Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

  • Development of Antiretroviral (anti-HIV) Drugs

    • The first antiretroviral drug approved for clinical use, zidovudine (AZT), was initially developed in anticipation of its efficacy as an anticancer chemotherapeutic drug.

      • Zidovudine (AZT)	Thymidine
        Zidovudine (AZT)	Thymidine
        Zidovudine is a dideoxynucleoside related to thymidine, differing in substitution of an azido (N3) group in place of the hydroxyl (OH) at the 3' position of the ribose ring.8

         However, the zidovudine did not prove effective in that application.

      • About 10 years later in 1972 zidovudine was found to inhibit, in vitro, murine type C retrovirus.⁸ 

      • Following another approximately 10 year interval, zidovudine was found to exhibit in vitro inhibitory activity with respect to human immunodeficiency virus (HIV).

        • In that study, the antiviral effects of the thymidine analog, 3'-azido-3'-deoxythymidine (zidovudine, AZT), then known as BW A509U, were evaluated in a human T-cell line, H9.^9,10

          • Zidovudine blocked p24 gag protein expression in both human T-lymphotropic virus type III (HTLV-III) or lymphadenopathy-associated virus (LAV).¹⁰

            • Zidovudine was also found to inhibit cytopathic effects of HTLV-III_B, a viral isolate from a group of American patients and HLV-III/RF-II (an isolate from a Haitian patient).

            • Further, zidovudine completely inhibited viral replication as measured by reverse transcriptase production in normal human peripheral blood mononuclear cells exposed to HTLV-III_B.¹⁰

      • Shortly thereafter zidovudine was evaluated in clinical trials and based on a randomized trial reported in 1987 zidovudine was approved and marketed as an anti-HIV agent.¹

        • The approval of AZT (azidothymidine, zidovudine), a nucleoside reverse transcriptase inhibitor, was initially based on a 282 patient double-blind, placebo-controlled trial evaluating the effectiveness of oral drug.¹¹ 

          • Patients selected for the trial exhibited either pneumocystis carinii (now correctly identified as pneumocystis jirovecii) or "with advanced AIDS-related complex".

            • Patients were assigned randomly to receive either 250 mg AZT or placebo, orally, every four hours for 24 weeks.

              • 145 patients received AZT and hundred and 137 patients received placebo. Most patients did not complete the 24 week study (27 subjects had completed 24 weeks; 152 patients completed 16 weeks; remaining patients completed at least 8 weeks).

                • 19 placebo recipients died during the study; however, only 1 AZT recipient died during the study.

                • Opportunistic infections characteristic of AIDS-related immunosuppression was noted in 45 patients receiving placebo but only in 24 patients receiving AZT.

                • An increase in the number of CD4⁺ T lymphocytes was found in patients receiving AZT.

                • The authors concluded that AZT (zidovudine) administration can both decrease mortality and opportunistic infections in patients with AIDS or AIDS-related complex during the 2 to 6 month study observation period.¹¹ (http://www.ncbi.nlm.nih.gov/pubmed/3299089)

        • Following zidovudine, other nucleoside analogues were evaluated for anti-retroviral reverse transcriptase inhibitor therapy.¹

      • Using viral enzyme (reverse transcriptase)-based assays, non-nucleoside reverse transcriptase inhibitors (nnRTIs) were also identified.

        • These agents when used therapeutically resulted in relatively rapid drug resistance probably as a result of intrinsically high mutation rates associated with retroviral replication.¹

      • Wei and collaborators used anti-retroviral experimental drugs, non-nucleoside reverse transcriptase inhibitors, to determine the lifespan of plasma virus and virus-producing cells.¹² 

        • Results indicated that plasma viral lifespan is short with a half-life of about two days.

        • Furthermore, wild-type virus in plasma is susceptible to replacement by drug-resistant mutational variants after about two weeks of drug administration.

        • This result suggested that HIV-1 viremia depends on continuous de novo viral infection and replication with rapid cell turnover.¹² 

        • The authors identified, as a result of viral kinetics and CD4⁺ T cell lymphocyte production and clearance analyses, several findings of particular biological and clinical importance.¹² 

          • Firstly, viral kinetics and CD4⁺ lymphocyte production/clearance indicate that HIV infection involves continuous de novo viral infection, replication with rapid cell turnover.

            • These characteristics were described as a primary "driving force", providing the basis for HIV-1 pathogenesis.

          • Secondly, the observation of nearly complete replacement of the initial, wild-type virus by drug-resistant virus after two weeks to a month of drug treatment indicated an extraordinary capacity exhibited by the virus for "biologically relevant change".

            • That HIV-1 possesses substantial capacity to mutate (evolve) in response to selection pressure was concluded.

        • Lastly, the authors note that the difference in lifespan comparing virus-producing cells and latently infected cells indicated that virus expression is directly involved in "CD4⁺ cell destruction".¹²

          • (http://www.ncbi.nlm.nih.gov/pubmed/7529365) 

        • Another class of antiretroviral drugs, the protease inhibitors, began to appear in 1989, with saquinavir being the first agent considered.¹  

          • Saquinavir was approved for clinical use (i.e. prescription use) in 1995.

          • Shortly thereafter, additional protease inhibitors ritonavir and indinavir were approved.¹

        •  

          Antiretroviral Protease Inhibitors¹

          Saquinavir	Ritonavir	Indinavir

   

  Antiretroviral Drugs Approved in the United States¹ 

   

• Nucleoside/Nucleotide Reverse Transcriptase Inhibitors^1,7

  Zidovudine (Retrovir,ZDV,AZT)
  	Adverse Effects:7  Asthenia (Weakness, reduced energy/strength), insomnia, headache, nausea, neutropenia (reduced number of circulating neutrophils; causes other than medication includes autoimmune disorders, cancer, radiation and others), macrocytic anemia (this is a type of anemia in which erythrocytes (red blood cells) are increased in volume but reduced in number of with reduced hemoglobin content per cell) Miscellaneous:7   Zidovudine should note be administered with concurrent use of stavudine or myelosupressive agents such as ribavirin or ganciclovir.
  Didanosine (Videx, DdI, dideoxyinosine)
  	Adverse Effects:7  Hyperuricemia (elevated uric acid blood levels; upper end of normal is 6 mg/dL for women and 6.8 mg/dL for men), nausea, diarrhea, pancreatitis (pancreatic inflammation, either acute or chronic; may be caused by drugs trauma, autoimmune disease, et al.), peripheral neuropathy. Miscellaneous:7 Didanosine should note be given  with other drugs that may cause neuropathy. Examples of such agents include stavudine, isoniazid, zalcitabine, ribavirin or alcohol. Didanosine should also not be administered with tenofovir.
  Stavudine (Zerit, d4T, didehydrodeothymidine)
  	Adverse Effects:7   Peripheral neuropathy, lipodystrophy (refers to abnormalities in body fat, including distribution; this class of agents, the nucleoside reverse transcriptase inhibitors is most associated with lipdystrophy compared to other classes of HIV antiretroviral drugs), pancreatitis (pancreatic inflammation, either acute or chronic; may be caused by drugs trauma, autoimmune disease, et al.), rarely neuromuscular weakness. Miscellaneous7 :  Concurrent stavudine admininistration with zidovudine or neuropathic agents such as ddI, zalcitabine, isoniazid should be avoided.
  Lamivudine (3TC)
  	Adverse Effects:7  Fatigue, vertigo, nausea, headache Miscellaneous:7   Should not be administered with zalcitabine (ddC, dideoxycytidine)
  Abacavir (Ziagen)
  	Adverse Effects:7 Hypersensitivity reaction, rash, nausea Miscellaneous:7 Alcohol should be avoided FDA bulletin (March 2015) approvided both lamivudine (Epivir) and abacavir sulfate (ziagen) labelling for once-dailing dosing in pediatric patients 3 months of age and older in combination with other antirretroviral drugs for HIV-1 infection treatment. (see: http://content.govdelivery.com/accounts/USFDA/bulletins/fa3e70 Abacavir is used in combination with other antiretroviral agents.
  Tenofovir (tenofovir disoproxil fumarate, Viread)
  	Adverse Effects:7 Nausea, diarrhea, vomiting, renal insufficiency, headache Miscellaneous:7 Should not be administered along with atazanvir, probenecid or didanosine. Nucleotide reverse transcriptase inhibitor class member
  Emtricitabine (Emtriva, formerly Coviracil)
  	Adverse Effects:7 Nausea, diarrhea, headache, weakness with reduced energy (asthenia), skin hyperpigmentation (<2%) Miscellaneous:7 Cross drug resistance with lamivudine13; should not be administered together with lamivudine. In oral preparation, disulfiram and metonidazole  should be avoided.