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Pharmacokinetic and Pharmacodynamic Parameters in HIV-1 Subjects Receiving Pegylated Interferon-a-2a Therapy: AIDS Clinical Trials Group Study 5192
David Asmuth*1, S Rosenkranz2, Y Cramer2, J Lertora3, C Rinaldo4, R Murphy5, R Schooley6, N Thielman7, X-D Li1, R Pollard1, and ACTG 5192
1Univ of California, Davis Sch of Med, US; 2Harvard Sch of Publ Hlth, Boston, MA, US; 3NIH, Bethesda, MD, US; 4Univ of Pittsburgh, PA, US; 5Feinberg Sch of Med, Northwestern Univ, Chicago, IL, US; 6Univ of California, San Diego Sch of Med, US; and 7Duke Univ, Durham, NC, US
Background: For 12 weeks,
interferon (IFN) was administered to HIV-1+ volunteers who were hepatitis
B and C virus (HBV, HCV) negative and not on ART. Pharmacokinetic and pharmacodynamic
parameters have not previously been measured in this patient population.
Methods: A total of 11
subjects received weekly IFN injections. HIV-1 load, IFN, and oligoadenylate
synthetase (OAS) levels were measured by polymerase chain reaction (PCR) and enzyme
immunoassay (EIA), respectively at weeks 0, 1, 2, 3, 4, 6, 8, 10, 12, 13, and
18. IFN and OAS at steady state were calculated (a priori definition) as the
arithmetic average of all available concentrations from weeks 6, 8, 10, and 12.
The primary study endpoint was change in viral load from baseline to week 12. Since
the largest observed changes in viral load were at weeks 1 and 2, this
exploratory, post hoc, analysis focused on relationships between viral load at
weeks 1, 2, and 12 and concurrent absolute levels and changes in IFN and OAS,
using the Spearman correlation coefficient.
Results: At week 12 of
treatment, HIV-1 load declined by a median 0.61 log10 copies/mL (90%CI
0.20 to 1.18). The maximum median change from baseline was at week 2 (1.30 log10
copies/mL; 90%CI 0.58 to 1.75). Average steady-state IFN levels ranged from
11,275 to 26,575 pg/mL and change from baseline to steady-state IFN ranged from
11,250 to 25,716 pg/mL (baseline IFN ranged from below the limit of
quantification (25 pg/mL; 7 subjects) to 859 pg/mL). Average steady-state OAS
levels ranged from 111.8 to 469.8 pmol/dL and change from baseline to
steady-state OAS ranged from –119.0 to 265.5 pmol/dL. At weeks 1, 2, and 12,
subjects with larger increases in OAS tended to have larger declines in viral
load (estimated Spearman correlation coefficients 0.77 [CI 0.33 to 0.93], 0.64
[0.13 to 0.88], and 0.57 [CI 0.07 to 0.84], respectively). Estimated
correlations of week 1, 2, and 12 viral load changes with IFN and OAS levels
and with IFN changes ranged from –0.53 to 0.29, none significant with n = 11.
Conclusions: This work
documents for the first time the pharmacokinetic and pharmacodynamic activity
of IFN in HBV/HCV– HIV-1+ patients. Differences in IFN
levels following therapy did not correlate with changes in viral load. In
contrast, the antiviral affects of IFN, as measured by OAS levels, were
associated with viral load decline, and likely represent a dominant pathway for
IFN suppression of HIV-1.
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