Nursing Pharmacology:  Antiviral Drugs

Protease Inhibitors

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Protease Inhibitors

    • Atazanavir (Reyataz)

    • Overview: and pharmacokinetics:^2,3  

      • Atazanavir (Reyataz) is an azapeptide HIV (HIV-1 and HIV-2)  protease inhibitor.^2,3  

      • The pharmacokinetic properties of this agent permits once-daily dosing; furthermore, atazanavir optimal absorption depends on an acidic medium (pH-dependent solubility in the aqueous environment) and as a result, this drug should be taken with meals.^2,3  

        • Administration following a "light meal" can increase the AUC (area-under-the-curve) by about 70%.

          • A meal high in fat can increase the AUC by about 35%.

        • Agents that decrease stomach acidity should not be used at least 12 hours prior to atazanavir administration and proton pump inhibitors (PPI, e.g.lansoprazole (Prevacid, esomeprazole,(Nexium))  specifically are contraindicated.

        • The plasma half-life is about six hours, although atazanavir half-life can be approximately doubled when the drug is administered with ritonavir (ritonavir-boosting. ATV/r).^2,3

        • Since the principal route of drug elimination is biliary, atazanavir with not be recommended for administration of patients exhibiting significant liver insufficiency.

          • Hepatic metabolism is mediated mainly by one of the cytochrome P450 liver microsomal isoforms, CYP3A4.

      • Atazanavir, however, is one of the recommended antiretroviral drugs for administration to pregnant women.

    • Mutations:

      • Resistance to atazanavir typically occurs as a result of a mutation at codon 50 of the HIV protease.^2,3  

        • This mutation results in nearly an order of magnitude (9-fold) decrease in drug effectiveness.

        • The specific mutation involves a change from isoleucine to leucine.

    • Side-Effects/Adverse Effects:^2,3

      • The most frequently observed adverse effects in patients administered atazanavir include:^2,3 

        • G.I. disturbances such as diarrhea with nausea, vomiting, abdominal pain

        • Peripheral neuropathy, headache and skin rash with this group of effects being less frequently noted.

      • Some patients (5%-10%) present with jaundice described as an indirect hyperbilirubinemia secondary to inhibition of the UGT1A1 glucuronidation enzyme.^2,3 

        • Nearly half of patients (40%) who receive once daily 400 mg Atanazavir dosing exhibit an increase in total bilirubin, as reported in early clinical trials.

          • As noted, this effect is due to inhibition of the UDP-glucuronosyltransferase enzyme described above. However, this effect is more likely to be observed in patients genetically deficient in this enzyme.

            • An example of such a patient group would be those with "Gilbert's syndrome", also known as Gilbert-Meulengract syndrome, a common genetic disorder that is noted in about 7% (3%-12%) of the population.

              • As a result of this genetic effect, baseline UGT1A1 glucuronidation activity may be reduced by about 70%-80%.

      • Nephrolithiasis has also been reported in association with atazanavir administration with extended use of boosted (ritonavir) atazanavir associated with progressive renal dysfunction.^2,3 

      • When compared with other protease inhibitors atazanavir appears not associated with fat redistribution,  dyslipidemia or metabolic syndrome.^2,3 

      • Atazanavir is metabolized by CYP3A4 and therefore atazanavir levels would be particularly affected by drugs that induce (increase the concentration) of CYP3A4.

        • For instance atazanavir AUC (area-under-the-curve) is decreased up to about 75% when administered in combination with a proton pump inhibitor, the basis for a contraindication.

        • Considering antiretroviral agents, efavirenz (600 mg/day single dosage) decreases unboosted atazanavir AUC by about 75%.

          • Atazanavir is also a moderate inhibitor of CYP3A4, thus affecting plasma levels of other CYP3A4 substrates (e.g. drugs).

            • Ritonavir increases atazanavir area-under-the-curve and decreases atazanavir clearance (ritonavir boosting).

              • This effect occurs because ritonavir inhibits CYP3A4, the enzyme responsible for atazanavir metabolism.^2,3

    • Therapeutic Applications: 

      • Nonboosted (i.e. without ritonavir) use of atazanavir (400 mg/once daily) was shown inferior to the combination of lopinavir + ritonavir given twice daily in treatment experienced patients.² 

        • Administration of this latter combination resulted in about 80% of patients exhibiting plasma HIV RNA concentrations <400 copies/mL at week 24.

          • This finding compared with about 60% of patients reaching the same HIV RNA concentration at week 24 when the patients were receiving atazanavir alone.

      • When atazanavir was coformulated with low-dose ritonavir reduction in HIV viral load appeared comparable to that noted with lopinavir + ritonavir.^2,12 

      • Furthermore atazanavir + ritonavir have been approved in management of pediatric patients over six years of age (dosing based on weight).² 

      • Based on clinical trial efficacy and safety findings, atazanavir + ritonavir (ATV/r) and atazanavir + cobicistat (ATV/c) + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) represent an "Alternative regimen for ART-naïve patients regardless of pre-treatment HIV RNA."

        • This recommendation is associated with a BI classification

          • (B: Moderate recommendation for the statement. I: One or more randomized trials with clinical outcomes and/or validated laboratory endpoints.)

      • Due to inferior virologic patient response in the presence of high baseline viral load, ATV/r or ATV/c + abacavir (ABC)/lamivudine (3TC) treatment is classified as an "Other regimens".

        • These regimens should be limited to individuals with pre-antiretroviral therapy HIV RNA <100,000 copies/mL.

          • This statement is associated with a  CI classification (see table below).

      • ATV/c in combination with TDF/FTC is not recommended in those patients with a creatinine clearance (CrCl) <70 mL/min.

  "Rating Scheme for Recommendation"⁴

  Strength of Recommendation	Quality of Evidence for Recommentation
  A:  Strong recommendation for the statement	I:  One or more randomized trials with clinical outcomes and/or validated laboratory endpoints
  B:  Moderate recommendation for the statement	II:  One or more well-designed, non-randomized trials or observational cohort studies with long-term clinical outcomes
  C:  Optional recommendation for the statement	III.  Expert opinion

References

Wang F Kieff E Medical Viriology, Chapter 177 Section 11:  Viral Diseases:  General Considerations (in Harrison's Principles of Internal Medicine, 18th edition, Longo DF Fauci AS Kasper DL Hauser SL Jameson JL Loscalzo J, eds) McGraw-Hill, New York, 2012, pp 1432-1433. Flexner C Chapter 59.  Antiretroviral Agents and Treatment of HIV Infection (in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12 e, Brunton LL Chabner BA Knollmann BC, eds) The McGraw-Hill Companies, Inc, 2011. Safrin S Chapter 49:  Antiviral Agents:  Antiretroviral Agents in Basic & Clinical Pharmacology 13e (Katzung BG Trevor AJ, eds) 2015, online edition. AIDSinfo:  Guidelines for the Use of Antriretroviral Agents in HIV-1-Infected Adults and Adolescents https://aidsinfo.nih.gov/guidelines (2015) Tsibris AMN Hirsch MS Chapter 130 Antiretroviral Therapy for Human Immunodeficiency Virus Infection in Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 8e (Bennett JE Bolin R Blaser, eds) Elsevier, Inc/Saunders 2015, online version. Woster PM Antiviral Agents and Protease Inhibitors.  Chapter 43  in Foye's Principles of Medicinal Chemistry, 6e Lemke TL; Williams DA, eds; Roche VF Zito SW, asst. eds), Lippincott Williams & Wilkins, a Wolters Kluwer business, 1219, 2008. Swaminathan J and MSD staff at the European Bioinformatics Institute  (http://www.ebi.ac.uk/) Renin:  molecular structure registered with 2rn code. https://commons.wikimedia.org/wiki/File:PDB_2ren_EBI.jpg Flexner C HIV-Protease Inhibitors The New England Journal of Medicine 338(18) 1281-1292, April 30, 1998. http://www.ncbi.nlm.nih.gov/pubmed/9562584 AIDSinfo:  Guidelines for the Use of Antriretroviral Agents in HIV-1-Infected Adults and Adolescents https://aidsinfo.nih.gov/guidelines (2015) LASA T. Bunupuradah, S. Kiertiburanakul, A. Avihingsanon P. Chetchotisakd, M. Techapornroong, N. Leerattanapetch, P. Kantipong, C. Bowonwatanuwong, S. Banchongkit, V. Klinbuayaem, S. Mekviwattanawan, S. Nimitvilai, S. Jirajariyavej, W. Prasithsirikul, W. Munsakul, S. Bhakeecheep, S. Chaivooth, P. Phanuphak, D.A. Cooper, T. Apornpong, S.J. Kerr, S. Emery, K. Ruxrungtham, LASA Study Group. Atazanavir/ritonavir 200/100 mg is non-inferior to atazanavir/ritonavir 300/100 mg in virologic suppressed HIV-infected Thai adults: a multicentre, randomized, open-label trial. (IAS 2015) https://www.youtube.com/watch?v=B6U2TRN8BIw Pakovna M 2AQU HIV and Atazanavir https://www.youtube.com/watch?v=Yc553iqR7Gw Croom KF Dhillon S Keam SJ  Atazanavir:  A Review of its Use in the Management of HIV-1 Infection.  Drugs 69(8) 1107-1140, 2009.

 

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