Early Virologic Non Response to Tenofovir, Abacavir and Lamivudine
Due
to their potential to simplify anti-HIV therapy and thereby improve
patient adherence and
quality
of life, fixed-dose
combinations are an attractive option compared to
individual dosing of drugs. In the current study, which appears
in the December 1, 2005 issue of The Journal of Infectious
Diseases, researchers compared 2 regimens dosed
as 2 pills once daily.
This
was a randomized, open-label, multicenter study
of tenofovir
(Viread) versus efavirenz
(Sustiva),
both administered once daily with the abacavir/lamivudine fixed-dose combination (Epzicom) in treatment-naive HIV patients.
Following
reports of early nonresponse, an unplanned interim
analysis was performed. Virologic non response
was defined as (1) a <2.0-log10 copies/mL
decrease in HIV-1 RNA level by week 8, (2)
an HIV-1 RNA rebound of 
1.0
log10 copies/mL above the nadir, or
(3) for subjects with 2 consecutive HIV-1 RNA
measurements <50 copies/mL, a subsequent increase
to >400 copies/mL on 2 consecutive occasions.
Results
- 340
subjects were randomized.
- Median
baseline HIV-1 RNA level and CD4+ cell
count were 4.7 log10 copies/mL and 251
cells/mm3, respectively;
- 194
subjects with HIV-1 RNA data from 8
weeks were included in the interim analysis.
- Virologic nonresponse
occurred in 50 (49%) of 102 subjects
in the tenofovir arm, compared with
5 (5%) of 92 of subjects in the efavirenz
arm (P < .001).
- Within
12 weeks, viral genotypes for nonresponders
in the tenofovir
disoproxil fumarate arm showed M184V
or I/M/V mixtures in 40 (98%) of 41
subjects and K65R and M184V or mixtures
in 22 (54%) of 41 subjects.
- The
protocol was immediately amended to modify
the tenofovir arm.
- The
efavirenz arm continued unchanged; after
48 weeks, 120 (71%) of 169 subjects achieved
HIV-1 RNA levels <50 copies/mL.
Based
on these results, the authors conclude, “The tenofovir disoproxil
fumarate/abacavir/lamivudine regimen resulted in an
unexpected and unacceptably high rate of non response
and incidence of K65R and M184V/I.”
“This
3-drug regimen should not be used.”
Discussion
According
to the authors, the most likely explanation for the
poor response to this combination regimen is the low
genetic barrier to resistance produced by synergistic
selection pressure from all 3 drugs for 2
point mutations, M184V and K65R.
The
authors note, “Both abacavir and tenofovir DF select
for the K65R mutation, which reduces susceptibility
to both drugs, as well as to lamivudine.
M184V is selected for by lamivudine and
abacavir, and it decreases susceptibility to both.”
“Thus,
the selection of 2 mutations, each of which
may preexist as minority species, leads to virologic
failure with this regimen.”
Division of Infectious Diseases,
Johns Hopkins University School
of Medicine, Baltimore, Maryland;
University of Miami, Miami,
Florida; Kaiser Permanente, Atlanta,
Georgia; Rose Medical Center,
Denver, Colorado; Northstar Medical
Center, Chicago, Illinois; GlaxoSmithKline,
Research Triangle Park, North
Carolina.
11/28/05
References
J
E Gallant and others (for the ESS30009
Study). Early Virologic Nonresponse
to Tenofovir, Abacavir, and
Lamivudine in HIV-Infected Antiretroviral-Naive
Subjects. The Journal of Infectious Diseases 192(11):
1921-1930. December 1, 2005.
