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Virologic Drug Resistance Is Not Associated with AIDS-defining Events or Mortality: An ACTG Longitudindal Linked Randomized Trials Analysis
Susan Swindells*1, H Jiang2, L Mukherjee2, M Winters3, R Bosch2, D Katzenstein3, and the AIDS Clinical Trials Group
1Univ of Nebraska Med Ctr, Omaha, US; 2Statistical and Data Analysis Ctr, Harvard Sch of Publ Hlth, Boston, MA, US; and 3Stanford Univ Med Ctr, CA, US
Background: We hypothesized that drug-resistance
mutations and ARV resistance could influence the pathogenicity of HIV-1
infection and the rate of clinical outcomes, such as disease progression and
mortality.
Methods: A matched case-control study of previously
ARV-naļve and -experienced participants in the ALLRT cohort. Cases experienced
an AIDS-defining event or non-accidental death at least 24 weeks after parent
ARV treatment study entry, and controls did not. We identified 134 cases from 8
ALLRT parent trials and matched to a total of 266 controls (planned 1:2) by
age, sex, treatment regimen, and length of follow-up. All had at least 1 HIV
RNA level ≥500copies/mL within 24 weeks of the event. We evaluated the effect
of resistance mutations on incidence of AIDS-defining events or death using
population-based genotyping of stored specimens. Conditional logistic
regression models evaluated the association between future drug options (the number
of drug classes that remain useful) or Stanford resistance score, and risk of
death or AIDS-defining event.
Results: We analyzed 104 case-control groups: 30
groups had unavailable specimens or sequencing failure in either case or
controls. For the 287 subjects in the analysis, 87% were male, 50% non-white,
median age 39 years; 33% of cases had 1 control, 59% had 2, and 9% had 3
controls; 46% were treatment-naļve. The median time to event was 99 weeks; 6
cases were deaths. At baseline, cases had lower CD4 (median 117 vs 235 cells/mm3,
p <0.0001) and higher HIV RNA levels (median 205,000 vs 57,000 copies/mL,
p = 0.003); comparisons were similar at the time of genotype. No
significant differences in resistance were seen between cases and controls (see
the table).
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Cases
(n = 104)
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Controls
(n = 183)
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Conditional logistic p-value
unadjusted (adjusted for baseline CD4 and HIV RNA)
|
|
|
|
Mean FDO
|
2.53
|
2.69
|
0.3 (0.5)
|
|
|
NRTI high-level resistance (%)*
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18.5
|
11.5
|
0.2 (0.6)
|
|
|
NNRTI high-level resistance (%)*
|
23
|
22
|
0.8 (0.9)
|
|
|
PI high-level resistance (%)*
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18
|
14
|
0.5 (0.9)
|
|
|
Mean number of classes with high-level resistance
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0.59
|
0.48
|
0.5 (0.9)
|
|
*Defined as Stanford resistance score >59.5
Conclusions: Compared to controls, cases
demonstrated significantly lower baseline CD4 counts and higher virus loads, as
well as lower CD4 counts and higher viral loads proximal to new AIDS-defining
event or death, in this rigorously designed case-control study. Viral resistance
was not associated with increased risk of AIDS-defining event or death.
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