Drug resistance patterns and virus re-suppression among HIV-1 subtype C infected patients receiving non-nucleoside reverse transcriptase inhibitors in South Africa.

Abstract

BACKGROUND: Emergence of HIV-1 drug resistance is at times an inevitable and anticipated consequence of antiretroviral therapy (ART) failure. We examined drug resistance patterns and virus re-suppression among subtype C-infected South African patients receiving first-line ART. METHODS: Treatment records of 431 patients on NNRTI-containing regimens for a median of 45 months were analyzed. Patients with viral load (VL) >400 copies/mL were followed and drug resistance mutations (DRM) were re-assessed. Associations between clinical/demographic measures and drug resistance/virologic outcomes were examined using Fisher exact and ordinal and logistic regression. RESULTS: Ten percent of patients (43/431) were viremic at enrollment (98% previously suppressed); sequences were obtained from 38/43. Of those, 82% had 1-7 DRM. In bivariate analysis remote exposure to single-dose nevirapine or prior ART; higher CD4 counts; lower VL; and >6 months of virologic failure were significantly associated with number of DRM. Of 25 viremic patients followed for a median of 8 months on a continued first-line regimen, 12 (48%) re-suppressed, six with K103N and three with M184V. Thirteen (52%) had continued virologic failure which was significantly associated with detectable VL>6 months prior to enrollment and number of DRM. CONCLUSION: Among these HIV-1 subtype C-infected patients, DRM numbers and patterns were associated with prior exposure to sub-optimal ART, adherence and duration of virologic failure. Viral re-suppression in the presence of K103N and M184V challenges assumptions about drug resistance. In resource-limited settings, where genotyping and alternative drug options are unavailable, continuing first-line treatment, reinforcing adherence and regular virologic monitoring may be effective even after virologic failure.

Full text

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Volume 2 • Issue 2 • 1000117
Open Access
Research Article
J AIDS Clinic Res
ISSN:2155-6113 JAR an open access journal
El-Khatib et al. J AIDS Clinic Res 2011, 2:2
http://dx.doi.org/10.4172/2155-6113.1000117
Drug Resistance Patterns and Virus Re-Suppression among HIV-1 Subtype
C Infected Patients Receiving Non-Nucleoside Reverse Transcriptase
Inhibitors in South Africa
Ziad El-Khatib1,2*, Allison K. DeLong3, David Katzenstein4, Anna Mia Ekstrom1, Johanna Ledwaba2, Lerato Mohapi5, Fatima Laher5,
Max Petzold6, Lynn Morris2 and Rami Kantor7
1Division of Global Health (IHCAR), Karolinska Institutet, Stockholm, Sweden
2AIDS Virus Research Unit, National Institute for Communicable Diseases (NICD), Johannesburg, South Africa
3Center for Statistical Sciences, Brown University, Providence, Rhode Island, USA
4Division of Infectious Diseases, Stanford University, California, USA
5Perinatal HIV Research Unit (PHRU), University of the Witwatersrand, Soweto, South Africa
6Nordic School of Public Health (NHV), Gothenburg, Sweden
7Division of Infectious Diseases, Brown University Alpert Medical School, Providence, Rhode Island, USA
Keywords: HIV-1; Subtype C; Drug resistance; Mutations; NNRTI;
First-line ART; South Africa; ART experienced
Background
More than 1 million HIV-1 subtype C infected patients in South
Africa are receiving antiretroviral therapy (ART) [43]. In 2004 a
national treatment program was initiated, including a first-line regimen
containing a non-nucleoside reverse transcriptase inhibitor (NNRTI),
either efavirenz or nevirapine, in combination with NRTI, stavudine
or zidovudine, and lamivudine [27] The virologic outcomes of first-
line regimens among subtype C-infected people in South Africa are
comparable to those among subtype B infected patients in Switzerland,
where approximately 10% of patients experience virologic failure after
12 months and up to 25% experience virologic failure by two years on
ART [20].
Risk factors contributing to virologic failure and drug resistance
in sub-Saharan Africa include incomplete adherence [1,11,30,36],
treatment interruptions [39,41], low CD4 cell counts [14,15,21,41] low
body weight before ART initiation [21] and prior exposure to single dose
nevirapine (sdNVP) for prevention of mother-to-child transmission
(pMTCT) and/or dual nucleoside treatment [6,22,25]. The majority
(>80%) of viremic patients harbor drug resistance mutations (DRM)
[2,11,14,28,33] and maintaining a failing ART regimen can lead to
accumulation of DRM [14,21,32] and increased ART cross-resistance
*Corresponding author: Ziad El-Khatib, Division of Global Health (IHCAR), Nobelsv
9, Karolinska Institutet, SE-171 77 Stockholm, Sweden, Tel: +46-73-776-4859; Fax:
+46-8-311590; E-mail: ziad.khatib@gmail.com
Received January 12, 2011; Accepted February 15, 2011; Published February
18, 2011
Citation: El-Khatib Z, DeLong AK, Katzenstein D, Ekstrom AM, Ledwaba J, et al.
(2011) Drug Resistance Patterns and Virus Re-Suppression among HIV-1 Subtype
C Infected Patients Receiving Non-Nucleoside Reverse Transcriptase Inhibitors in
South Africa. J AIDS Clinic Res 2:117. doi:10.4172/2155-6113.1000117
Copyright: © 2011 El-Khatib Z, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
Abstract
Background: Emergence of HIV-1 drug resistance is at times an inevitable and anticipated consequence of
antiretroviral therapy (ART) failure. We examined drug resistance patterns and virus re-suppression among subtype
C-infected South African patients receiving first-line ART.
Methods: Treatment records of 431 patients on NNRTI-containing regimens for a median of 45 months were
analyzed. Patients with viral load (VL) >400 copies/mL were followed and drug resistance mutations (DRM) were
re-assessed. Associations between clinical/demographic measures and drug resistance/virologic outcomes were
examined using Fisher exact and ordinal and logistic regression.
Results: Ten percent of patients (43/431) were viremic at enrollment (98%) sequences were obtained from
38/43. Of those, 82% had 1-7 DRM. In bivariate analysis remote exposure to single-dose nevirapine or prior ART;
higher CD4 counts; lower VL; and >6 months of virologic failure were significantly associated with number of DRM. Of
25 viremic patients followed for a median of 8 months on a continued first-line regimen, 12 (48%) re-suppressed, six
with K103N and three with M184V. Thirteen (52%) had continued virologic failure which was significantly associated
with detectable VL >6 months prior to enrollment and number of DRM.
Conclusion: Among these HIV-1 subtype C-infected patients, DRM numbers and patterns were associated
with prior exposure to sub-optimal ART, adherence and duration of virologic failure. Viral re-suppression in the
presence of K103N and M184V challenges assumptions about drug resistance. In resource-limited settings, where
genotyping and alternative drug options are unavailable, continuing first-line treatment, reinforcing adherence and
regular virologic monitoring may be effective even after virologic failure.
[5,18].
Five recent Southern African studies among NNRTI recipients
identified treatment failure by virologic or immunologic criteria
[11,14,28,33,42]. The prevalence of DRM ranged from 62% to 95%
[14,15,28,33,42]. In the first year of treatment Marconi et al. [28] in
KwaZulu-Natal (n=115) and Orrell et al. [33] in Cape Town (n=110),
identified DRM among 83% and >87% respectively. In longer term
studies, Hoffmann et al. [3,14] in South Africa (n=68) and Hosseinipour
et al. [15] in Malawi (n=94) reported DRM after a median >36 months
among 62%, and 95% respectively. Wallis et al. [42] in Johannesburg

AIDS & Clinical
Research

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Citation: El-Khatib Z, DeLong AK, Katzenstein D, Ekstrom AM, Ledwaba J, et al. (2011) Drug Resistance Patterns and Virus Re-Suppression among
HIV-1 Subtype C Infected Patients Receiving Non-Nucleoside Reverse Transcriptase Inhibitors in South Africa. J AIDS Clinic Res 2:117.
doi:10.4172/2155-6113.1000117
Page 2 of 11
Volume 2 • Issue 2 • 1000117
J AIDS Clinic Res
ISSN:2155-6113 JAR an open access journal
reported DRM among 84% of 226 viremic patients, however duration
of treatment was not reported.
Previously [11], we surveyed viremia and drug resistance
prevalence among 998 patients in Soweto, South Africa and found that
94/883 (11%) receiving first-line regimens for a median of 42 months
were viremic and 78/94 (83%) had drug resistance. Here, we obtained
retrospective data on 431 of these patients, enrolled at a single clinic,
and examined factors associated with the evolution and patterns of
DRM. Additionally, we followed 25 of these viremic patients to explore
the implications of DRM on continued NNRTI-based treatment.
Methods
Study sites and patients
The study was done at the Perinatal HIV Research Unit (PHRU), a
non-governmental organization (NGO) research clinic in Chris Hani
Baragwanath Hospital, Soweto, outside Johannesburg, South Africa(11,
29). At the time of the study, the clinic staff consisted of five medical
doctors, two nursing assistants and two counselors managing around
1500 ART recipients, with 50 daily visits [11].
Consenting patients were enrolled from March through September
2008 if they were ≥18 years old and >12 months on a first-line regimen
[11]. At study enrollment, viral load (VL), CD4 cell count and HIV-
1 reverse transcriptase (RT) genotype were assessed and basic
demographic information obtained. Virologic failure was defined as
VL>400 copies/mL at study enrollment [11]. Persistent virologic failure
and re-suppression were defined as VL>400 copies/mL and return to ≤
400 copies/mL, respectively, at follow-up (Figure 1).
Medical records were reviewed retrospectively to extract
information on potential risk factors that may be associated with
DRM or re-suppression, including age, gender, year of HIV diagnosis,
ART regimens and dates, history of sdNVP or other ART exposure,
tuberculosis (TB) treatment, pre-ART initiation VL and CD4 cell
counts, WHO stage prior to ART initiation and any treatment
interruptions in the last six months prior to study enrollment. Virologic
failure prior to study enrollment, was defined as VL>400 copies/mL
at either of the prior two visits in the last 12 months. Poor adherence
was considered to be returning more than seven days late for the drug
refill appointment pre-study enrollment. An instrument was designed
and tested to extract information from medical records using Epi Data
[9,10]. The study and consent forms were approved by the University of
the Witwatersrand Human Research Ethics Committee in South Africa
and the Regional Medical Ethics Board in Stockholm, Sweden.
Laboratory assessments
CD4 cell counts were performed by FACSCountTM (Becton
Dickinson BioSciences, Immunocytochemistry Systems, San Jose,
California, USA) and VL was measured using the Roche Amplicor,
version 1.5 (Roche Molecular Diagnostics, Basel, Switzerland)
with a lower limit of detection of 400 copies/mL. Both assays were
performed at the National Institute for Communicable Diseases
(NICD), Johannesburg. VL data extracted from medical records that
were done as part of routine clinical care used the Versant HIV-1 RNA
3.0 (Siemens Deerfield, IL, USA) bDNA technology. For HIV-1 drug
resistance testing, an in-house genotyping assay was performed at the
NICD [35].
Drug resistance mutations and susceptibility scoring
Mutations were identified by the Stanford HIVdb genotypic
resistance algorithm [13] and coded as major DRM as defined by the
International AIDS Society (IAS) December 2009 list [16]. Subtype
was established using the Rega subtyping tool v.2.0, which incorporates
rigorous phylogenetic analyses [7]. Sequence quality was confirmed
prior to analysis by[18] inspecting sequences for possible frame shifts,
high numbers of ambiguous nucleic and/or amino acids, extreme levels
of pair-wise genetic distances, and unique amino acids or stop codons.
To predict phenotypic drug resistance the Stanford HIV database
(HIVdb) scoring system was applied [13] and a resistance score
calculated as (i) susceptible (0-9) to potentially low-level (10-14); (ii)
low (15-29); (iii) intermediate (30-59); and (iv) high level of resistance
(score ≥ 60).
Data analysis and statistics
Risk factors were examined for associations with two drug
resistance outcomes: (i) number of all-class DRM at enrollment; and
(ii) continued viremia versus re-suppression at follow-up. Associations
between viral re-suppression and presence of any DRM, number of
NRTI and NNRTI DRM and the total number of DRM at enrollment
were examined. Due to the small sample size, bivariate analysis was
performed without adjusting for confounding variables and the results
must be interpreted with this in mind.
Ordinal logistic regression was used to examine the association
between risk factors and the number of DRM at enrollment expressed
as odds ratios (OR), and 95% confidence intervals (95% CI). Unlike
Poisson regression, ordinal logistic regression can be fitted to zero-
inflated data and does not assume that the events (i.e. accumulation
of DRM) are independent and occur at a constant rate. Each model
was checked to ensure the assumption of proportional odds between
successive DRM categories was met. To examine risk factors associated
with persistent virologic failure at follow-up, Fisher exact tests were
used for categorical risk factors (OR, 95% CI) and Wilcoxon rank
sum tests for continuous risk factors (difference in median, 95% CI).
Analysis was performed using Stata/SE College Station, Texas (version
10.1) (38) and R (version 2.11.1) (40). P-values less than 0.05 were
considered statistically significant.
Figure 1: Study design
VL, virus load
Study enrollment
Follow-up
10% (43/431)
VL >400 copies/ml
(Table 1)
12% (5/43) not amplifiable
82% (31/38)
with drug resistance
mutations (Table 2)
18% (7/38)
without drug resistance
mutations
58% (25/43)
Median 8 months
after enrollment
(Table 3)
48% (12/25)
VL≤ 400 copies/ml
(Table 4b)**
52% (13/25)
VL> 400 copies/ml
with drug resistance
mutations (Table 4a)*
* At study enrollment: 1/13 wild type and 1/13: not amplifiable
**At study enrollment 2/12 wild type and 3/12: not amplifiable

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Citation: El-Khatib Z, DeLong AK, Katzenstein D, Ekstrom AM, Ledwaba J, et al. (2011) Drug Resistance Patterns and Virus Re-Suppression among
HIV-1 Subtype C Infected Patients Receiving Non-Nucleoside Reverse Transcriptase Inhibitors in South Africa. J AIDS Clinic Res 2:117.
doi:10.4172/2155-6113.1000117
Page 3 of 11
Volume 2 • Issue 2 • 1000117
J AIDS Clinic Res
ISSN:2155-6113 JAR an open access journal
Results
Patient characteristics
(Table 1) displays characteristics of the 431 patients who had been
on ART for at least 12 months where 75% were females, 96% were born
in South Africa, 90% had above primary school education and the
median age at study enrollment was 38 years. Ninety-one percent were
receiving efavirenz-based therapy and 9% a nevirapine-based therapy.
Before ART initiation, the median VL and CD4 were 71,995
(range 1,078 to >500,000) copies/mL and 93 (range 1 to 444) cells/
mm3 respectively. At study enrollment, patients had received ART
for a median of 45 months (range 13 to 152) and the CD4 cell count
increased to 419 (range 16 to 1,270).
Forty-three patients (10%) had VL>400 copies/mL (median 6,510;
range 407 to >500,000) at enrollment, almost all (98%) previously
suppressed on ART. Median time on ART was similar among patients
with VL < and >400 copies/mL (p=0.86). However at study enrollment,
those with VL>400 copies/mL had a significantly lower CD4 cell count
compared to patients with VL<400 copies/mL (p<0.01).
Among 40/43 patients for whom there was a record of previous
ART exposure: 8/31 (26%) females had received sdNVP prior to
initiating ART and 5/40 (13%) patients had been exposed to other ART
before initiating the current ART regimen. Compared to unexposed
individuals, there was a borderline association between viremia at study
enrollment and exposure to sdNVP (p=0.05).
Drug resistance mutations at study enrollment
Thirty-eight of 43 samples were successfully genotyped; 31/38
(82%) had at least one DRM and 24 (63%) had ≥3 DRM (Table 2).
Of the genotyped samples 5/38 (13%) had K103N alone; 2/38 (5%)
had M184V and K103N; and 10/38 (26%) had three mutations with
M184V/I, K103N and an additional NNRTI mutation. Finally 14/38
(37%) had ≥4 mutations: 13/14 (93%) M184V/I and 8/14 (57%) K103N,
all with ≥2 NNRTI and most with one or more thymidine analogue
mutations (TAM) or other NRTI mutations. Overall, 8/38 (21%) had
one or more TAMs, three had A62V or V75I and only one patient had
K65R.
Several risk factors were significantly associated with increased
numbers of DRM (Table 3). Patients with prior exposure to either
sdNVP or other ART had more mutations than those not previously
exposed. The ordinal regression OR was 3.8 (95%CI 1.1 to 15.2; p=0.03),
i.e. it was 3.8 times more likely for patients with prior ART exposure to
have ≥1 vs. 0, ≥2 vs. ≤1, ≥3 vs. ≤2 DRM and so on. Number of DRM
was positively associated with being female (OR 5.6; 95%CI 1.3 to 24.5;
p=0.02), having a higher CD4 cell count (OR 1.7 per 100 CD4 cells;
95%CI 1.1 to 2.7; p=0.02) and having detectable VL at one of two earlier
scheduled visits (OR 8.4; 95%CI 1.9 to 42.4; p<0.01). The association
with gender was mainly explained by prior exposure to pMTCT, mainly
sdNVP, among the women. Only one male had any prior exposure to
ART. The number of DRM was negatively associated with coming
late for the drug refill visit in the last month (OR 0.1; 95%CI 0 to 0.5;
p=0.01) and with VL such that for participants with 1-log unit higher
VL the odds of having a higher number of DRM was 0.5 (95%CI 0.2 to
1.0; p=0.04). Finally the median VL of the seven patients with no DRM
was 83,000 copies/mL compared with a median VL of 6,510 copies/mL
among those with at least one DRM, providing evidence for existing but
incomplete drug pressure amongst those with DRM.
Risk factors for persistent virologic failure and drug resistance
mutations at follow-up
Follow-up data and samples were available for 25/43 (58%) of the
viremic patients, after a median of 8 (range 4 to 10) months (Figure
1). Persistent virologic failure at follow-up, in 13/25 (52%) patients,
was associated with a detectable VL in the two visits prior to study
enrollment (p<0.01) and the number of DRM at study enrollment
(OR 2.36; 95%CI 1.11 to 5.02; p=0.04), particularly NRTI mutations
(OR 3.68; 95%CI 1.11 to 12.17; p=0.05) (Table 3). All 13 patients had
genotypic resistance with six additional DRM acquired at follow-up,
leading to high level predicted resistance to efavirenz and/or nevirapine
(100%) and lamivudine (100%) and intermediate to low predicted
resistance to etravirine in 7/13 (54%) (Table 4a). Although viremic,
patient number 35 did not have any DRM at study enrollment, but with
continued treatment and presumably better adherence, three DRM
were selected at follow-up with a persistent, albeit lower, VL for nine
months. At study enrollment nine of these patients had failed first-line
regimens with full predicted susceptibility to NRTIs.
Twelve of the 25 (48%) patients re-suppressed at follow-up, after
a median of eight additional months on treatment with the same
NNRTI (mostly efavirenz)-based regimen. Comparison of clinical
and laboratory characteristics of these 12 patients with the 13 who
had persistent virologic failure showed no significant differences in
sex, median CD4 and VL prior to ART initiation. At study enrollment
3/12 (25%) re-suppressed patients could not be amplified and three
(25%) had no DRM. However, the remaining six patients who were re-
suppressed had NNRTI DRM, three had K103N, one had K103N and
M184V and one had K103N, V106M and M184V (Table 4b). The sixth
patient had three NNRTI and 3 NRTI mutations. Thus, six patients with
high level NNRTI resistance and three patients with high level NNRTI
and lamivudine resistance achieved re-suppression while continuing
the same first-line regimen.
Discussion
HIV-1 drug resistance is a potential cause and is often a consequence
of virologic failure. In this study, we examined drug resistance in HIV-
1 subtype C infected South African patients failing first-line regimens
after a minimum of 12 months on ART. Of 43 long-term ART recipients
with viremia, most had multiple DRM. Among 25 of these patients
followed on continued NNRTI-based ART, 12 achieved virologic
suppression and 13 had persistent VL>400 copies/mL. We examined
the characteristics and patterns of DRM, the estimated drug resistance
and implications for further therapies among these ART experienced,
subtype C infected patients.
In examination of co-occurrence of DRM, 82% of 38 available
RT sequences demonstrated a wide spectrum (range 1 to 7) of co-
occurring, DRM. The majority (63%) had ≥3 DRM, mostly including
K103N accompanied by M184V/I, at times with complex mixtures
of additional NRTI and NNRTI mutations. Patients with prior ART
drug exposure and those with detectable VL and higher CD4 cell
counts prior to or at study enrollment, respectively, tended to have a
higher number of DRM. These results are likely to reflect the selection
of drug resistance due to lapses in adherence, reduced drug exposure
and inadequate drug pressure. Conversely, patients who were late to
pharmacy or who had higher VL at study enrollment tended to have
fewer DRM, perhaps reflecting a very low adherence.
Drug resistance mutations among subtype C NNRTI recipients
have been identified after virologic or immunologic failure based on

Page 4

Citation: El-Khatib Z, DeLong AK, Katzenstein D, Ekstrom AM, Ledwaba J, et al. (2011) Drug Resistance Patterns and Virus Re-Suppression among
HIV-1 Subtype C Infected Patients Receiving Non-Nucleoside Reverse Transcriptase Inhibitors in South Africa. J AIDS Clinic Res 2:117.
doi:10.4172/2155-6113.1000117
Page 4 of 11
Volume 2 • Issue 2 • 1000117
J AIDS Clinic Res
ISSN:2155-6113 JAR an open access journal
Table 1: Demographic, clinical and laboratory characteristics of patients
ART, antiretroviral therapy; VL, virus load; WHO, world health organization, PMTCT, prevention mother-to-child-transmission by administrating a single dose nevirapine;
N, number
aYes: cohabitation, married, sexual relationship, No: Single/divorced/separated/widow
bThe other drug option was nevirapine
cThe other drug option was zidovudine
dVL done using Versant HIV-1 RNA 3.0 (Siemens Deerfield, IL, USA) bDNA technology
eExposure to other antiretroviral drugs prior to ART initiation
f2-sided Fisher exact test
Number of drug resis-
tance mutations
(n pts)
≥5 (n=8 pts)
1*
2**
3*,^
4
5*
6*
7*
8
4 (n=6 pts)
9
10
11
Months on ART Sex
VL at study
enrollment
(copies/mL)
CD4 at study
enrollment
(cells/mm3)
NNRTINRTI
48
49
41
44
22
45
44
45
F
F
F
F
F
F
F
F
3 010
2 680
4 310
75 000
1 850
773
2 530
18 200
524
213
354
89
342
384
199
496
K101E+V108I+Y181C
K101H+K103N+V106M+G190A+F227L
K101E+V106M+G190A
K103N+P225H
K103N+V108I
V106M+G190A
V106M+Y188LH
V106M+Y188L
D67N+K70R+M184V+K219E
D67N+M184V
D67N+M184V
D67N+K70R+M184V+T215F+K219E
A62V+V75I+M184V
M41L+D67N+K70R+M184V
D67N+M184V+ K219E
M41L+D67N+K70R+ M184V+T215Y
15
45
46
F
F
F
16 900
11 000
3 000
160
464
354
K101E+V108I+G190A
K101H+K103N+G190A
K103N+P225H
M184V
M184V
V75I+M184V
All patients
N=431
Suppressed at study enroll-
ment N=388
291 (75%)
38 (21, 64)
373 (96%)
Viremic at study enrollment
N=43
34 (79%)
36 (25, 60)
41 (95%)
p value
Female
Age, median in years (range)
Born in South Africa
Education
Never been to school
Primary school
Secondary school
Tertiary school
In any form of a relationshipa
Yes
No
Months on ART, at study enrollment
(range)
ART regimen
Efavirenz containingb
Stavudine containingc
VL prior to starting ART
Median copies/mL (range)d
CD4 prior to starting ART
Median cells/mm3 (range)
Mean
CD4 at study enrollment
Median cells/mm3 (range)
Prior exposure to ART
No
PMTCT only
Othere
Exposure to sdNVP or other ART vs. no
exposuree
WHO stage prior to starting ART
I
II
III
IV
325 (75%)
38 (21, 64)
414 (96%)
0.56
0.35
0.80
7 (2%)
42 (10%)
357 (83%)
25 (6%)
6 (2%)
39 (10%)
319 (82%)
24 (6%)
1 (2%)
3 (7%)
38 (88%)
1 (2%)
0.64
250 (58%)
181 (42%)
227 (59%)
161 (41%)
23 (54%)
20 (46%)0.53
45 (13, 152)45 (13, 152)45 (13, 55) 0.86
393 (91%)
254 (59%)
357 (92%)
225 (58%)
36 (94%)
29 (67%)0.35
70 870 (1 078, >500 000)67 315 (2 102, >500 000)86 718 (1 078, >500 000) 0.48
93 (1, 444)
96
95 (1, 760)
104
107 (6, 314)
109
0.34
0.74
419 (16, 1 270)437 (119, 1 270) 276 (16, 642)<0.01
335 (81%)
45 (11%)
35 (8%)
308 (82%)
37 (10%)
30 (8%)
27 (68%)
8 (20%)
5 (13%)
0.05f
0.21
80 (19%)67 (18%)13 (32%)0.03f
61 (21%)
86 (29%)
137 (47%)
9 (3%)
55 (20%)
82 (31%)
123 (46%)
9 (3%)
6 (25%)
4 (17%)
14 (58%)
0 (0%)
0.32f
1.00f
---

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Citation: El-Khatib Z, DeLong AK, Katzenstein D, Ekstrom AM, Ledwaba J, et al. (2011) Drug Resistance Patterns and Virus Re-Suppression among
HIV-1 Subtype C Infected Patients Receiving Non-Nucleoside Reverse Transcriptase Inhibitors in South Africa. J AIDS Clinic Res 2:117.
doi:10.4172/2155-6113.1000117
Page 5 of 11
Volume 2 • Issue 2 • 1000117
J AIDS Clinic Res
ISSN:2155-6113 JAR an open access journal
different clinical guidelines. Here, the frequency of DRM upon virologic
failure using a threshold of >400 copies/mL was similar to thresholds of
VL >1,000 or >5,000 copies/mL [14,28,33,42] or immunologic failure
criteria (8, 15). We compared the patterns of DRM found here to 418
published sequences from adult patients failing first-line regimens in
subtype C studies, mostly from Southern Africa and India (8, 15, 19,
28, 35, 37, 42), accessed, in July 2010 at the Stanford HIV Sequence
Database (13). Patterns of DRM, including the overall frequency of any
DRM (82% in the current study vs. 83% among published sequences),
≥1 NRTI resistance mutations (11% vs 9%), the prevalence of K103N
(55% vs 42%), M184V/I (66% vs. 74%), and K65R (3% vs. 6%) were
not significantly different. However, the data presented here compared
to the published sequences demonstrated significant differences in the
frequency of ≥1 NNRTI mutation (58% vs 40%, p=0.03) and a lower
rate of TAM (21% vs 37%, p=0.05). These modest differences may be
ascribed to differences in clinical management strategies, specific drug
combinations or duration of virologic failure. Among eight patients
with TAMs, the most common pathway (seen in 6/8 patients) was
TAM-2 related (D67N, K70R, K219Q/R/E),; and the rest (2/8) were
mixed with the TAM-1 pathway (M41L, L210W, T215Y) extending
similar prior Southern African observations [28,31] .
Although K103N and other NNRTI resistance mutations confer
high level NNRTI resistance [12,13] , six patients in our study who
harbored such mutations, re-suppressed VL after 4 to 10 months with
no change in their first-line regimen. Three of these patients had high
level resistance to two drug classes, with the addition of the M184V
mutation, conferring resistance to lamivudine. These findings extend
observations by Hoffmann and colleagues who reported 11 males with
either NNRTI and NRTI mutations, who re-suppressed with continued
first-line regimens, raising questions about potential cautious re-use
or continuation of those medications in certain circumstances [14] .
It is plausible that improved adherence was a factor in this observed
resuppression, though this could not be confirmed in this patient
population. The observation that successful re-suppression was strongly
associated with recent failure and a low number of DRM seems logical,
but should be confirmed prospectively in larger studies.
Thirteen patients found to be viremic both at enrollment and at
12*
13^
14
3 (n=10 pts)
15*
16
17
18*
19
20*
21
22**
23*
24
2 (n=2 pts)
25
26**,^
1 (n=5 pts)
27**
28**
29**
30*
31^
32
33**
34**
35*,^
36^
37**,^
38^
Not amplifiable (n=5 pts)
39
40*,^
41**,^
42**
43**
Pts, patients; F, female; M, male; ART, antiretroviral therapy; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-NRTI, VL: virus load; *Persistent virologic failure
at follow-up; ** Re-suppressed at follow-up; ^ Came late >7 days for the last drug-refill visit
37
47
47
M
F
F
49 900
54 700
9 670
16
419
377
K103N+Y181C+P225H
K103N+G190A+P225H
K103N+V106A+G190A
M184I
M184V
K65R
48
13
41
46
47
47
47
47
40
84
F
F
F
F
F
F
M
F
F
F
18 300
6 890
5 340
407
6 510
1 330
31 000
1 280
955
43 800
331
214
319
269
190
277
99
642
276
174
K101E+Y188L
K101E+V106M
K103N
K103N+P225H
K103N+V108I
K103N+V108I
K103N+V108I
K103N+V106M
V106M
V106M+Y188C
M184I
M184V
D67N+M184V
M184V
M184V
M184V
M184V
M184V
A62V+M184V
M184V
43
47
M
F
430
1 370
151
320
K103N
K103N
M184V
M184V
44
46
45
45
46
46
41
47
43
47
43
50
M
F
F
M
F
F
F
F
M
F
M
M
178 000
56 500
42 800
1 130
43 900
552
882 000
1 450
83 000
77 500
312 000
493 000
47
187
100
439
193
369
90
192
103
232
203
157
K103N
K103N
K103N
K103N
K103N
No major mutations
No major mutations
No major mutations
No major mutations
No major mutations
No major mutations
No major mutations
---
---
---
---
---
No major mutations
No major mutations
No major mutations
No major mutations
No major mutations
No major mutations
No major mutations
44
43
41
13
55
F
F
M
F
F
463
4 660
1 060
557
66 800
357
554
430
445
379
---
---
---
---
---
---
---
---
---
---
Table 2: Patterns of reverse transcriptase drug resistance mutations

Page 6

Citation: El-Khatib Z, DeLong AK, Katzenstein D, Ekstrom AM, Ledwaba J, et al. (2011) Drug Resistance Patterns and Virus Re-Suppression among
HIV-1 Subtype C Infected Patients Receiving Non-Nucleoside Reverse Transcriptase Inhibitors in South Africa. J AIDS Clinic Res 2:117.
doi:10.4172/2155-6113.1000117
Page 6 of 11
Volume 2 • Issue 2 • 1000117
J AIDS Clinic Res
ISSN:2155-6113 JAR an open access journal
follow-up, had a longer duration of virologic failure on treatment and
a higher number of DRM. These findings substantiate the observation
that resistance evolves as a function of continued, albeit suboptimal,
drug pressure due to reduced adherence, treatment interruptions or
both. Despite the relatively short time between sequences - 8 months,
and a median of 3 DRM per patient, mutations accumulated with a
rise in high level predicted 2-class resistance. This is consistent with
observations in HIV-1 subtype B [5,18]. Some of the accumulated DRM
were associated with etravirine resistance, conferring intermediate
resistance to this drug after first-line regimen failure, suggesting
the need for further studies of the use of this NNRTI in subsequent
regimens [23].
Among women, we found a borderline association between
exposure to sdNVP and virologic failure, albeit years afterwards and
with a period of suppression, consistent with the results of a recent
study from the Western Cape, South Africa [6] and another report
of a significant association between detection of minority NNRTI
mutations and treatment failure, even after 18 months had elapsed since
sdNVP [4] . These findings are not entirely in line with other reports
Number of DRM
at study enrollment
(n=43)
Odds ratio
(95% CI)a
5.6 (1.3, 24.5)
Persistent virologic failure (n=13) vs. re-suppression (n=12) at
follow-up
Risk factor p-value Effect (difference in median, 95% CI 95% CI)b p-value
Female vs. Male
0.02
1.1 (0.1, 10.5) 1.00
Age (years) 1.0 (0.9, 1.0) 0.17 1.4 (-6.0, 9.0) 0.62
Current TB therapy (yes/no)c - - 0.9 (0, 78.4) 1.00
Tested HIV positive after 2003 (yes/no) 0.4 (0.1, 1.8) 0.23 0.7 (0.1, 5.5) 1.00
Number of months on ART 1.0 (0.9, 1.0) 0.16 2.1 (-1.4, 6.4) 0.17
ARV exposure prior to ART initiationd - 0.78
none reference
pMTCT --- --- 0.3 (0, 4.3) 0.59
Other ARV --- --- 0.8 (0, 70.5) 1.00
Exposure to sdNVP or other ART vs. no
exposured
3.8 (1.1, 14.2)
0.03
0.42 (0, 3.8) 0.64
CD4 at study enrollment per 100 cells/mm3 1.7 (1.1, 2.7)
0.02
-0.7 (-1.9, 1.0) 0.41
CD4 pre-ART initiation per 100 cells/mm3 0.8 (0.3, 2.1) 0.64 0 (-0.6, 0.5) 0.98
Log10 (VL) at study enrollmente 0.5 (0.2, 1.0)
0.04
0.4 (-0.2, 1.6) 0.27
Log10 (VL) pre-ART initiatione 1.3 (0.5, 3.4) 0.60 -0.4 (-1.0, 0.2) 0.22
VL >400 copies/mL at least once in the two
tests prior to study enrollment (yes/no)e
8.4 (1.9, 42.4)
<0.01
infinity (2.4, infinity)
<0.01
Late to the drug refill visit at least 7 days in
previous month (yes/no)
0.1 (0, 0.5)
0.01
0.9 (0.1, 8.6) 1.00
History of treatment interruption in the last 6
months (yes/no)c
--- --- infinity (0.2, infinity) 0.48
Taking d4T vs. AZT 0.6 (0.2, 1.9) 0.36 0.3 (0, 2.8) 0.38
Taking EFV vs. NVPc ---

---

1.1 (0.1, 17.8)
5.1 (0.3, 313.7)
1.00
0.27
Number of NRTI DRM mutations 3.7 (1.1, 12.2)
0.05
Number of NNRTI DRM mutations 2.9 (0.9, 9.0) 0.08
Total number of DRM mutations
NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-NRTI; VL, virus load; TB, tuberculosis; DRM, drug resistance mutations; d4T, stavudine; AZT,
zidovudine; EFV, efavirenz; NVP, nevirapine; ARV, antiretroviral drugs
2.4 (1.1, 5.0)
0.04
Table 3: Risk factors associated with the number of DRM at study enrollment and persistent virologic failure versus re-suppression at follow-up
aFor each 1-unit difference in the covariate (e.g. going from no to yes) the odds ratio expresses (for each possible value of the # DRM (0-7)) the ratio of the
odds of having at least that number of DRM versus fewer than that number of DRM.
bEffects presented as the odds ratio for categorical risk factors and the difference in medians for continuous risk factors (difference in median, 95% CI).
cThe ordinal logistic regression model could not be fitted because there was too little variability in the risk factor or the assumption of proportional odds ratios
was not met (i.e. only 4 were on TB therapy, 4 had taken other ARV prior to starting ART, 3 had treatment interruption, and the assumption was not met for
EFV vs. NVP.
dOne female was exposed to both of sdNVP and other ARV, pre-ART initiation, and she had VL <400 copies/mL at study enrollment.
eVL done using Versant HIV-1 RNA 3.0 (Siemens Deerfield, IL, USA) bDNA technology

Page 7

Citation: El-Khatib Z, DeLong AK, Katzenstein D, Ekstrom AM, Ledwaba J, et al. (2011) Drug Resistance Patterns and Virus Re-Suppression among
HIV-1 Subtype C Infected Patients Receiving Non-Nucleoside Reverse Transcriptase Inhibitors in South Africa. J AIDS Clinic Res 2:117.
doi:10.4172/2155-6113.1000117
Page 7 of 11
Volume 2 • Issue 2 • 1000117
J AIDS Clinic Res
ISSN:2155-6113 JAR an open access journal
Table 4a: Genotypic and predicted phenotypic drug resistance among patients with persistent virologic failure at follow-up
NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-NRTI; VL, virus load (copies/mL); ART, antiretroviral therapy; EFV, Efavirenz; NVP, Nevirapine; ETR,
Etravirine; 3TC, Lamivudine; d4T, Stavudine; TDF, Tenofovir; ABC, Abacavir; AZT, Zidovudine; DDI, Didanosine; S, Susceptible; PL, potentially low-level of resis-
tance; L, low-level resistance; I, intermediate level of resistance; H, High level of resistance; Line 1a, EFV + 3TC + d4T; Line 1b, NVP + 3TC + d4T
Underlined mutations = lost mutations; Bolded mutations=gained mutations and Italic mutations=Minor mutations, for Etravirine, according to the IAS USA-2009 list.
Background colors for predicted phenotypic resistance were: White if susceptible or potentially-low; Light gray if low or intermediate and dark gray if highly resistant.
Study enrollmentFollow-up
Predicted phenotypic
resistance
Predicted phenotypic
resistance
Patien
t
VL
(ART
used)*
NNRTI
mutations
NRTI
mutatio
ns
NNRTI NRTI
Months
after
enroll
ment
VL
(ART
used)*
NNRTI
mutations
NRTI
mutations
NNRTI NRTI
1
3,010
(1b)
K101E+
V108I+
Y181C
D67N+
K70R+
M184V
+
K219E
H: NVP
I: EFV;
ETR
H: 3TC
I: AZT
L: d4T; ABC
PL: ddI
S: TDF
H: 3TC
L: ABC
PL: ddI
S: d4T; AZT
TDF
H: 3TC
L: ddI; ABC
S: d4T; AZT
TDF
7
3,680
(1b)
K101E+
Y181C
D67N+
K70R+
M184V+
K219E
H: NVP
I: EFV
ETR
H: 3TC
I: AZT
L: d4T; ABC
PL: ddI
S: TDF
H: 3TC
I: AZT
L: d4T; ABC
PL: ddI
S: TDF
H: 3TC
L: ddI; ABC
S: d4T; TDF
AZT
H: 3TC
I: AZT
L: d4T
ABC
PL: ddI
S: TDF
3
4,310
(1a)
K101E+
V106M+
G190A
D67N+
M184V
H: EFV;
NVP
I: ETR
11
3,790
(1a)
K101E+
V106M+
G190A
D67N+
K70R+
M184V+
K219Q
H: EFV; NVP
I: ETR
5
1,850
(1a)
K103N+
V108I
A62V+
V75I+
M184V
H: EFV;
NVP
S: ETR
6
6,150
(1a)
K103N+
V108I
A62V+
V75I+
M184V
H: EFV; NVP
PL: ETR
6
773
(1a)
V106M+
G190A+
A98G
M41L
D67N+
K70R+
M184V
H: EFV;
NVP
L: ETR
H: 3TC
I: d4T, ABC
AZT
L: TDF
ddI
9
4,530
(1a)
A98G+
V106M+
G190A
D67N+
K70R+
M184V+
K219Q
H: EFV; NVP
L: ETR
7
2,530
(1a)
V106M+
Y188LH
D67N+
M184V
+
K219E
H: EFV;
NVP
L: ETR
H: 3TC
L: d4T; ABC
AZT
PL: ddI
S: TDF
H: 3TC
PL: ABC
S: d4T; TDF
AZT
H: 3TC
PL: ABC
S: d4T; TDF
ddI; AZT
H: 3TC
PL: ABC
S: d4T; TDF
DDI; AZT
H: 3TC
PL: ABC
S: d4T; DDI
TDF; AZT
12
25,000
(1a)
V90I+
V106M+
Y188L
M184V
H: EFV; NVP
L: ETR
H: 3TC
PL: ABC
S: d4T; TDF
ddI; AZT
12
49,900
(1a)
K103N+
Y181C+
P225H
M184I
H: EFV;
NVP
I: ETR
6
8,540
(1a)
V90I+
K103N+
Y181C+
P225H
M184V
H: EFV; NVP
I: ETR
H: 3TC
PL: ABC
S: d4T; TDF
AZT; ddI
H: 3TC
PL: ABC
S: d4T; TDF
ddI; AZT
H: 3TC
PL: ABC
S: d4T; TDF
ddI; AZT
H: 3TC
PL: ABC
S: d4T; TDF
ddI; AZT
15
18,300
(1a)
K101E+
Y188L
M184I
H: EFV;
NVP
L: ETR
9
3,710
(1a)
K101E+
Y188L
M184V
H: EFV; NVP
L: ETR
18
407
(1a)
K103N+
P225H
M184V
H: EFV;
NVP
L: ETR
10
937
(1b)
K103N M184V
H: EFV, NVP
S: ETR
20
1,330
(1a)
K103N+
V108I
M184V
H: EFV;
NVP
S: ETR
10
3,010
(1a)
K103N+
V108I
M184V
H: EFV; NVP
S: ETR
23
955
(1b)
V106M
A62V+
M184V
H: EFV;
NVP
PL:
ETR
H: 3TC
PL: ABC
S: d4T; TDF
DDI; AZT
11
2,540
(1b)
V106M+
E138A
A62V+
M184V
H: EFV; NVP
L: ETR
H: 3TC
PL: ABC
S: d4T; TDF
ddI; AZT
PL: d4T; ddI
S: 3TC; TDF
ABC;
AZT
H: 3TC
PL: ABC;
AZT
S: d4T;
TDF;
ddI
H: 3TC
L: ABC; DDI
S: d4T;
AZT;
TDF
30
1,130
(1a)
K103N ---
H: EFV;
NVP
S: ETR
S: all drugs 9
15,700
(1a)
K103N V75I
H: EFV; NVP
S: ETR
35
83,000
(1a)
Wild type
Wild
type
S: all
drugs
S: all drugs 9
2,670
(1a)
V106M
K70R+
M184V
H: EFV; NVP
PL: ETR
40 4 660
Not
amplifiable
Not
amplifia
ble
--- --- 9 31,300
K103N+
P225H
V75I+
M184V
H: EFV; NVP
L: ETR

Page 8

Citation: El-Khatib Z, DeLong AK, Katzenstein D, Ekstrom AM, Ledwaba J, et al. (2011) Drug Resistance Patterns and Virus Re-Suppression among
HIV-1 Subtype C Infected Patients Receiving Non-Nucleoside Reverse Transcriptase Inhibitors in South Africa. J AIDS Clinic Res 2:117.
doi:10.4172/2155-6113.1000117
Page 8 of 11
Volume 2 • Issue 2 • 1000117
J AIDS Clinic Res
ISSN:2155-6113 JAR an open access journal
NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-NRTI; VL, virus load (copies/mL); TB, tuberculosis; DRM, drug resistance mutations; Line 1a, Efavirenz (EFV)
+ Lamivudine (3TC) + Stavudine (d4T); Line 1b, Nevirapine (NVP) + 3TC + d4T; Colors for predicted phenotypic resistance were: White if susceptible (S) or potentially-low
(PL); Light gray if low (L) or intermediate (I) and dark gray if highly (H) resistant.
Table 4b: Characteristics of patients with virologic failure at study enrollment and re-suppression at follow-up
from sub-Saharan Africa and Asia that suggest that in the short-term,
administration of ART >12 months after sdNVP may not jeopardize the
efficacy of NNRTI based ART [17,26].
Where genotyping is routinely available, the interpretation of
DRM following the failure of first-line regimens drives decisions about
clinical management, adherence counseling, switching to second-line
regimens and the need for new ART combinations. Among these
HIV-1 subtype C infected patients, a proportion of those failing first-
line regimens responded to continuing their current regimen despite
predicted high-level resistance. In resource-limited settings, where
genotyping is not available, the practice of reinforcing adherence,
continuing a first-line regimen and repeating a VL test after 6 months
may be justified. However, it will be important to monitor such patients
closely to determine if they ultimately fail due to the presence of
archived resistance mutations. In such cases, switching to a second-line
regimen, as mandated by treatment national guidelines, should not be
deferred.
There are several limitations to this study. First, the number of
patients with drug resistance, longitudinal sequences and re-suppression
was relatively small and longer term CD4 cell counts and VLs from
25 failing patients were not available. Second, a small proportion of
patients’ samples, particularly among those who resuppressed, could
not be successfully amplified and sequenced. Third, genotyping at
onset of ART was not available. However, the prevalence of transmitted
ART resistance, in South Africa, is still low (<5%) [24,34] . Finally,
confirmation of VL was not immediately available, and clinical practice
included continued first line-treatment for 4-6 months between
detection of virologic failure, reinforcing adherence and re-testing
VL. The fact that patients were not switched to second-line regimens,
despite repeated virologic failure, reflects the current limited treatment
options in this setting.
In summary, this study extends observations of the range of
DRM patterns among HIV-1 subtype C patients in South Africa
receiving long-term first-line regimens. Surprisingly, a number of
patients with DRM that predict high-level resistance, K103N with or
without M184V, were successfully re-suppressed on the same first-line
regimen. Reinforcing adherence without changing treatment among
Study enrollment
Routine clinical VL
testing
Predicted
phenotypic
resistance
Routine clinical VL testing Study follow-up
Patient
N months
before
enrollmen
t
VL
(ART
used)*
VL
(copies/m
L)
Mutations
NNR
TI
NRTI
N months
after study
enrollment
VL
(copies/m
L)
N months of
last VL test
after study
enrollment
VL
(copies/mL)
2 6
535
(1a)
2 680
D67N+
K101H+
V106M+
M184V+
G190A+
F227L
K103N+
V106M+
M184V
H:
EFV;
NVP
H: 3TC
S: d4T
6 982 10 ≤400
22 2
42,187
(1a)
1 280
H:
EFV;
NVP
H:
EFV;
NVP
H: 3TC
S: d4T
6 64,312 9 ≤400
26 7
≤400
(1a)
1 370
K103N+
M184V
H: 3TC
S: d4T
6 ≤400 9 ≤400
27
Treatment
was
interrupted
for 10
months
NA (1a) 178 000 K103N
H:
EFV;
NVP
S: 3TC;
d4T
NA NA 5 ≤400
28 6
191
(1a)
56 500 K103N
H:
EFV;
NVP
H:
EFV;
NVP
S:
EFV;
NVP
S:
EFV;
NVP
S:
EFV;
NVP
S: 3TC;
d4T
4 ≤400 7 ≤400
29 3
19,653
(1a)
42 800 K103N
S: 3TC;
d4T
3 ≤400 10 ≤400
33 7
≤400
(1b)
882 000 Wild type
S: 3TC;
d4T
NA NA 6 ≤400
34 2
20,758
(1b)
1 450 Wild type
S: 3TC;
d4T
NA NA 4 ≤400
37 7
≤400
(1a)
312 000 Wild type
S: 3TC;
d4T
3 ≤400 8 ≤400
41 6
≤400
(1a)
≤400
(1a)
≤400
(1a)
1 060
Not
amplifiable
Not
amplifiable
Not
amplifiable
--- --- 6 ≤400 9 ≤400
42 4
557
--- -- 1 ≤400 8 ≤400
43 4
66 800
--- -- 3 ≤400 7 ≤400

Page 9

Citation: El-Khatib Z, DeLong AK, Katzenstein D, Ekstrom AM, Ledwaba J, et al. (2011) Drug Resistance Patterns and Virus Re-Suppression among
HIV-1 Subtype C Infected Patients Receiving Non-Nucleoside Reverse Transcriptase Inhibitors in South Africa. J AIDS Clinic Res 2:117.
doi:10.4172/2155-6113.1000117
Page 9 of 11
Volume 2 • Issue 2 • 1000117
J AIDS Clinic Res
ISSN:2155-6113 JAR an open access journal
patients with first-line virologic failure could spare the expense and
toxicity of second-line regimens in resource-limited settings with high
HIV burdens. While additional studies are needed to confirm these
observations and examine their longevity, detection of viremia on
treatment should prompt repeat testing, adherence counseling and, if
viremia is persistent, provision of second-line therapy.
Acknowledgments
We would like to thank patients for agreeing to participate, Ms. Albertina
Dambuza and Belinda Dambuza for assisting in reviewing medical records; Sisters
Noreen Boikanyo, Rebecca Phofa, Catherine Lephoto, Agnes Ramashiga and
Fikile Mbatha for study logistics; Ms Sarah Cohen, Mary Phoswa and Maphuti
Madiga for processing blood specimens; Ms Ewalde Cutler and Professor Adrian
Puren for the VL and CD4 cell counts; Drs. Penny Moore for technical assistance
and Robert Shafer for constructive critiques.
This study was funded by: the Swedish International Development Cooperation
Agency to Z.EK and NICD; Sven Gard’s Fund for Virology Research, The Royal
Swedish Academy of Sciences and a Karolinska Institutet Faculty Funds (KID) to
Z.EK; African Programme for Training in HIV/TB Research Fogarty International
Center/NIH/2U2RTW006878 and from the Freeman-Spogli Institute at Stanford
University; D.K, A.DL and R.K are funded by an NIH/RO1 grant/AI66922. A.DL
is also funded by the National Institute Of Allergy And Infectious Diseases/
P30AI042853.
Gen Bank accession number: HQ12279-12308;HQ12354-12365.
Competing Interests: The authors have declared that no competing interests
exist
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Citation: El-Khatib Z, DeLong AK, Katzenstein D, Ekstrom AM, Ledwaba J, et al. (2011) Drug Resistance Patterns and Virus Re-Suppression among
HIV-1 Subtype C Infected Patients Receiving Non-Nucleoside Reverse Transcriptase Inhibitors in South Africa. J AIDS Clinic Res 2:117.
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