Background:
The K65R mutation in HIV RT has been selected
in vitro
by
tenofovir and has also developed at low incidence (3%) in
treatment-experienced patients (pts) with up to 96 weeks of TDF add on therapy.
Methods:
Study 903 is a 3 year, randomized,
double-blind, active-controlled study of TDF therapy in 600 treatment-naive
pts. Pts received either TDF (n=299)
or d4T (n=301)
with
3TC and EFV. HIV from pts with virologic failure (>400 copies/ml of HIV RNA
at week 96 or upon early discontinuation, ITT) was
analysed genotypically and phenotypically (ViroLogic).
Results:
In this interim week 96 analysis, 12.3% of pts were
classified as virologic failures (36 TDF, 38
d4T;
P=0.90).
Resistance to EFV (K103N + others)
or 3TC (M184V) occurred most frequently (6.5% and 4.5%, respectively) with
no significant difference between arms. Through 48 weeks, the K65R mutation
developed in seven TDF pts versus two d4T pts. From week 48–96, K65R
developed in one additional
TDF pt (overall 2.7% TDF vs 0.6% d4T,
P=0.06).
EFV resistance preceded or accompanied development
of K65R in all cases, either with (n=5)
or without (n=3)
M184V. More pts in the d4T arm (n=18)
vs the TDF arm (n=11,
P=0.25)
failed with wild-type HIV. Among HIV isolates from TDF-treated pts with K65R
(n=8),
there were only low-level changes in tenofovir susceptibility
in vitro
(mean 1.2-fold, range 0.9–2.2), increased
susceptibility for AZT (0.5-fold),no change for d4T (0.9-fold), and
low-level changes for other NRTIs (4/8 and 5/8 below cut-offs for ddI and
ABC, respectively). The mean replication capacity of HIV from these pts was
45% of wild-type and their mean plasma HIV RNA remained 0.9 log10 below
baseline. All 8 pts began a new regimen with a PI and other NRTIs, including
2 pts who remained on TDF. 5/8 achieved <50 copies/ml of HIV RNA (median
follow-up 76 weeks); 2 pts were without follow-up and 1 pt was non-adherent.
No cases of virologic failure to the second regimen
have been observed.
Conclusions:
Among treatment-naive pts, virologic failures
occurred with similar frequency in patients on TDF+3TC+EFV and d4T+3TC+EFV
and was associated most commonly with EFV- and 3TC-associated mutations. The
K65R mutation occurred in 2.7% of TDF-treated pts and was associated with
low-level phenotypic changes, decreased HIV replication capacity, and
reduced viral load from baseline. Successful and durable virologic outcomes
were achieved in pts who failed with K65R upon initiation of second-line
therapy. |
