three antiretroviral agents (FDA-approved), lamivudine (3TC, Epivir, Epivir HBV), emtricitabine, tenofovir disoproxil fumarate suppress hepatitis B viral replication by inhibiting its DNA polymerases.

                  • Another agent, entecavir inhibits HIV reverse transcriptase as well as offering a treatment for chronic hepatitis B viral infection.

                   

                  • Lamivudine (3TC, Epivir, Epivir HBV)

                  •  

                    Emtricitabine (Emtriva, formeral Coviracil)

                  •  

                     Tenofovir disoproxil fumarate (TDF, Viread)

                • Entecavir administration may result in selection for an HIV-resistant mutation which reduces human immunodeficiency virus sensitivity to lamivudine and emtricitabine.

                  •  

                    Entecavir (ETV, Barclude)

                • To reduce the likelihood of the development of such resistance, drugs active against both viruses should not be used alone would rather is a part of an anti-retroviral combination therapy protocol (cART, HAART).

                  •  Contemporary treatment guidelines for HIV-infected individuals with chronic hepatitis B viral infection be treated for both infection using cART regimens including tenofovir plus emtricitabine or lamivudine.

                    • Treatment of only one of the two viral infections i.e. HIV or HBV alone is not recommended.