Low-Level
NNRTI Resistance Linked to Treatment Failure
SUMMARY
Nearly 20% of HIV positive people on first-line antiretroviral
therapy have low-frequency or minority NNRTI resistance
mutations, which increase the likelihood of virological
treatment failure. |
By
Paul Dalton
Antiretroviral
therapy (ART) regimens containing non-nucleoside reverse
transcriptase inhibitors (NNRTIs) are the most widely used
for first-line HIV treatment in the U.S. and worldwide. However,
resistance to NNRTIs is somewhat common and is known to lead
to increased risk of treatment failure and disease progression.
Resistance may emerge due to incomplete HIV suppression (for
example, due to less than optimal adherence), but people can
also become infected with virus that is already resistant
to certain drugs.
Commercially
available drug-resistance tests can detect resistance mutations
present in 15% or more of an individual's viral population.
Lower concentrations of drug-resistance mutations can be detected
by tests used in research settings. The effect of such low-level,
or minority variant drug resistance on risk of treatment failure
is not well understood.
As
described in the April
6, 2011, Journal of the American Medical Association,
Jonathan Li and colleagues performed a review of 10 studies
to analyze the effect of minority variant drug resistance
on the risk of first-line treatment failure.
The
researchers searched medical publication databases for relevant
work, and interviewed investigators from 10 selected studies.
Altogether, these studies included 985 people, 83% of whom
were men, with a median CD4 T-cell count of 229 cells/mm3
and median HIV viral load of 5 logs.
Results
 |
Overall,
drug resistant minority variants were found in 187 of
985 study participants (19%). |
|
People
with any minority resistance variants were 2.6 times more
likely to experience treatment failure. |
|
NNRTI
resistance was associated with treatment failure, while
resistance to only nucleoside/nucleotide reverse transcriptase
inhibitors (NRTIs) was not -- although only 3 people in
this study had only NRTI resistance. |
|
People
with minority resistance variants had lower average CD4
counts (208 vs 234 cells/mm3). |
|
No
difference in treatment failure rates was seen between
people with NNRTI resistance taking efavirenz
(Sustiva) vs nevirapine
(Viramune). |
|
There
was also no difference between people with the K103N vs
Y181C mutations, which are the most common NNRTI-associated
resistance mutations. |
|
People
with minority resistance variants and < 95% treatment
adherence were 5.1 times more likely to experience treatment
failure compared to those with no detectable resistance
and > 95% adherence. |
|
The
effect of minor variant drug resistance was dose-dependant,
with higher levels of resistance mutations (> 1% vs
< 1%) increasing the risk of treatment failure. |
|
People
without any detectable drug resistance were 9 times more
likely to achieve undetectable viral load than those with
detectable resistance. |
"In
a pooled analysis, low-frequency HIV-1 drug resistance mutations,
particularly involving NNRTI resistance, were significantly
associated with a dose-dependent increased risk of virologic
failure with first-line ART," the researchers concluded.
Because
NNRTI-based regimens are so common and single mutations can
lead to treatment failure, this study is important in further
understanding the role of drug resistance in treatment failure.
Commercially available tests with a greater sensitivity to
detect low concentrations of NNRTI drug-resistance mutations
could reduce the likelihood of treatment failure and extend
the duration of effective antiretroviral treatment. This study
also highlights the importance of high-level adherence to
treatment.
Previous
research looking at the presence of minority variant mutations
conferring resistance to protease inhibitors (PI) and integrase
inhibitors has not found that they significantly increase
the risk of treatment failure. While NNRTI-based regimens
are most widely used as part of first-line therapy, this research
suggests that until more sensitive drug-resistance testing
is commercially available, PI-based regimens may offer some
advantages in terms of resistance-associated treatment failure.
Investigator
Affiliations: Section of Retroviral Therapeutics, Brigham
and Women's Hospital, Harvard Medical School and Center for
Biostatistics in AIDS Research, Harvard School of Public Health,
Harvard University, Boston, MA; IrsiCaixa AIDS Research Institute
and Lluita Contra la SIDA Foundation, Hospital Universitari
Germans Trias i Pujol, Badalona, Spain; Gilead Sciences Inc,
Foster City, CA; Division of Infectious Diseases and Hospital
Epidemiology, University Hospital Zurich, University of Zurich,
Zurich, Switzerland; Yale University School of Medicine AIDS
Program and VA Connecticut Healthcare System, New Haven, CT;
Division of Biostatistics, University of Minnesota, Minneapolis,
MN; Institute of Virology, University of Cologne, Cologne,
Germany; Departments of Medical Microbiology and Immunology,
Aarhus University, and Infectious Diseases, Aarhus University
Hospital, Skejby, Denmark; Department of Virology, University
College London Medical School, London, UK; INSERM, U897 Epidemiology
and Biostatistics, Bordeaux School of Public Health, Bordeaux,
France; Laboratoire de Virologie, CHU de Bordeaux, and Université
de Bordeaux, Microbiologie fondamentale et Pathogénicité,
Bordeaux; Division of HIV/AIDS Prevention, National Center
for HIV, STD, and TB Prevention, Centers for Disease Control
and Prevention, Atlanta, GA.
5/3/11
Reference
JZ
Li, R Paredes, HJ Ribaudo, et al. Low-Frequency HIV-1 Drug
Resistance Mutations and Risk of NNRTI-Based Antiretroviral
Treatment Failure: A Systematic Review and Pooled Analysis.
Journal of the American Medical Association 305(13):
1327-1335 (abstract).
April 6, 2011.
