Low level viremia and HIV-1 drug
resistance in patients with virological
rebound after suppression with a first
line antiretroviral regimen
Manuela Colafigli
Catholic University of S. Heart
Rome, Italy
Background and objective
• Low level virological rebound (LLVR) may
be observed in HIV-infected patients
even after virological suppression
• LLVR may be associated with subsequent
virological failures
• Consequences on the development of drug
resistance unclear
• Objective of this study was to evaluate
the association of LLVR with appearance
of resistance mutations at VF in patients
on a first line antiretroviral regimen
Methods
• Patients with a GRT available after starting a
first line regimen based on NNRTI or bPI and
achieving at least one VL<50 copies/mL selected
(years 1999-2012)
• Data regarding viroimmunological tests and
treatment history collected
• first available GRT after virologic suppression
chosen as a proxy of VF
Statistical analysis
• Definitions
– LLVR: VL>50 copies/mL and <1000 copies/mL.
(in patients with > 1 LLVR the highest VL was
considered)
– Presence of drug resistance mutations
(DRM): any major IAS mutation fall 2011
• Analysis
– Univariate and multivariate logistic
regression  predictors of presence of DRM
Results – Patients’ characteristics (n=222)
Variable
Age, median (IQR)
40 (34-47)
Male gender, n (%)
155 (72)
Geographic area, n (%):
Northern Italy
Central Italy
Southern Italy
123 (55.4)
91 (41.4)
7 (3.2)
Subtype, n(%):
B
CRF02_AG
F1
C
G
Other
181 (81.5)
14 (6.3)
11 (5)
4 (1.8)
4 (1.8)
8 (3.6)
Year of sampling, median (IQR)
2007 (2004-2009)
Baseline VL, median log10 copies/ml (IQR)
4.87 (3.72-5.36)
Baseline CD4, median cells/µL (IQR)
191 (71-362)
LLVR and Drug Resistance
Mutations at virologic failure
Variable
Log10 VL at LLVR, median (IQR)
2.30 (1.93-2.60)
VL at LLVR, n (%)
No LLVR <50 copies/mL
50 to 100 copies/mL
101 to 500 copies/mL
501 to 1000 copies/mL
102 (45.9)
29 (13.1)
76 (34.2)
15 (6.8)
Presence of any major IAS-defined DRM, n (%)
85 (38.3)
Presence of any NRTI DRM, n (%)
65 (29.3)
Presence of any NNRTI DRM, n (%)
50 (22.5)
Presence of any major PI DRM, n (%)
24 (10.8)
Antiretroviral drugs
7% Backbone
12%
2%
Third Drug
35%
NNRTI
35%
44%
56%
9%
3(F)TC/TDF
ABC/3TC
AZT/3TC
D4T+DDI
D4T+3TC
Other
15%
2%
PIr
7%
PIr type
1%
NN type
EFV
15%
NVP
42%
60%
58%
LPV
ATV
DRV
IDV
APV/TPV
SQV
Predictors of any major DRM
Variable
Univariate analysis
OR (95% CI)
P value
Multivariate analysis
OR (95% CI)
P value
Presence vs absence of LLVR*
2.83 (1.60-5.01)
<0.001
2.95 (1.59-5.46)*
<0.001*
Calendar year of sequencing, per 1 year
more recent
0.92 (0.84-0.99)
0.040
0.97 (0.85-1.11)
0.692
0.552
0.001
<0.001
Reference
1.55 (0.59-4.07)
2.92 (1.47-5.80)
16.9 (3.87-74.31)
0.374
0.002
<0.001
0.125
0.863
0.323
0.199
0.476
0.020
VL at LLVR, n (%)
No LLVR <50 copies/mL
50 to 100 copies/mL
101 to 500 copies/mL
501 to 1000 copies/mL
Reference
1.32 (0.53-3.25)
2.92 (1.55-5.50)
11.69 (3.06-44.71)
NRTI backbone:
3(F)TC/TDF
ABC/3TC
AZT/3TC
D4T/DDI
D4T/3TC
Other
Reference
0.422 (0.11-1.56)
1.57 (0.81-3.03)
9.00 (0.96-84.83)
2.25 (0.91-5.57)
2.89 (0.96-8.68)
0.201
0.183
0.055
0.080
0.058
Reference
0.32 (0.76-1.37)
0.92 (0.37-2.33)
3.56 (0.29-44.19)
2.13 (0.67-6.72)
1.62 (0.43-6.14)
Use of NNRTI-based vs PI-based cART
2.09 (1.20-3.62)
0.009
2.11 (1.13-3.94)
Atripla vs other
0.91 (0.37-2.28)
0.845
Not evaluated
Age, male gender, baseline VL and CD4 cell count: not significant at univariate analysis
*: substitute for “VL at LLVR” in an alternative multivariate model
Predictors of NNRTI resistance
Variable
Univariate analysis
OR (95% CI)
P value
Calendar year of sequencing, +1 year
more recent
0.949 (0.862-1.05)
Multivariate analysis
OR (95% CI)
P value
0.284
1.03 (0.86-1.24)
0.768
0.474
0.022
0.002
Reference
0.69 (0.15-3.24)
1.40 (0.52-3.77)
8.60 (1.53-48.25)
0.635
0.506
0.015
0.346
0.531
0.545
0.628
0.274
VL at LLVR, n (%)
No LLVR <50 copies/mL
50 to 100 copies/mL
101 to 500 copies/mL
501 to 1000 copies/mL
Reference
0.62 (0.17-2.30)
2.33 (1.13-4.81)
6.14 (1.95-19.33)
NRTI backbone:
3(F)TC/TDF
ABC/3TC
AZT/3TC
D4T/DDI
D4T/3TC
Other
Reference
0.28 (0.03-2.27)
1.72 (0.79-3.77)
3.33 (0.51-21.97)
1.50 (0.51-4.46)
5.00 (1.59-15.74)
0.232
0.173
0.211
0.466
0.006
Reference
0.31 (0.03-3.49)
0.65 (0.17-2.48)
2.23 (0.17-29.75)
0.62 (0.09-4.22)
2.74 (0.45-16.66)
Presence of the RT mutation D67N
14.08 (3.71-53.54)
<0.001
0.33 (0.02-4.77)
0.416
Presence of the RT mutation K70R
15.89 (4.23-59.67)
<0.001
58.29 (1.80-1883.60)
0.022
Presence of the RT mutation M184V
10.50 (5.06-21.78)
<0.001
10.29 (3.58-29.60)
<0.001
Presence of the RT mutation K219Q
9.44 (1.77-50.29)
0.009
0.15 (0.004-5.48)
0.297
Exposure to NNRTIs:
None
NVP
EFV
Reference
6.58 (2.72-15.87)
6.95 (3.08-15.69)
<0.001
<0.001
Reference
11.35 (3.05-42.28)
9.47 (3.23-27.78)
<0.001
<0.001
Age, male gender, baseline VL and CD4 cell count, other major NRTI DRM, presence or absence of LLVR, time to VS, time to
LLVR, time to VF: not significant at univariate analysis
Predictors of PI resistance
Variable
Univariate analysis
OR (95% CI)
P value
Multivariate analysis
OR (95% CI)
P value
Calendar year of sequencing, +1 more recent
0.91 (0.80-1.03)
0.135
0.94 (0.74-1.19)
0.598
VL at LLVR, n (%)
No LLVR <50 copies/mL
50 to 100 copies/mL
101 to 500 copies/mL
501 to 1000 copies/mL
Reference
1.06 (0.27-4.14)
1.24 (0.48-3.21)
1.42 (0.28-7.19)
0.931
0.664
0.675
Reference
3.28 (0.64-16.91)
0.75 (0.09-6.54)
0.65 (0.07-5.87)
0.155
0.826
0.703
NRTI backbone:
3(F)TC/TDF
ABC/3TC
AZT/3TC
D4T/DDI
D4T/3TC
Other
Reference
0.56 (0.07-4.88)
1.32 (0.47-3.75)
2.54 (0.25-25.93)
1.84 (0.49-6.89)
1.45 (0.27-7.72)
0.602
0.599
0.433
0.363
0.664
0.95 (0.09-10.82)
0.80 (0.14-4.52)
3.79 (0.18-79.38)
0.75 (0.09-6.54)
0.68 (0.06-7.17)
0.969
0.800
0.390
0.795
0.747
Presence of the RT mutation M41L
13.18 (3.98-43.66)
<0.001
1.87 (0.23-14.97)
0.556
Presence of the RT mutation K65R
5.91 (0.94-37.31)
0.059
9.23 (0.97-88.09)
0.054
Presence of the RT mutation D67N
7.18 (2.08-24.83)
0.002
1.38 (0.22-8.74)
0.733
Presence of the RT mutation M184V
6.75 (2.77-16.47)
<0.001
4.46 (1.18-16.86)
0.028
Presence of the RT mutation T215F
17.91 (1.56-205.59)
0.020
7.29 (0.36-147.38)
0.195
Presence of the RT mutation T215Y
32.5 0(7.84-134.65)
<0.001
16.34 (1.74-153.02)
0.014
Exposure to ritonavir-boosted IDV
3.46 (1.12-10.65)
0.031
3.35 (0.62-18.26)
0.162
Age, male gender, baseline VL and CD4 cell count, calendar year of sequencing, exposure to other PIr, other major NRTI
DRM, presence or absence of LLVR, time to VS, time to LLVR, time to VF: not significant at univariate analysis
Conclusions
• LLVR are associated with an increased
risk of resistance at subsequent
virological failure, particularly to
NNRTI and when NNRTI-based
therapies are employed
• The type of backbone does not influence
the risk of resistance after LLVR
• A closer virological monitoring is
required with NNRTI-based regimens in
case of LLVR
Acknowledgments
Università Cattolica del S. Cuore
• Simona Di Giambenedetto
• Roberta Gagliardini
• Roberto Cauda
Divisione Universitaria Mal.
Infettive, Siena
• Andrea De Luca
Dipartimento di biotecnologie,
Università di Siena
• Maurizio Zazzi
• Genny Meini
Università di Bergamo
• Franco Maggiolo
Clinica Mal. Infettive, Università di
Perugia
• Daniela Francisci
Virologia, Università di Torino
• Valeria Ghisetti
Ospedale S. Maria Annunziata,
Firenze
• Massimo Di Pietro
Ospedale S. Martino, Genova
• Antonio Di Biagio
Virologia, Università di Modena
• Monica Pecorari
Università di Genova
• Maurizio Setti
Clinica Mal. Infettive, Modena
• Vanni Borghi
Ospedale S. Raffaele, Milano
• Nicola Gianotti