FM DECEMBER 2018 ISSUE - digital edition

HIVDR mutations are needed for proper
management and ensuring optimal
therapy to patients. As patients with
acquired drug resistance are increasing,
so are newly infected patients with
transmitted drug resistance.
This clearly suggests that the 21
million people receiving ART are at
risk as also the target of eliminating
HIV as a public health threat by
2030. More than 1 patient in 10 are
becoming ART-resistant in low and
middle income countries with respect
to non-nucleoside reverse transcriptase
inhibitors (NNRTIs). Pretreatment
drug resistance is associated with
an increased risk of virological
failure, impaired immune recovery,
accumulation of drug resistance,
increased risk of treatment switches
and death. WHO recommends a shift to
alternative, non-NNRTI-based first-line
ART (i.e., based on integrase inhibitors
or protease inhibitors) or individualised
pretreatment drug resistance testing to
guide the choice of an appropriate
first-line treatment. Additionally,
continuous resistance surveillance
is recommended as a part of the
WHO Global Action Plan on HIV
drug resistance. One technological
breakthrough has led to the
development of highly robust next
generation sequencing (NGS)
technologies with the ability to detect
low-frequency, minority HIV variants at
increasingly affordable prices.
Importance of HIV-1 genotyping
A recent case-control study nested
within a prospective multicountry
cohort by Seth C Inzaule et al (The
Lancet HIV, http://dx.doi.org/10.1016/
S2352-3018(18)30177-2), studied the
International Antiviral Society (IAS)-
USA mutation list or the Stanford HIV
Drug Resistance Database (HIVDB)
using Illumina MiSeq next-generation
sequencing technology. They compared
the conventional pretreatment drug
resistance detection threshold of 20%
or more for Sanger-based sequencing
to diagnostic accuracy measurements
and the odds of virological failure using
PRETREATMENT DRUG
RESISTANCE IS ASSOCIATED
WITH AN INCREASED
RISK OF VIROLOGICAL
FAILURE, IMPAIRED IMMUNE
RECOVERY, ACCUMULATION
OF DRUG RESISTANCE
conditional logistic regression for 1%,
5% and 10%. A 12-month follow-up
of 1896 participants suggested that
virological failure had an odds ratio (OR)
of 9.2 (95% CI 4·2–20·1) at a detection
threshold of 20% or more, for patients
with pretreatment resistance compared
to without pretreatment drug resistance.
Lowering the threshold to 10% resulted
in an odds ratio of 6.8 (95% CI 3·3–13·9),
5% to 7·6 (3·4–17·1) and 1% to 4·5
(2·0–10·2). This suggests that lowering
the threshold does improve the ability to
identify at-risk participants, but a slight
reduction of specificity from 98% to
96% was observed. This suggests that
in the era of ARTs, HIV-1 genotyping
is very important for both clinical
management and public health
surveillance for anyone living with HIV-1
anywhere in world.
Detecting low-frequency mutations
Ultrasensitive genotyping tests can
improve the clinical evaluation and
identification of low-frequency drug
resistance mutations (LFDRM). LFDRMs, if
detected robustly, can impact the efficacy
of treatment protocols of ART and the
outcomes. Furthermore, the level at
which each drug resistance mutation is
present in the virus population can play
an important role. Several studies (Simen
et al., 2009b, Li et al., 2011 and Cozzi-
Lepri et al., 2015) evaluated the dosedependent
association between LFDRMs
and the risk of virological failure of
first-line NMRTI therapy. The mutational
load (ie., the mutant frequency multiplied
by the total HIV-1 RNA levels) may be
a better predictor of virological failure
(Gupta et al 2014, Goodaman et al 2011).
DECEMBER 2018 / FUTURE MEDICINE / 31