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

        • Heart disease has been identified in about 40% of autopsy cases (25%-75% considering various autopsy series) in HIV patients.² 

          • During life, heart disease using echocardiography has been identified in about 25% of AIDS patients.

        • In the early stages of the HIV epidemic, cardiomyopathy (heart muscle disease) was the major cardiovascular complication of HIV infection.^2,9 

          • Tuberculosis pericarditis, cardiomyopathy, pericardial effusion and pulmonary hypertension both initially and at the present time remain important cardiac diseases in Africa.

            • These presentations relate to the small number of patients (about 5%) who may have access to contemporary antiretroviral agents.

        • One of the major studies concerning the effects of HIV/AIDS on heart disease was conducted in South Africa.¹¹ 

          • The study was known as the Heart of Soweto Study. In this prospective analysis of all de novo heart disease cases presented to the Cardiology Unit during 2006-2008 of the Chris Hani Baragwanath Hospital 5328 de novo heart disease cases were considered.¹¹ 

            • About 10% of these cases (518/5328) represented HIV-positive patients and about half of these patients were given cART (HAART: highly active antiretroviral treatment) upon presentation.

            • The most frequently noted primary diagnosis related to HIV/AIDS was HIV-related cardiomyopathy (38% of the 518 patients).¹¹  

              • An additional 25% (128 cases) were diagnosed with pericarditis/pericardial effusion.

              • About 8% of cases were diagnosed as HIV-related PAH (Pulmonary Arterial Hypertension).

              • Finally, about 2% of cases (14) were diagnosed as coronary artery disease (CAD) in the HIV-positive group. The distribution of cardiac-related diagnoses is presented in the pie chart below.¹¹

        • At present heart disease in HIV patients is now manifest in developed countries as coronary heart disease.^2,9

          • The rate of myocardial infarction (MIs) is approximately 3.5/1000 patient-years. Furthermore, about 30% of these incidences were fatal.

          • The use of cART (HAART), highly active antiretrovirals, often consisting of two nucleoside reverse transcriptase inhibitors [NRTIs] along with one or two protease inhibitors appears to be the basis of the change in heart disease pattern since the beginning of the epidemic.

            • cART-induced metabolic abnormalities, especially insulin resistance and hyperlipidemia appear important aspects of the problem.⁹

        • Generally, in HIV patients, cardiovascular disease may be accounted for by expected risk factors including smoking, HIV infection-related, or complication of antiretroviral drugs.² 

          • Patients with HIV infection exhibit both lower levels of high-density lipoprotein cholesterol (HDL, "good cholesterol") and higher levels of triglycerides; furthermore a higher incidence of smoking appears to be present in HIV-populations compared to comparable cohorts without HIV infection.

          • The rate of cardiovascular disease has been shown lower to be in patients treated with antiretroviral drugs.

            • This finding identified a relationship between HIV replication and cardiovascular disease risk.² 

              • CD4⁺ T cell counts of <500/μl appears to be an independent risk factor for cardiovascular disease.

                • This risk factor appears comparable to the risk factor smoking.² 

      • Cardiomyopathy

        • Idiopathic Cardiomyopathy, Gross Pathology¹²

          CDC/Ewing Jr EP Gross pathology of idiopathic cardiomyopathy:  gross pathology (1972) "Opened left ventricle of heart shows a thickened, dilated left ventricle with a subendocardial fibrosis manifested as increased whiteness of endocardioumm. Autopsy."

        • HIV-associated cardiomyopathy is characterized as a dilated cardiomyopathy presenting with congestive heart failure (CHF).² 

          •  

            Distribution of HIV-related Primary Cardiovascular Diseases^10,11

            Thienemann F Sliwa K Rockstroh JK HIV and the heart: the impact of antiretroviral therapy: a global perspective. Eur heart J 34(46): 3538-3546 Dec. 2013. http://eurheartj.oxfordjournals.org/content/ehj/early/2013/10/14/eurheartj.eht388.full.pdf Sliwa K Carrington MJ Becker A Thienemann F Ntsekhe M Stewart S Contribution of the human immunodeficieny virus/acquired immunodeficiency syndrome epidemic to de novo presentations of heart disease in the Heart of Soweto Study cohort. Eur heart J 33(7): 866-874, 2012. (second sourced from reference 10). Figure attribution: This figure corresponds to Figure 3 in reference 10 and Figure 1 in reference 11.

          • This cardiomyopathy occurs in the latter stages of HIV infection and histologically resembles myocarditis.

            • Accordingly, one possible treatment utilizes IV immunoglobulin (IVIG).

          • Although the virus can be found in cardiac tissue in this circumstance, its direct involvement in the commission remains to be determined.

            • HIV virus may also be responsible for AIDS myocarditis; however, this conclusion remains to be substantiated.

              • Human cardiac myocytes do not express CD4 receptors, although HIV could infect monocytes or macrophages as well as myocardial interstitial cells.

                • Nonetheless, endomyocardial biopsies from HIV-positive individuals have been shown by PCR to contain HIV gene sequences.²

        • Dilated cardiomyopathy associated with HIV infection was initially described in 1986 and exhibits characteristics similar to idiopathic dilated cardiomyopathy in HIV-negative individuals.⁹ 

          • Associated isolated left ventricular dysfunction in HIV-AIDS patients may be due to a self-limiting myocarditis, since the dysfunction may resolve on its own.⁹

            • The differential diagnosis of cardiomyopathy in the HIV/AIDS setting takes into account:⁹

              • Left ventricular dysfunction due to ischemic heart disease

              • Hypertension

              • Diabetes

              • Coronary vasospasm (secondary to cocaine use) as well as

              • Drug hypersensitivity reactions.⁹

            • Heart muscle disease is associated with prevalence of about 4.5% for cardiomyopathy and 6.5% for left ventricular dysfunction.⁹ 

              • These conditions may present as clinical symptoms in about 6% of HIV/AIDS patients.⁹ 

          • Cardiomyopathy has a poor prognosis, suggesting poor survival in these patients when compared to similar patients with structurally normal myocardium.⁹

            • The HIV cardiomyopathy-associated poor prognosis remains poor even after taking into account CD4 levels.

              • The underlying mechanism for cardiomyopathy and left ventricular dysfunction in HIV/AIDS remains incompletely understood.

              • Suggestions of possible mechanisms include:

                • Pathologies due to HIV and HIV-associated proteins

                • Cytokines

                • Lymphocytic myocarditis

                • Autoimmune response abnormalities

                • Drugs,

                • Suboptimal nutrition et al.⁹

        • Other Cardiovascular Dysfunctions Described in HIV Patients²

          • In patients with HIV infection other cardiovascular dysfunctions in addition to those previously described may also be present.²  

            • Advanced HIV disease may cause pericardial effusions.²  

              •  

                Pericardial Effusion with Tamponade

                "A 2D transthoracic Echocardiogram of pericaridal effusion. The Swinging Heart" Attribution:  By Jer5150 (Own work) [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons http://commons.wikimedia.org/wiki/File%3APericardial_effusion_with_tamponade.gif

              •  

                Pericardial Effusion (Chest X-ray):  "Water-bottle Shaped Heart"

                Jer5150 "Water bottle" May 26, 2012 http://commons.wikimedia.org/wiki/File:Water_bottle.png

              • Factors that may increase the likelihood of pericardial effusion include:

                • Tuberculosis

                • Congestive heart failure

                • Cryptococcal or myobacterial infection

                • Pulmonary infection

                • Kaposi's sarcoma

                • Lymphoma.

              • Pericardial Kaposi's sarcoma may be associated with both tamponade and death, probably due to acute hemorrhage.

              • Occasionally, nonbacterial thrombotic endocarditis may occur.

              • Finally, IV pentamidine, if administered too rapidly, may precipitate cardiovascular collapse manifested as a hypotensive response.²