The impact of the NRTI backbone
resistance on the public health
approach to PI-based second-line
therapy in resource limited settings
Thuy Le, MD, DPhil
Hospital for Tropical Diseases
Oxford University Clinical Research Unit
Ho Chi Minh City, Viet Nam
Background
 The WHO recommendations to recycle NRTIs in
2nd-line therapy are based largely on expert
opinions
1st line NRTI
2nd line NRTI
AZT or d4T
TDF
TDF + 3TC (or FTC)
AZT + 3TC (or FTC)
 It is unclear whether at least one fully-active drug in
the NRTI backbone is needed or is sufficient to
achieve 2nd-line ART success
Research objective
We aimed to assess the impact of the
genotypic susceptibility score of the NRTI
backbone on the clinical and virological
performance of a cohort of patients on 2nd-line
therapy in Ho Chi Minh City.
Study design
 Study population: 2nd-line LPVr-based ART cohort at the
Hospital for Tropical Diseases in HCMC from 2006-20131,2
• confirmed virological failure to 1st-line ART
• genotyping before 2nd-line ART switch
 Study outcomes:
• Primary outcome: time to death or WHO-defined
immunological/clinical failure
• Secondary outcome: virological failure (confirmed VL
≥1000 copies/mL) assessed cross-sectionnally
1. Thao VP, et al, Medicine 2015
2. Thao VP, et al. JAC 2015
Genotypic susceptibility score (GSS)
 The susceptibility of the NRTI backbone is determined
by the sum of GSS for each NRTI drug using the
Stanford algorithm
HIVdb scoring
for 1 drug
HIVdb intepretation
GSS for
1 drug
0-9
Susceptible
1
10-14
Potential low-level
resistance
0.75
15-29
Low-level resistance
0.5
30-59
Intermediate resistance
0.25
≥60
High-level resistance
0
Statistical analyses
 Cox regression model was used to evaluate
time to death or immunological/clinical failure
 Logistic regression model was used to evaluate
risk of virological failure
 Explanatory variables: age, history of IDU,
baseline CD4 counts and HIV RNA loads,
history of PI exposure, and ART adherence
Results
326 patients initiating 2nd-line LPVr-based ART
(2006-2012)
Clinical outcome cohort (N=246)
- Had documented VF to 1st-line regimen
- Had HIV genotyping
Virological outcome cohort (N=173)
- Were in active follow up
- Had VL assessment
40 failure events
(16%). Median
follow up: 29
(IQR:15-44) months
- 8 IF
- 1 AIDS
- 31 deaths
17 virological failure
(10%)
Characteristics of 246 patients in the clinical
outcome cohort
Characteristics
Sex, male (%)
Median age (years)
Previous history of IDU (%)(n=235)
Median CD4 count (cells/mm3)
Median HIV RNA (log copies/mL)
Second-line regimens (%)
LPVr + 3TC + TDF
LPVr + 3TC + TDF + AZT
LPVr + 3TC + either ddI/d4T/ABC
Adherence
≥95%
<95%
N=246
201 (81.7%)
32 (28-36)
97 (41.3%)
41 (14-82)
5.1 (4.6-5.5)
138 (56.1%)
93 (37.8%)
15 (6.1%)
219 (89.0%)
27 (11.0%)
Resistance mutations at time of 2nd-line therapy switch
Predicted susceptibility to NRTI drugs
Calculated GSS of the 2nd-line NRTI backbone
GSS of the NRTI Number of patients (%)
backbone
0
68 (27.7%)
0.25-0.75
113 (45.9%)
≥1
65 (26.4%)
Predictors of clinical failure (N=246)
Covariates
Univariate HR
(95% CI)
GSS=0
0.25≤ GSS <1
GSS≥1
1
0.59 (0.27-1.27)
1.11 (0.52-2.37)
0.195
1
0.74 (0.31-1.77)
1.49 (0.59-3.67)
0.313
Age (by +10 years)
1.38 (0.91-2.07)
0.127
1.89 (1.06-3.36)
0.031
History of IDU
1.62 (0.84-3.11)
0.151
2.91 (1.14-7.41)
0.025
0.031
0.643
1.81 (0.95-3.45)
0.85 (0.55-1.31)
0.072
0.461
0.875
0.98 (0.58-1.67)
0.958
CD4 count (by -50 cells)
1.86 (1.06-3.25)
in first year
subsequent years 0.92 (0.63-1.33)
HIV RNA (by + log10
1.04 (0.65-1.65)
copies/ml)
p-value
Adjusted HR
(95% CI)
p-value
Adherence <95%
2.97 (1.44-6.09)
0.003
3.59 (1.47-8.80)
0.005
Prior PI use
0.65 (0.31-1.35)
0.252
2.59 (1.15-5.86)
0.021
Predictors of virological failure (N=173)
Covariates
GSS=0
0.25≤ GSS <1
GSS≥1
Univariate HR
(95% CI)
1
2.29 (0.67-10.48)
1.55 (0.27-8.84)
p-value
Adjusted HR
(95% CI)
p-value
0.443
1
2.79 (0.70-14.85)
1.63 (0.18-12.43)
0.348
Age (by +10 years)
1.57 (0.75-3.12)
0.211
1.80 (0.59-5.29)
0.289
History of IDU
0.70 (0.22-2.00)
0.529
3.40 (0.67-20.11)
0.151
0.91 (0.56-1.28)
0.638
0.81 (0.39-1.37)
0.496
2.55 (1.16-5.99)
0.025
3.09 (1.18-8.95)
0.027
Adherence <95%
3.12 (0.08-10.28)
0.074
5.36 (1.08-26.92)
0.036
Prior PI use
5.33 (1.18-15.62)
0.002
11.13 (2.71-54.34)
0.001
CD4 count (by -50
cells/µl)
HIV RNA (by +log10
copies/ml)
Limitations
 Low CD4 counts indicate late therapy switching and
a severe population where clinical events are likely
driven by the consequences of immuno-suppression
rather than by the effectiveness of 2nd-line therapy
 Extensive NRTI resistance could mask possible
association between NRTI resistance and outcomes
 One-center study with limited generalisability
Conclusions
 NRTI resistance does not predict clinical or virological
outcomes of second-line ART in Vietnam
 Findings are consistent with data from the EARNEST trial
showing that despite extensive resistance, the NRTI backbone
adds to the potency and durability of LPVr-based 2nd-line
therapy
 Supports the current public health strategy to recycle NRTIs in
2nd-line ART in resource-limited settings
 Continued adherence support, early detection of treatment
failure, and timely therapy switching can improve the outcomes
of patients on 2nd-line therapy