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Atazanavir (Reyataz)
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Class
Background
U.S. Manufacturer
Approval
Generic Approvals
Formulation and Dosing
Clinical Use
Combinations
Use in Initial vs Subsequent Therapy
Factors Affecting Adherence
Resistance
Implications of atazanavir resistance for treatment with other antiretrovirals
Implications of resistance to other antiretrovirals for atazanavir treatment
References
Related Resources
DHHS Guidelines
Characteristics of PIs
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Adverse Events of ARVs
Dosage Adjustments for ARV-ARV Drug Interactions (Adult Dosing)
Interactions Database
Stanford Resistance Figures/Notes
Drug Labeling (Package Insert)
Atazanavir (Reyataz)
Class

Protease inhibitor

Background
U.S. Manufacturer

Bristol-Myers Squibb

Approval

Atazanavir was approved by the FDA in June 2003 for use in combination with other antiretroviral agents in adults with HIV infection. Approval was based primarily on 2 Phase II studies showing that previously untreated individuals on atazanavir + stavudine + didanosine had rates of viral suppression and CD4 increase at 48 weeks that were comparable to those treated with nelfinavir + stavudine + didanosine.(1,2) A Phase III study comparing atazanavir + zidovudine + lamivudine with efavirenz + zidovudine + lamivudine in treatment-naive subjects showed equivalent rates of viral suppression and CD4 increase at 48 weeks.(3)

Generic Approvals

The FDA has granted a generic version of atazanavir "tentative approval" status for purchase and use only as part of the President's Emergency Plan for AIDS Relief (PEPFAR) in resource-limited countries. For a table of FDA-approved drugs for use under PEPFAR, see HIV InSite's PEPFAR overview.

Formulation and Dosing

Atazanavir is available in capsule formulation. Standard dosing is once daily.

Dosing of Atazanavir
Adult*Unboosted (single PI)400 mg QD
Boosted (+ ritonavir)Atazanavir 300 mg QD + ritonavir 100 mg QD
AgeNotes
PediatricBirth to 3 monthsNot FDA approved; should not be administered
3 months to 6 yearsNot FDA approved; under investigation
6 to <18 years

Weight 15 to <25 kg#: atazanavir 150 mg QD + ritonavir 80 mg QD

Weight 25 to <32 kg: atazanavir 200 mg QD + ritonavir 100 mg QD

Weight 32 to <39 kg: atazanavir 250 mg QD + ritonavir 100 mg QD

Weight ≥39 kg§: atazanavir 300 mg QD + ritonavir 100 mg QD

Abbreviations: PI = protease inhibitor; QD = once daily

* For antiretroviral-experienced adult patients, the recommended dosage is atazanavir 300 mg QD + ritonavir 100 mg QD.

# For treatment-naive pediatric patients only; data are not sufficient to support dosage recommendations for treatment-experienced pediatric patients who weigh <25 kg.

§ For treatment-naive pediatric patients of age ≥13 years and weight >39 kg who do not tolerate ritonavir: may use atazanavir 400 mg QD (without ritonavir).

Atazanavir should be taken with food.
Atazanavir interacts with a number of antiretroviral medications, including other protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and the nucleotide analogue tenofovir. Pharmacologic boosting of atazanavir is recommended when coadministered with certain interacting medications, including tenofovir, efavirenz, and nevirapine; dose adjustment of certain interacting protease inhibitors may be required when coadministered with atazanavir. See Dosage Adjustments for ARV-ARV Drug Interactions for information on recommended dosing adjustments for atazanavir with other antiretrovirals.
No dosage adjustment is necessary in renal insufficiency.
Please consult product labeling for detailed dosing information.
FDA Pregnancy Category B.
Clinical Use
Combinations

Regimens containing atazanavir plus 2 nucleoside analogues have been shown to achieve effective viral suppression in initial and subsequent therapy (see "Use in Initial vs Subsequent Therapy").

Atazanavir is a substrate of the cytochrome P450 3A4 isoenzyme, and may alter serum concentrations of other drugs metabolized by this pathway, such as rifabutin, clarithromycin, lipid-lowering agents, and others.(4,5) Similarly, drugs that induce or inhibit the action of this isoenzyme may cause therapeutically significant alterations in atazanavir levels. For example, coadministration with ritonavir increases atazanavir levels, whereas coadministration with efavirenz decreases atazanavir levels.(6-9) Coadministration of atazanavir with tenofovir has been found to lower serum atazanavir concentrations and to raise tenofovir concentrations; the mechanism of this interaction is not clear.(10) Coadministering atazanavir with low-dose ritonavir may boost serum atazanavir levels enough to compensate for interactions with tenofovir or nonnucleoside reverse transcriptase inhibitors. Certain antacids, including proton pump inhibitors, significantly interfere with the absorption of atazanavir and can cause subtherapeutic serum atazanavir levels; coadministration of atazanavir with ritonavir does not compensate for this adverse interaction.(11) Proton pump inhibitors should not be used with atazanavir. H2 receptor antagonists and other antacids should be avoided, if possible. If an H2 receptor antagonist is used, atazanavir should be coadministered with ritonavir and should be taken at least 2 hours before and at least 10 hours after the H2 receptor antagonist. Information on drug interactions should be consulted, as dose adjustments are frequently required, and certain combinations are contraindicated.

Use in Initial vs Subsequent Therapy

Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services include ritonavir-boosted atazanavir in combination with tenofovir/emtricitabine as a "preferred" regimen and boosted atazanavir in combination with abacavir/lamivudine as an "alternative" regimen for initial treatment of HIV infection. The guidelines designate unboosted atazanavir in combination with abacavir/lamivudine or zidovudine/lamivudine as an "acceptable" regimen for initial treatment.

Atazanavir has been studied in both initial and salvage therapy. In the Phase II comparison (1) between atazanavir (at 3 dose levels) and nelfinavir, each combined with stavudine + didanosine in initial therapy, similar rates of viral suppression to <50 HIV copies/mL were seen in the 4 treatment arms (28-42% in intention-to-treat analysis [ITT], 33-52% in on-treatment analysis [OT]). A second study comparing atazanavir (at 2 dose levels) with nelfinavir, each combined with stavudine + lamivudine in treatment-naive subjects, demonstrated comparable rates of viral suppression to <50 HIV copies/mL at 48 weeks (31-38% in ITT, 39-42% in OT).(2) In an ongoing follow-up of these subjects, approximately 50% of those on atazanavir had viral loads of <50 copies/mL at a mean of 108 weeks (ITT), whereas subjects switched from nelfinavir to atazanavir had comparable rates of viral suppression.(12) In these studies, CD4 responses were comparable across treatment arms.

A randomized, controlled comparison of atazanavir + zidovudine + lamivudine with efavirenz + zidovudine + lamivudine in treatment-naive subjects has shown comparable rates of viral suppression to <50 copies/mL (32% vs 37%) and CD4 increase (approximately 170 cells/µL) at 48 weeks in ITT analysis.(3)

Although in these studies atazanavir resulted in virologic responses comparable to those obtained with previously licensed drugs, the response rates for all treatment arms were surprisingly low, and the efficacy of unboosted atazanavir in initial therapy remains unclear. The efficacy and safety of ritonavir-boosted atazanavir in initial therapy has not yet been determined.

In patients with prior treatment failure on protease inhibitor-based therapy, treatment with unboosted atazanavir plus 2 nucleoside analogues was found to be less effective at 48 weeks than treatment with lopinavir/ritonavir plus 2 nucleoside analogues.(13)

In a cohort with multiple virologic failures and prior exposure to 3 classes of antiretrovirals, patients treated with ritonavir-boosted atazanavir (combined with tenofovir and 1 nucleoside analogue) achieved rates of viral suppression and CD4 increase at 48 weeks statistically similar to those observed in patients treated with lopinavir/ritonavir + tenofovir + 1 nucleoside analogue (by ITT analysis, viral load <400 copies/mL in approximately 57% in both groups; CD4 increase 110-121 cells/µL).(14) However, patients with ≥4 primary protease inhibitor mutations had a poorer response to atazanavir + ritonavir (by ITT analysis, 28% in the atazanavir + ritonavir group vs 40% in the lopinavir/ritonavir group). The response rates in the atazanavir + ritonavir and lopinavir/ritonavir arms were significantly better than those in a third treatment arm, atazanavir + saquinavir + tenofovir + 1 nucleoside analogue.

Factors Affecting Adherence

Symptomatic side effects may include jaundice (in approximately 10% of individuals), nausea, diarrhea, and rash. The most common laboratory abnormality is isolated hyperbilirubinemia; elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) may occur. Unlike other currently available protease inhibitors, atazanavir has not been found to cause significant elevations in total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels.(1-3) Cardiac conduction abnormalities (particularly PR prolongation) have been observed.

Atazanavir has a low pill burden and is dosed once daily; these factors may encourage adherence.

It is important to assess patient motivation and discuss possible side effects and strategies for their management before treatment with atazanavir is initiated.

Resistance

Resistance to atazanavir is associated with the selection of 1 or more of several resistance mutations.

Implications of atazanavir resistance for treatment with other antiretrovirals

Resistance to atazanavir has been associated with various known protease inhibitor mutations as well as with the novel I50L substitution. Some atazanavir resistance mutations have been associated, in vitro, with decreased susceptibility to other protease inhibitors, while the I50L mutation has been associated with increased susceptibility to other protease inhibitors.(15,16,17) Results from clinical studies are needed to elucidate atazanavir resistance and its implications for subsequent therapy. Genotypic or phenotypic testing may be useful in predicting the likelihood of response to other protease inhibitors following failure of regimens containing atazanavir.

Implications of resistance to other antiretrovirals for atazanavir treatment

Resistance mutations selected by other protease inhibitors may confer or contribute to resistance to atazanavir. Substitutions at a number of specific sites have been associated with decreased in vitro susceptibility to atazanavir. Although no single mutation was found to confer high-level resistance to atazanavir, the accumulation of 5 or more of these key mutations predicted reduced susceptibility to atazanavir.(16) The clinical significance of these findings is under study.

Genotypic or phenotypic testing may be useful in predicting the likelihood of response to atazanavir following failure of regimens containing other antiretrovirals.

References
1.   Sanne I, Piliero P, Squires K, Thiry A, Schnittman S; AI424-007 Clinical Trial Group. Results of a phase 2 clinical trial at 48 weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr. 2003 Jan 1;32(1):18-29.
2.   Murphy RL, Sanne I, Cahn P, Phanuphak P, Percival L, Kelleher T, Giordano M. Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results. AIDS. 2003 Dec 5;17(18):2603-14.
3.   Squires K, Lazzarin A, Gatell JM, Powderly WG, Pokrovskiy V, Delfraissy JF, Jemsek J, Rivero A, Rozenbaum W, Schrader S, Sension M, Vibhagool A, Thiry A, Giordano M. Comparison of Once-Daily Atazanavir With Efavirenz, Each in Combination With Fixed-Dose Zidovudine and Lamivudine, As Initial Therapy for Patients Infected With HIV. J Acquir Immune Defic Syndr. 2004 Aug 15;36(5):1011-1019.
4.  Agarwala S, Mummaneni V, Randall D, Geraldes M, Stoltz R, O'Mara E. Pharmacokinetic (PK) Effect of Rifabutin (RIF) on Atazanavir (ATV) with and without Ritonavir (RTV) in Healthy Subjects. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, February 24-28, 2002, Abstract 445-W.
5.  Mummaneni V, Randall D, Chabuel D, Geraldes M, O'Mara E. Steady-State Pharmacokinetic (PK) Interaction Study of Atazanavir (ATV) with Clarithromycin (CLR) in Healthy Subjects. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, September 27-30, 2002, Abstract H1717.
6.  Agarwala S, Russo R, Mummaneni V, Randall D, Geraldes M, O'Mara E. Steady-State Pharmacokinetic (PK) Interaction Study of Atazanavir (ATV) with Ritonavir (RTV) in Healthy Subjects, 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, September 27-30, 2002, Abstact H-1716.
7.  O'Mara E, Mummaneni V, Bifano M, Randall D, Uderman H, Knox L, Geraldes M. Steady-State Pharmacokinetic Interaction Study Between BMS-232632 and Ritonavir in Healthy Subjects. 8th Conference on Retroviruses and Opportunistic Infections, Chicago, Sept. 4-8, 2001, Abstract 740.
8.  Preston S, Piliero P, O'Mara E, Mummaneni V, Randall D, Morvillo C, Geraldes M, Agarwala S, Drusano G. Evaluation of Steady-State Interaction between Atazanavir (ATV) and Efavirenz (EFV). 9th Conference on Retroviruses and Opportunistic Infections, Seattle, February 24-28, 2002, Abstract 443-W.
9.  Tackett D, Child M, Agarwala S, Geiger M, Geraldes M, Laura B, O'Mara E. Atazanavir: A Summary of Two Pharmacokinetic Drug Interaction Studies in Healthy Subjects. 10th Conference on Retroviruses and Opportunistic Infections, Boston, February 10-14, 2003. Abstract 543
10.   Taburet AM, Piketty C, Chazallon C, Vincent I, Gerard L, Calvez V, Clavel F, Aboulker JP, Girard PM. Interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 2004 Jun;48(6):2091-6.
11.  Dear Health Care Provider, Re: Reyataz (atazanavir sulfate) With or Without Norvir (ritonavir) and Proton Pump Inhibitors Should Not Be Coadministered: Important New Pharmacokinetic Data. Bristol-Myers Squibb. December 2004.
12.   Wood R, Phanuphak P, Cahn P, Pokrovskiy V, Rozenbaum W, Pantaleo G, Sension M, Murphy R, Mancini M, Kelleher T, Giordano M. Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir. J Acquir Immune Defic Syndr. 2004 Jun 1;36(2):684-92.
13.   Cohen C, Nieto-Cisneros L, Zala C, Fessel WJ, Gonzalez-Garcia J, Gladysz A, McGovern R, Adler E, McLaren C; BMS AI424-043 Study Group. Comparison of atazanavir with lopinavir/ritonavir in patients with prior protease inhibitor failure: a randomized multinational trial. Curr Med Res Opin. 2005 Oct;21(10):1683-92.
14.   Johnson M, Grinsztejn B, Rodriguez C, Coco J, DeJesus E, Lazzarin A, Lichtenstein K, Rightmire A, Sankoh S, Wilber R. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS. 2005 Apr 29;19(7):685-94.
15.  Colonno R, Rose R, Cianci C, Aldrovandi G, Parkin N, Friborg J. Emergence of Atazanavir Resistance and Maintenance of Susceptibility to Other PIs is Associated with an I50L Substitution in HIV Protease. 10th Conference on Retroviruses and Opportunistic Infections, Boston, February 9-14, 2003. Abstract 597.
16.   Colonno RJ, Thiry A, Limoli K, Parkin N. Activities of Atazanavir (BMS-232632) against a Large Panel of Human Immunodeficiency Virus Type 1 Clinical Isolates Resistant to One or More Approved Protease Inhibitors. Antimicrob Agents Chemother. 2003 Apr;47(4):1324-33.
17.  Colonno R , Parkin N , McLaren C, Seekins D, Hodder S, Schnittman S, and Kelleher T. Pathways to Atazanavir Resistance in Treatment-experienced Patients and Impact of Residue 50 Substitutions. 11th Conference on Retrovirus and Opportunistic Infections, San Francisco, February 8-11,2004. Abstract 656.