777 
Analysis of the Relationship between Antiretroviral Medication Adherence and Class-specific Resistance in a Large Prospective Randomized Clinical Trial
Edward Gardner*1, G Peng2, E Telzak3, S Sharma2, K Huppler Hullsiek2, W Burman1, M Chesney4, G Friedland5, R MacArthur6, S Mannheimer7, and The International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)
1Denver Publ Hlth, CO, US; 2Univ of Minnesota, Minneapolis, US; 3Bronx-Lebanon Hosp Ctr, NY, US; 4Natl Ctr for Complementary and Alternative Med, NIH, Bethesda, MD, US; 5Yale Univ Sch of Med, New Haven, CT, US; 6Wayne State Univ, Detroit, MI, US; and 7Columbia Univ Coll of Physicians and Surgeons, New York, NY, US
Background: The FIRST study (CPCRA 058) was a prospective,
randomized ART strategy trial for ART-naive persons.
Methods: We assessed the association between ART
adherence and class-specific genotypic resistance at first virologic failure
(HIV RNA >1000 at or after 4 months) by randomized strategy (protease
inhibitor [PI] or NNRTI) in FIRST. Adherence was measured by 7-day self-report at
months 1 and 4, and then every 4 months. Predictors of first virologic failure
with resistance using Cox regression analyses adjusted for demographics,
baseline clinical factors, and time updated indicators for ART use and cumulative
mean adherence were determined. Additional Cox models evaluated levels of
cumulative mean adherence (80 to 99% and <80%, both compared to 100%). On-treatment
analyses were also performed.
Results: In 903 participants, mean age was 38, 22%
were women, and 74% were non-white. Mean baseline CD4 was 211 cells/µL; HIV RNA
was 5.0 log10 copies/mL. Median follow-up was 5 years. In the NNRTI
strategy, as adherence decreased the risk of NNRTI resistance at first virologic
failure increased (HR 1.2, 95%CI 1.1 to 1.3 per 10% decline) but in the PI
strategy no association was found between adherence and PI resistance (HR 1.1,
95%CI 0.9 to 1.4). In both strategies lower adherence was significantly
associated with NRTI resistance. In analyses using levels of adherence, in the
NNRTI strategy there was an increased risk of NNRTI resistance in the 80 to 99%
(HR 2.3, 95%CI 1.4 to 3.7) and the <80% adherent groups (HR 6.5, 95% CI 3.9 to
10.7) compared to the 100% adherent group; in the PI strategy there was no
association between adherence level and PI resistance. As treated analyses for
unboosted PI prescribed at initiation showed no association between adherence and
PI resistance. Boosted PI analyses were not possible due to the rarity of
failure with PI resistance.
|
Randomization
Strategy
|
n
|
Virologic failure
n (%)
|
Median time to Virologic failure
(years)
|
PI-resistance
n (%)
|
NNRTI-resistance
n (%)
|
NRTI-resistance
n (%)
|
|
NNRTI
|
446
|
262 (59%)
|
3.0
|
5 (1%)
|
112 (25%)
|
62 (14%)
|
|
PI (overall)
Boosted-PI*
|
457
116
|
325 (71%)
83 (72%)
|
1.2
1.5
|
37 (8%)
2 (2%)
|
18 (4%)
11(13%)
|
121 (26%)
22 (19%)
|
*PI type was not randomized
Conclusions: This is the largest prospective analysis
of adherence-resistance relationships to date. It supports published analyses
of the inverse relationship between adherence and NNRTI resistance. PI
resistance was uncommon in this study (especially for boosted-PI), which may
explain the lack of association between adherence and PI resistance.
|
