Medical Pharmacology Chapter 36:  Antiviral Drugs

Protease Inhibitors

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Protease Inhibitors

    • Atazanavir (Reyataz)

      • Atazanavir (Reyataz)

       

    • Overview: and pharmacokinetics:^2,3  

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

      • The concentration of atazanavir required to inhibit HIV protease activity by about 50% (IC₅₀) is about 10 nM (range: 2-15 nM).^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.

          • Isoleucine	→	Leucine
            	→

          • The substitution may be compared with the isoleucine to valine substitution associated with fosamprenavir and darunavir.

          • The atazanavir mutation (isoleucine to leucine) is observed in 100% of patients exhibiting treatment failure, at least in one reported a clinical trial. HIV proteases exhibiting this mutation remain sensitive to inhibition by other HIV protease inhibitors.

            • Resistance to atazanavir is also influenced by other primary and secondary mutations which are observed in individuals who have failed other HIV protease inhibitors.

            • Significant resistance is related to the number of additional mutations and "high-level" resistance may be expected with 5 or more additional mutations.

          • In some circumstances the development of atazanavir resistance mutations (in vitro) reduces protease inhibitor susceptibility to other, alternative protease inhibitors; on the other hand, the isoleucine to leucine codon 50 mutation may result in enhanced susceptibility to alternative protease inhibitors.^2,3  

    • 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.

  Abbreviations:  Antiretroviral Drugs, Combinations, and Classifications⁹

  3TC = lamivudine	ABC = abacavir	ARV = antiretroviral	ATV/c = cobicistat-boosted atazanavir	ATV/r = ritonavir-boosted atazanavir ear
  DRV/r= ritonavir-boosted darunavir	DTG = dolutegravir	EFV = efavirenz	EVG/c/TDF/FTC = elvitegravir/cobicistat/tenofovir DF/emtricitabine	FTC = emtricitabine
  LPV/r = ritonavir-boosted lopinavir	RAL = raltegravir	RPV =rilpivirine	RTV = ritonavir	TDF = tenofovir disoproxil fumarate
  INSTI = integrase strand transfer inhibitor	NNRTI = nonnucleoside reverse transcriptase inhibitor	NRTI = nucleoside reverse transcriptase inhibitor	PI = protease inhibitor	CrCl = creatinine clearance

   

  "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