Nursing Pharmacology:  Antiviral Drugs

• Antiviral Drugs

  • Anti-viral drugs with activity against HIV (Human Immunodeficiency Virus)

    • HIV-1 Pathophysiology/Pathogenesis

      • Long-term Infection:  Latency Phase

        • After the primary infection there is about a one week period before an initial viremia, which lasts 2-3 months.⁸ 

          • In many patients an acute mononucleosis-like presentation develops about a month following initial infection.

            • HIV Infection Progression¹⁴

              "The Progression of HIV Infection from Primary Infection through the Acute HIV Syndrome to the Stage of Clinical Latency"14 Attribution:  The above figure corresponds to Figure 2 in reference 14 [Panteleo G Graziosi Fauci AS The Immunopathogenesis of Human Immunodeficiency Virus Infection (Mechanism of Disease, Epstein FH, ed) The New England Journal of Medicine 328(5) 327-335, 1993.]

              • About 50-70% of individuals with HIV infection progress through an acute clinical syndrome about a month following primary infection. (See figure above).²

                • Despite variability in clinical severity during this period, no correlation between initial viremia level in the acute HIV infection stage and subsequent evolution of disease has been found.

                • Symptoms of acute HIV syndrome include:

                  • Fever

                  • Skin rash

                  • Myalgia and

                  • Pharyngitis.

                • These symptoms may occur less frequently in those infected via drug injection compared to those infected due to sexual contact.²

                • Opportunistic infections may occur during this early stage of HIV infection and may be due to both diminished CD4⁺ T cells and dysfunctional CD4⁺ T cells, secondary to viral protein and cytokine-mediated cell effects.

                • Immunological abnormalities are associated with acute HIV syndrome.²

                  • These abnormalities include various anomalies in circulating lymphocyte subsets with reduction in total lymphocytes as well as CD4⁺ and CD8⁺ both noted.

                  • Lymphadenopathy is documented in about 70% of individuals with primary acute HIV infection with most patients recovering spontaneously with many exhibiting only slightly depressed but initially stable CD4⁺ T cell count, prior to a progressive CD4⁺ T cell level decline.

                  • Absent treatment some patients may exhibit a rapid immunologic and clinical deterioration; however, most patients exhibit clinical latency (smoldering disease).

                    • Following acute HIV infection, several disease courses may be described (absent treatment):⁶

                      • Rapid progressors (10-15%); these patients develop "late stage" symptoms in about 2-3 years.

                      • Slow progressors (70-80%); these patients develop "late stage" symptoms in about 8-10 years.

                      • Long-term non-progressors (5%); these patients show no decline in CD4⁺ T-cell counts.⁶

            • In this early phase a notable decline in circulating CD4⁺ T cells is observed.

            • An immune response to HIV-1, developing one week to three months following infection, results in a reduction of HIV-1 viral load (reduce viremia) with an increase in previously suppressed CD4⁺ cell number.²

          • For reasons discussed earlier, the immune response is insufficient to resolve the infection and persistent presence of HIV-1 in infected cells (latent) has been documented.⁸  

          • Clinical latency itself may extend to 10 years, while viral replication continues at a high level.⁸  

            •  

              HIV Infection Stages⁹

              Stages of HIV Infection https://www.aids.gov/hiv-aids-basics/just-diagnosed-with-hiv-aids/hiv-in-your-body/stages-of-hiv/index.html9

            • In this circumstance about 10 billion HIV virions are produced and destroyed each day.

            • The viral plasma half-life is about six hours with a complete virus lifecycle lasting about 2.5 days.

              •  

                Steps in the HIV Lifecycle¹⁰

                AIDSinfo (NIH): HIV Overview, The HIV Life Cycle (last reviewed, 9/23/2014)

              • A similar high turnover rate for CD4⁺ T lymphocytes, targeted by HIV-1, has also been described, with a half-life of an infected CD4⁺ lymphocyte estimated at 1.5 days.⁸ 

            • The uniqueness of HIV infection, compared to other human viral infections, rests in its indefinite persistence in the body, despite a cellular and humoral immune response, and its ability to emerge from a period of latency.²

              • (Note that herpes simplex viral infections, HSV infections, also persist but enter both a clinical and microbiological latent state).

              • For HIV, as noted earlier, a chronic infection is established that exhibits varying degrees of viral replication with a latent period of about 10 years prior to the untreated patient exhibiting signs of clinical disease.² 

                • In untreated, infected patients viral replication is detectable both by direct assays for plasma HIV RNA and by identification of cell-associated HIV RNA in CD4+ T cells and macrophages both in lymphoid tissue and in the circulation.

                • In HIV patients undergoing treatment with cART ("effective combination AntiRetroviral Therapy"), also known as HAART ("Highly Active AntiRetroviral Therapy), although plasma viremia may be suppressed to <50 HIV/ml copies, viral replication persists.²

      • HIV-Latency:  CD4⁺ T Cell Reservoir:

        • After the HIV virus has integrated into host cell DNA, postintegration latency results in some cells causing a stable, proviral reservoir.¹¹ 

          • This reservoir is localized within resting memory CD4⁺ T cells.

            • Within a few days following the initial infection, within the acute phase, latency develops.^11,13 

              • Although the latent, integrated viral genome is not transcriptionally active, activation of the host cell allows transition of the transcriptionally inactive viral genome to a transcriptionally active viral genome fully capable of producing infectious virions.

              • This transition may be induced by "recall" antigens or cytokines or upon discontinuation of anti-retroviral drugs.¹¹ 

          • Normally, naïve CD4⁺ T cells remain in a resting state prior to encountering an antigen.¹¹  

            • After that, the CD4⁺ T cells become activated, proliferate and thus generate effector cells that remove the associated pathogen from the body.¹¹  

              • Most of these activated cells remain alive only a few weeks.

              • However, some of the same cells revert back to a resting state, continuing to exist as a "memory T cell" which are capable of responding at a later time to the same antigen.

                • The longevity of the memory T cell and their daughter cells allow these cells, if they have been infected by HIV-1, to serve as a primary reservoir for the latent HIV provirus.

                  • Accordingly, memory T cells may be viewed as an ideal cellular HIV reservoir with the proviral genome remaining inactive and hidden.¹¹  

              • As stated above, activation of these memory T cells by reexposure to antigen or through cytokine activation (e.g. NF-κB, NFAT) , both leading to transcription factor induction, result in reactivation of latent HIV provirus.

                • NF-κB (Nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex controlling DNA transcription.

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. Safrin S Antiviral Agents, Chapter 49 in Basic & Clinical Pharmacology, 12 e (Katzung BG Masters SB Trevor AJ) The McGraw-Hill Companies, 2012 (on-line edition). Cochrane A Retroviruses Chapter 28 in Fundaments of Molecular Virology, 2e, Acheson NH, ed., John Wiley & Sons pp 342-353 2011. Cochrane A Human Immunodeficiency Virus Chapter 29  in Fundaments of Molecular Virology, 2e, Acheson NH, ed., John Wiley & Sons pp 354-364 2011. Ryan KJ, Ray C. Chapter 18. Retroviruses: Human T-Lymphotropic Virus, Human Immunodeficiency Virus, and Acquired Immunodeficiency Syndrome. In: Ryan KJ, Ray C. eds. Sherris Medical Microbiology (Part editor, Ahmad N Ray CG Drew WL), 5e. New York, NY: McGraw-Hill; 2010. Butel JS Chapter 44:  AIDS and Lentiviruses (Brooks FG, Carroll KC Butel JS Morse SA, Mietzner TA in Jawetz, Melnick & Adelberg's Medical Microbiology, 26th edition), 2013, on-line edition. AIDS.gov  Stages of HIV Infection https://www.aids.gov/hiv-aids-basics/just-diagnosed-with-hiv-aids/hiv-in-your-body/stages-of-hiv/index.html AIDSinfo (NIH):  HIV Overview, The HIV Life Cycle (last reviewed, 9/23/2014) http://aidsinfo.nih.gov/education-materials/fact-sheets/19/73/the-hiv-life-cycle Ruelas DS Greene WC An Integrated Overview of HIV-1 Latency (Leading Edge Review) Cell 155:  519-529 October 24, 2013 "BogHog" NFKB mechanism of action http://commons.wikimedia.org/wiki/File:NFKB_mechanism_of_action.png Chun TW Engel D Berrey MM Shea T Corey L Fauci AS.  Early establishment of a pool of latently infected resting CD4(+) T cells during primary HIV-1 infection. Proc. Natl. Acad. Sci USA 95, 8869-8873. Panteleo G Graziosi Fauci AS The Immunopathogenesis of Human Immunodeficiency Virus Infection (Mechanism of Disease, Epstein FH, ed) The New England Journal of Medicine 328(5) 327-335, 1993.

 

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