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Rate of Viral Evolution and Risk of Losing Future Drug Options in Heavily Pre-treated Patients Remaining on a Stable Partially Suppressive Regimen
Hiroyu Hatano*1, P Hunt1, J Weidler2, E Coakely2, R Hoh1, T Liegler1,3, J Martin1, and S Deeks1
1Univ of California, San Francisco, US; 2Monogram Biosci, South San Francisco, CA, US; and 3Gladstone Inst of Virology and Immunology, Univ of California, San Francisco, US
Background: Many treatment-experienced patients with
limited therapeutic options for complete viral suppression remain on a
partially suppressive regimen pending the availability of at least 2 fully
effective agents. The major risk of this approach is ongoing viral evolution
and the loss of future drug options. The rate at which drug options are lost in
such patients has not been carefully defined.
Methods: ART-treated patients with drug resistance
were sampled from a clinic-based cohort of chronically HIV-infected patients. Subjects
were included in this analysis if they had: stable antiretroviral regimen for ³120
days, plasma HIV RNA level >1000 copies/mL, at least 1 genotypic resistance
mutation, and at least 1 follow-up visit. Phenotypic and genotypic resistance
testing was performed every 4 months and observations were censored at the time
of any treatment modification. The primary endpoints were time to loss of
phenotypic susceptibility to at least 1 fully effective drug (or 2 partially
effective drugs), as well as time to development of 1 new nucleoside analogue
mutation (NAM) or 1 new major protease mutation (IAS-USA guidelines).
Results: A total of 106 patients were eligible;
the median duration of observation was 48 weeks (IQR 32 to 90). The median
baseline CD4 cell count and plasma HIV RNA levels were 292 cells/mm3
and 3.74 log copies/mL, respectively. Subjects had previously received a median
8 prior drugs. Using a Kaplan-Meier analysis, the estimated risk of losing 1
fully suppressive drug (or 2 partially suppressive drugs) was 32% at 1 year
(95% CI 22 to 45). The risk of developing a new NAM at 1 year was 23% (CI 12 to 40),
and of developing a new major protease mutation was 17% (CI 8 to 33). We also
assessed the risk of deferring the use of a single new drug (tipranavir). Only an estimated 5% (CI 2 to 16) of protease
inhibitor (PI)-treated patients experienced genotypic loss of tipranavir
susceptibility. Viral load, CD4+ T cell counts, phenotypic
susceptibility score, replicative capacity, number of previous drugs, and
number of missed doses in last 30 days were not consistently predictive of rate
of viral evolution.
Conclusions: In
a cohort of heavily pretreated HIV patients with incomplete viral suppression,
the risk of losing future drugs options appeared to be moderate. This risk
should be considered when deciding to maintain patients on a partially
suppressive regimen.
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