Abacavir-Lamivudine vs. Tenofovir-Emtricitabine for Initial HIV-1

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Abacavir-Lamivudine vs. Tenofovir-Emtricitabine for Initial HIV-1 Powered By Docstoc
					Abacavir-Lamivudine vs.
Tenofovir-Emtricitabine for
Initial HIV Therapy
(Sax et al. N ENGL J MED 2009;361: 2230-40)

Christina Sarubbi, Pharm.D., BCPS
UCSD Infectious Diseases Pharmacy Resident
February 11, 2010
  Patient Case
WS is a 53 yo M who was diagnosed with HIV/AIDS on
12/8/09 by his PCP following complaints of oral thrush.

PMH: GERD, hyperlipidemia, hemorrhoids
Labs: CD4 118; VL 413,570 copies/mL; SCr 1.2
Meds: Atovaquone, rosuvastatin, nystatin, MVI, esomeprazole
Allergies: Sulfa (rash with Septra)

Assessment: HIV/AIDS: ARV-naïve, needs to have genotype
faxed from PCP, HLA pending. WS is well-educated and is a
good candidate for adherence. Start on appropriate therapy
once resistance test results have been reviewed.
   HIV treatment guidelines recommend use of
    two NRTIs + NNRTI or a ritonavir-boosted PI
    for initial treatment

   Abacavir/lamivudine (ABC/3TC) and
    tenofovir/emtricitabine (TDF/FTC) are widely
    used NRTIs for initial HIV treatment

   Which NRTI combination has greater efficacy
    and safety?
    Study Patients
   Included HIV-1 infected patients
    ◦ ≥16 years of age
    ◦ Received at most 7 days of ARV therapy
    ◦ HIV RNA >1000 copies/mL within 90 days of
      study entry

   Excluded: breastfeeding, use of
    immunomodulators, allergy to study drug,
    evidence of major resistance-associated
    mutation, etc.
    Study Design – ACTG A5202
   Ongoing phase 3B, randomized, partially
    blinded study comparing four ARV regimens
    for the initial treatment of HIV

   Planned duration of 96 weeks

   Genotypic resistance test was required at
    screening in patients with recent HIV

   HLA-B*5701 allele testing was permitted
    Study Design – ACTG A5202
            Arm A                  Arm B
       EFV 600 mg QD + FTC    EFV 600 mg QD + ABC
        200 mg/TDF 300 mg       600 mg/3TC 300 mg
               QD +                   QD +
       ABC/3TC placebo QD      FTC/TDF placebo QD

            Arm C                  Arm D
        ATV 300 mg QD with     ATV 300 mg QD with
       RTV 100 mg QD + FTC    RTV 100 mg QD + ABC
            200 mg/TDF             600 mg/3TC
       300 mg QD + ABC/3TC    300 mg QD + FTC/TDF
            placebo QD             placebo QD

   Stratified at screening based on HIV RNA levels
    <100,000 and ≥100,000
    Study Objectives
   Primary efficacy endpoint: time from
    randomization to virologic failure
    ◦ HIV RNA ≥1000 copies/mL at or after 16 wks and before
      24 weeks or ≥ 200 copies/mL at or after 24 weeks

   Primary safety endpoint: time from initiation to the
    first grade 3 or 4 sign, symptom or lab abnormality
    that is at least one grade higher than at baseline

   Tolerability endpoint: time to change in one or
    more drugs in initial treatment regimen
    Statistical Analysis
   Regimens considered equivalent if the two-sided 95%
    CI for the hazard ratio was between 0.71 and 1.40.

   Planned sample size of 1800 subjects would provide
    an 89.8% probability of declaring equivalence

   Analysis of efficacy data followed the intention-to-
    treat principle

   Hazard ratios were estimated with the use of Cox
    proportional-hazard models
Statistical Analysis
   Early stopping guidelines for inferiority were

   During the first efficacy review on January 29,
    2008, excess virologic failures in patients
    receiving regimens with ABC/3TC were noted
    among patients with HIV RNA ≥100,000.

   Further study of ABC/3TC was stopped among
    participants with HIV RNA ≥100,000 at
   Baseline Characteristics
    ◦ 1858 patients enrolled
    ◦ 797 patients with HIV RNA ≥100,000 at
      screening included in this analysis
    ◦ Diverse study population:
      26% Black, 25% Hispanic, 15% Female
    ◦ Median CD4 count: 145
    ◦ 43% genotype tested at screening
    ◦ 24% reported history of AIDS
Results – Primary Outcome
Time to protocol-defined virologic failure
    Results – Primary Outcome

Timing of Virologic Failure According to Treatment Group (no. of patients)
Virologic Failure                           Abacavir-        Tenofovir-
                                            Lamivudine       Emtricitabine
                                            (N=57)           (N=26)
≥1000 copies/mL at 16 to <24 weeks                19                9
without previous level of <200 copies/mL
≥200 copies/mL at ≥24 wk without previous         9                 2
level of <200 copies/mL
≥200 copies/mL at ≥24 wk with previous            29                15
level of <200 copies/mL
Results – Secondary Outcomes
Time to first occurrence of either virologic or modification of an NRTI
  Results – Secondary Outcomes
Proportions of patients with an HIV RNA level below 50 copies/mL,
  regardless of whether they had previously discontinued their assigned
  NRTI or had virologic failure.
Estimated effect of ABC/3TC vs. TDF/FTC on the Hazard of Virologic Failure,
                   According to Baseline Characteristics
  Results – Adverse Events
Time to Safety End Point.
Selected Clinical and Laboratory Events
                            ABC/3TC                 TDF/FTC
AIDS events                  26 (7%)                 17 (4%)
HIV-related cancers             8                       4
Bone Fractures                  7                       10
Myocardial Infarctions          0                       0
Renal Failure                   2                       2

Emergence of Major Drug-Resistance Mutations
                              ABC/3TC                 TDF/FTC
                         25 (45% of group with   10 (38% of group with
                           virologic failures)     virologic failures)
   Patients with a screening HIV RNA
    ≥100,000 copies/mL were significantly less
    likely to have virologic failure if treated
    with TDF/FTC

   Time to primary safety endpoint was also
    significantly shorter among patients
    receiving ABC/3TC
 Is ABC/3TC is less potent than TDF/FTC?
 Occurrence of hypersensitivity reactions did
  not appear to influence study outcomes
 Differences in PK of individual drugs?
 Differences in types of emerging drug-
  resistance mutations?
 Influence of these mutations on the antiviral
  activity of the individual drugs
                                       Smith et al.             Sax et al.
                                       (HEAT study)             (ACTG A5202)
 Conclusion                            Comparable antiviral     Time to virologic failure
                                       activity, safety, and    and first adverse event
                                       tolerability between     were significantly
                                       ABC/3TC and TDF/FTC      shorter in pts receiving
 Baseline characteristics
   Median CD4                          202                      145
   CD4 < 50                            19%                      30%
   HIV RNA ≥100,000                    43%                      49%
 Study end points                      Proportion of patients   Time from
                                       with HIV RNA <50 at      randomization to
                                       48 weeks                 virologic failure
 % Discontinued                        22% (counted as          10%
 prematurely                           virologic failures)
 Third drug in treatment               Lopinavir/ritonavir      Efavirenz or
 regimen                                                        atazanavir/ritonavir

Smith et al. AIDS 2009; 23: 1547-56.
   Limitations
    ◦ Cannot fully describe resistance data or effect
      of third drug on the outcome of NRTI
    ◦ Combined four treatment groups into two

   Clinical Implications
    ◦ HIV treatment guidelines recommend data
      from this study be considered in selecting
      NRTIs for patients with high HIV RNA levels
      in treatment-naïve patients
Patient Case
Genotype results: K103N mutation
HLA-B*5701: not present

(1) Tenofovir/emtricitabine 1 tablet once
(2) Darunavir 800 mg once daily/ ritonavir
    100 mg once daily

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