Nursing Pharmacology:  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

              • 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.

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

                • 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.

References

Flexner C Antiretroviral Agents and Treatment of HIV Infection, Chapter 59  in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th edition (Brunton LL Chabner BA Knollmann BC, eds; Brunton LL, ed; Blumenthal DK  Murri N Hilal-Dandan R, assoc eds, Knollmann BC, consulting ed, on-line edition) The McGraw-Hill Companies, 2011. Fauci AS Lane HC Chapter 189, Human Immunodeficiency Virus Disease:  AIDS and Related Disorders, in Harrison's Online   (Dan L. Longo, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, J. Larry Jameson, Joseph Loscalzo, Eds.),  Harrison's Principles of Internal Medicine, 18th edition, The McGraw-Hill Companies, Inc. 2012. Longo DL Fauci AS  188, The Human Retroviruses, in Harrison's Online   (Dan L. Longo, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, J. Larry Jameson, Joseph Loscalzo, Eds.),  Harrison's Principles of Internal Medicine, 18th edition, The McGraw-Hill Companies, Inc. 2012. Woster PM Chapter 43:  Antiviral Agents and Protease Inhibitors in Foye's Principles of Medicinal Chemistry 6e, Lemke, TL Williams DA, eds; Roche VG Zito SW, asst eds) Wolters Kluwer|Lippincott Williams & Wilkins 1214, 2008. Knox TA Wanke C Gastrointestinal Manifestations of HIV and AIDS  Chapter 397, pp 2196-2199 Goldman's Cecil Medicine 24e (Goldman L and Schafer AI, eds) Elsevier/Saunders, 2012. Public Domain:  Digestive system diagram. http://commons.wikimedia.org/wiki/File:Digestive_system_showing_bile_duct.png Emannuelm Opened gall bladder containing numerous gallstones. http://en.wikipedia.org/wiki/Gallstone; http://commons.wikimedia.org/wiki/File:Gallstones.jpg . Heilman J "A 1.9 cm gallstone impacted in the neck of the gallbladder and leading to cholecystitis. http://commons.wikimedia.org/wiki/File:Gallstones.PNG Haines C Sulkowski MS Gastrointestinal, Hepatobiliary and Pancreatic Manifestations of Human Immunodeficiency Virus Infection.  Chapter 126, 1567-1573 in Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 8e, Bennett, JE Dolin R Blaser MJ, eds, 2015). Rosenthal E Salmon-Ceron D Lewden C Bouteloup V Pialoux G Bonnet F Karmonchkine M May T Francois M Burty C Jougla E Costagliola D Morlat P Chene G Cacoub P and the Mortavic/Mortalite 2005 Study Group. HIV Medicine 10:  282-289, 2009. Thio CL Seaberg ED Skolasky  Jr R Phair J Visscher B Munoz A Thomas DL HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS) Lancet 360:  1921-1926, 2002.

 

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