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

      • Cardiovascular Diseases

        • Drug-Induced Myocardial Disease

          • Some concerns about possible relationships between combination highly active antiretroviral treatment (cART a.k.a. HAART) and heart disease were evaluated by the "Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D)" study which began in 1999.⁵ 

            • This group considered over 23,000 patients from 11 previously defined cohorts initially from December 1999 to April 2001.⁷ 

              • Follow-up data was obtained until February 2002.

              • The data considered possible relationships between HIV infection and risk factors for and the incidence of myocardial infarction.

                • For the purpose of this study initially, combination antiretroviral drugs was defined as any combination of antiretroviral agents which included a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor.

              • Considering a period of about 36,000 person-years, 126 patients experience myocardial infarction.

                • As noted below, the group of patients being treated with combination antiretrovirals experienced an increase risk for myocardial infarction.

                • The incidence of myocardial infarction was shown to increase with duration of combination anti-retroviral treatment.⁷ 

                   

                  • "Incidence of Myocardial Infarction According to the Duration of Exposure to Combination Antiretroviral Therapy"⁷

                    "The incidence of primary events was assessed beginning at base line according to the cumulative duration of combination antiretroviral therapy since the initiation of therapy, stratified in one-year intervals from the initiation of therapy to four years, more than four years of exposure, and no exposure. "The rate of myocardial infarction was generally lower among the patients not exposed to combination antiretroviral therapy than in any of the treated groups."7

            • The study group concluded that cART was an independent risk factor accounting for about a 25% relative increase in the rate of myocardial infarction/year of exposure during the first 4-6 years of cART therapy.

            • In 2003 cumulative exposure to protease inhibitors (PIs) was found to also increase myocardial infarction rate in HIV patients to an extent not fully accounted for by protease inhibitor-associated dyslipidemia.⁵

          • The basis for clinical effectiveness of HIV protease inhibitors is that HIV protease is required for viral growth.⁶ 

            • HIV protease catalyzes conversion of viral core proteins of the structural proteins.⁶ 

            • For example, the pol gene is responsible, following translation and protease action, for the p7, p9, p17, and p24 structural proteins.

              • These proteins are important in HIV infectivity.

                • gag and gag-pol genes code for polyproteins which are later cleaved to form the individual structural proteins.

                  • The cleavage of these precursor polyproteins is catalyzed by a pol-encoded aspartic (aspartyl) protease.

            • Additionally, HIV protease is an activator of reverse transcriptase (RT) and has a role in infectious virion release.⁶ 

          • Inhibitors of HIV protease has been identified as an important pharmacological group for inhibition of HIV replication.⁶

          • The HIV viral aspartyl protease is composed of two 99-amino acid monomers (homodimer) with each monomer contributing an aspartic amino acid residue required for catalysis.¹ 

            •  

              HIV Protease with Active Site⁸

              MLGProGamer123 Cartoon structure of HIV protease enzyme "HIV-1 protease has the classic AspThrGly of aspartyl proteases. These amino acids are located at position 25,26, and 27, and are responsible for the catalytic activity." http://commons.wikimedia.org/wiki/File:HIV-1_Protease_with_Active_Site.png http://en.wikipedia.org/wiki/HIV-1_protease

            • Human aspartyl proteases, such as renin, pepsin, gastricsin, and cathepsins D and E), consist of only one polypeptide chain and are not appreciably inhibited by HIV protease inhibitors.

            • Human aspartyl proteases exhibit poor affinity for HIV protease inhibitors and this characteristic is the basis for viral vs. human aspartyl protease pharmacological selectivity.¹

              •  

                HIV Protease with Experimental Inhibitor BEA369 and Active Site (Red) Depicted⁹

                Boghog HIV protease 1EBY http://en.wikipedia.org/wiki/File:HIV_protease_1EBY.png "The structure of HIV-1 proteases complexed with the inhibitor BEA369 based on the 1EBY coordinates. "The enzyme subunits are colored green and cyan and the active site red. "The inhibitor is depicted as a multicolored tube (carbon atoms = white, nitrogen = blue, oxygen =red)" http://en.wikipedia.org/wiki/HIV-1_protease

          • A number of studies have been published that investigated possible association between specific antiretroviral drugs and myocardial infarction risk in HIV-infected patients.^5,10

            • A recent study examined the relationship between abacavir (Ziagen) administration and myocardial infarction risk.¹⁰ 

              • The risk of exposure to other nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs) and non-NRTIs was also evaluated.

                • Short-term/recent abacavir (Ziagen) administration was associated with an increased likelihood of myocardial infarction but only in the subset of individuals using cocaine or intravenous drugs.¹⁰

            • An increased risk of myocardial infarction was noted following cumulative exposure to all protease inhibitors except saquinavir (Invirase).

              • Particular association was described for amprenavir/fosamprenavir (Agenerase/Lexiva) with or without ritonavir (Norvir) as well as for lopinavir+ritonavir (Kaletra, Aluvia) .¹⁰

                • The association described with abacavir (Ziagen) was not considered causal.

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              Abacavir (Ziagen): HIV Protease Inhibitor

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              Saquinavir (Invirase):  HIV Protease Inhibitor

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              Amprenavir (Agenerase):  HIV Protease Inhibitor

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              Fosamprenavir (Lexiva):  HIV Protease Inhibitor

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              Ritonavir (Norvir):  HIV Protease Inhibitor

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              Lopinavir:  HIV Protease Inhibitor Used in Combination with Ritonavir

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              Indinavir (Crixivan):  HIV Protease Inhibitor

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              Atazanavir (Reyataz):  HIV Protease Inhibitor 

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              Tipranavir (Aptivus):  HIV Protease Inhibitor