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Introduction
We live in an era in which antiretroviral drugs have become
widely available for people living with HIV (PLHIV)
globally. However, the widespread use of antiretroviral
therapy (ART) over time (Fig. 1) has contributed to the
emergence of epidemics of transmitted HIV drug resistance (TDR) [1]. The spread of TDR can substantially
reduce therapeutic choices of ARTand increase the chance
of virological treatment failure among undiagnosed
patients on treatment [25]. Consequently, further
accumulation of drug-resistant mutations may exhaust
The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia, and bDepartment for Disease Control
and Prevention, The Pasteur Institute, Ho Chi Minh City, Vietnam.
Correspondence to Lei Zhang, PhD, The Kirby Institute, University of New South Wales, Level 6, Wallace Wurth Building, UNSW
Australia, Sydney, NSW 2052, Australia.
Tel: +61 2 9385 0869; fax: +61 2 9385 0920; e-mail: lzhang@kirby.unsw.edu.au
Received: 18 June 2014; revised: 5 September 2014; accepted: 16 September 2014.
DOI:10.1097/QAD.0000000000000494
ISSN 0269-9370 Q 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
2751
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AIDS
2014, Vol 28 No 18
Global scale-up of ART for PLHIV
in LMIC with the 3 by 5 initiative
Primary infection with zidovudineresistant HIV strains was first
diagnosed in a homosexual man
2013
2012
2011
2010
2009
2008
2007
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
1987
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Fig. 1. Timeline of the development of transmitted HIV drug resistance and responses. ART, antiretroviral therapy; CDC, Centers
for Disease Control and Prevention; HIC, high-income countries; LMIC, low/middle-income countries; PLHIV, people living with
HIV; TDR, transmitted HIV drug resistance; UNAIDS, Joint United Nations Programme on HIV/AIDS; US FDA, United States Food
and Drug Administration.
Methods
Search strategy and selection criteria
We conducted a systematic review by searching available
electronic English literature on PubMed, Embase, Scopus
and Web of Science databases, according to the following
search strategy: HIV and (drug or antiretroviral or
antiviral or ARV or ART) and (resistance or resistant
or mutation or mutant) not (review or modelling).
We further searched the peer-reviewed abstracts from
major conferences including the International AIDS
Conference, the Conference on HIV Pathogenesis,
Treatment and Prevention and the International HIV
Drug Resistance Workshop during 20012013. Searches
were conducted between June and August 2013.
Quantitative TDR studies with any study designs that
recruited participants at any stage of HIV infection were
eligible for inclusion in this review. These were screened
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Data extraction
From each selected publication, a single unblinded
investigator (Q.D.P.) extracted relevant study-level
information [see more details in Table S3 (appendix),
http://links.lww.com/QAD/A588]. For each at-risk
group, we collected the numbers of samples sequenced,
the number of people diagnosed with TDR and resistance to nucleoside reverse transcriptase inhibitor
(NRTIs), non-nucleoside reverse transcriptase inhibitors
(NNRTIs) and protease inhibitors to calculate the
relevant prevalence levels. We categorized countries as
high-income and low/middle-income countries according to the 2012 classification of the World Bank [20].
Statistical data analysis
The distributions of TDR prevalence were highly rightskewed so we used the FreemanTukey double arcsine
transformation to normalize these rates before metaanalysis [21,22]. We conducted DerSimonianLaird
random-effects meta-analysis [23] to pool transformed
rates and 95% confidence intervals (CIs). We assessed
cross-study heterogeneity with both Cochrans Q tests
and the I2 statistics (values of I2 <25%, 2575% and
>75% indicating low, moderate and high heterogeneity,
respectively) [24]. In our exploratory analysis, we
identified moderate-to-high levels of heterogeneity
(MSM: Q test P < 0.001, I2 77.8%; PWID:
P < 0.001, I2 66.7%; heterosexuals: P < 0.001,
I2 76.3%) and conducted meta-regression analysis to
identify sources of these heterogeneities. We identified
that large geographical and country income levels
influenced between-study heterogeneity in transformed
prevalence rates in all at-risk populations. Therefore, we
then conducted subgroup analysis by these two factors.
Notably, stages of HIV infection for recruits, study
design, sampling locations and sampling method were not
significant contributors to heterogeneity. Stratified
analyses by drug class were also conducted when data
were available. We also compared TDR frequency across
key transmission modes of HIV. Odds ratios (ORs) were
calculated with a standard adjustment of 0.5 in the
contingency table if it contained a zero value. The effect
rates of odds of TDR and resistance to specific drug
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Results
Study characteristics
A comprehensive search of 17 866 publications resulted in
212 selected studies (Fig. S1, appendix, http://links.lww.com/QAD/A588). Overall, information on antiretroviral drug resistance of 84 595 antiretroviral-naive PLHIV,
including 37 846 MSM (89.2% from high-income
countries), 6531 PWID (81.3% from high-income
countries) and 26 934 heterosexuals (70.7% from highincome countries), were extracted from samples in 46
low/middle-income countries (94 studies) and 34 highincome countries (118 studies). The median numbers of
sequenced samples in MSM, PWID and heterosexuals
were 110 (range 103220), 46 (range 101358) and 69
persons (range 112874), respectively. About onequarter of the studies (56/212) recruited participants at
an early (acute/recent) stage of HIV infection and men
were predominant (50% of the samples) in over 80% of
the studies (160/198). About 70% (148/212) of the
studies reported the mean or median age of participants
(range 1844 years). The mean or median CD4 T-cell
count and viral load at recruitment were within the ranges
of 56807 cells/ml in 116 studies and of 2.66.4
log10 copies/ml in 106 studies when data were available,
respectively. In 74/165 studies (45%), 50% or more of the
participants were infected with HIV non-B subtypes.
This was mostly observed among studies in low/middleincome countries. Most samples used traditional population-based genotypic assays (201/212 studies) and
nearly half (93/212) of the selected studies interpreted
detected drug resistance-associated mutations according
to the TDR mutational lists of Shafer et al. [27] or the
WHO [28]. Study-level characteristics stratified by time
period, country income and region are further summarized in Table 1.
Global disease burdens of transmitted HIV drug
resistance
Disease burdens of TDR varied substantially across
geographical regions (Fig. 2). North America exhibited
consistently high TDR prevalence in all populations [MSM: 13.7% (95% CI 12.315.2%); PWID:
9.1% (8.010.2%); heterosexuals: 10.5% (8.612.4%)],
followed by western Europe [MSM: 11.0% (9.912.2%);
PWID: 5.7% (4.56.9%); heterosexuals: 6.9% (5.68.3%)]
and South America [MSM: 8.3% (6.010.9%); PWID:
13.5% (7.620.4%); heterosexuals: 7.5% (6.38.8%)].
Significant publication biases were found in TDR
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195 (1)
141 [261778], (12)
78 [15104], (7)
368 [270466], (2)
40
30
31
1
16
18
74 [22116], (6)
35 [26165], (6)
66 [191358], (18)
16 [1065], (5)
58 (1)
23 (1)
39 [12348], (31)
44 [1883], (10)
77 [151516], (22)
85 [15299], (24)
62 [32354], (30)
35 (1)
78 [112874], (46)
25 [1467], (10)
2/2 (100%)
16/16 (100%)
11/15 (73%)
38/39 (97%)
24/28 (86%)
3/31 (10%)
1/1 (100%)
51/52 (98%)
14/14 (100%)
3539 (2)
3144 (14)
2039 (12)
2043 (25)
2439 (20)
1844 (20)
34 (1)
2839 (41)
2439 (13)
2043 (84)
1844 (64)
2/2 (100%)
1/16 (6%)
7/18 (39%)
15/40 (38%)
4/30 (13%)
4/31 (13%)
0/1 (0%)
20/58 (34%)
3/16 (19%)
41/118 (35%)
15/94 (16%)
12/21 (57%)
19/64 (30%)
25/127 (20%)
109/111 (98%)
51/87 (59%)
2839 (14)
1939 (40)
1844 (94)
58
16
71 [112874], (83)
65 [141025], (73)
16/17 (94%)
47/58 (81%)
97/123 (79%)
33 [14172], (9)
53 [12490], (50)
79 [112874], (97)
118
94
52 [1483], (7)
44 [12206], (26)
48 [101358], (45)
40 [11270], (16)
118 [151487], (43)
125 [103220], (84)
Range mean
or median
years of
age
(studies)
21
64
127
No. studies
with 50%
male
patients/total
studies (%)
110 [103220], (143) 46 [101358], (78) 69 [112874], (156) 160/198 (81%) 1844 (148) 56/212 (26%)
Median [minmax]
no. heterosexual
samples genotyped
per study (studies)
212
All studies
Published period
19992003
20042008
20092013
Country income
High-income
Low/middleincome
Region
Western Europe
Eastern Europe
and central
Asia
North America
South America
Sub-Saharan Africa
North Africa and
Middle East
East Asia
South and southeast Asia
Oceania
No.
study
Median [minmax]
no. PWID samples
genotyped
per study (studies)
No. studies
recruiting
patients at
acute or
recent
infection/
total studies
(%)
0/2 (05)
9/16 (56%)
16/16 (100%)
0/18 (0%)
5/23 (22%)
29/29 (100%)
0/1 (0%)
6/46 (13%)
9/14 (64%)
10/82 (12%)
64/83 (77%)
2/14 (14%)
19/46 (41%)
53/105 (50%)
74/165 (45%)
No. studies
with 50%
patients
infected
HIV-1 subtype
non-B/total
studies (%)
Range mean
or median
level of
viral load,
log10
copies/ml
(studies)
524 (1)
206409 (9)
56614 (10)
220602 (18)
179560 (17)
285656 (12)
350 (1)
230807 (41)
261417 (7)
139807 (72)
56656 (44)
283807 (8)
139678 (31)
56656 (77)
6.4 (1)
4.65.5 (8)
3.85.9 (7)
4.16.1 (18)
3.65.4 (15)
2.65.7 (8)
4.25.6 (41)
4.55.3 (8)
4.16.4 (73)
2.65.7 (33)
4.36.4 (8)
3.85.6 (30)
2.66.1 (68)
Range mean
or median
no. CD4
T-cell
count,
cells/ml
(studies)
AIDS
Median [minmax]
no. MSM samples
genotyped
per study (studies)
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2014, Vol 28 No 18
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2755
Western Europe
11.0% (9.912.2%)
East Asia
7.8% (5.410.6%)
South America
8.3% (6.010.9%)
Country prevalence
5.0%
5.0110.0%
10.0115.0%
15.0120.0%
>20.0%
Study conducted, data not reported
No data
Oceania
15.5% (12.818.3%)
Western Europe
5.7% (4.56.9%)
East Asia
2.7% (1.24.7%)
South America
13.5% (7.620.4%)
Country prevalence
5.0%
5.0110.0%
10.0115.0%
15.0120.0%
>20.0%
Study conducted, data not reported
No data
Western Europe
6.9% (5.6 8.3%)
East Asia
4.5% (2.47.0%)
South America
7.5% (6.38.8%)
Country prevalence
5.0%
5.0110.0%
10.0115.0%
15.0120.0%
>20.0%
Study conducted, data not reported
No data
Sub-Saharan Africa
2.2% (1.43.2%)
Fig. 2. Global prevalence of transmitted HIV drug resistance in HIV-infected antiretroviral-nave MSM, people who inject
drugs and heterosexual populations by regions (19992013). PWID, people who inject drugs; TDR, transmitted HIV drug
resistance. () Prevalence estimate was yielded from a meta-analysis of seven studies with only small numbers of MSM (10120
men).
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2014, Vol 28 No 18
Discussion
We demonstrate a high but stable TDR prevalence across
MSM, PWID and heterosexuals in high-income
countries. Conversely, TDR levels are relatively low
but rapidly increasing in low/middle-income countries.
Notably, MSM is the population most affected by TDR
regardless of the countries economic status worldwide.
Transmitted HIV drug resistance prevalence is largely
heterogeneous across continental regions, particularly
between high-income and low/middle-income settings.
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(b)
20.0
20.0
19992003
20042008
20092013
2757
15.0
P = 0.011
10.0
P = 0.265
7.8
P < 0.001
4.8
5.0
4.2
4.1
2.6
2.4
No data
0.0
No data
625 3,346
MSM
447
700
PWID
19992003
20042008
20092013
P = 0.296
10.9
10.0
9.0
8.3
NRTI
P = 0.045
2,002
4,230
3,259
2,446
0.0
1,257
20092013
730
238 3,52713,721
PWID
MSM
Heterosexuals
(e)
n
251
n
399
581
2,275
938
5,023
5,514
19992003
20042008
5.6
5.2
5.0
715
P < 0.001
NNRTI
8.0
6.4
(d)
n
730
P = 0.296
12.6
11.7
Heterosexuals
(c)
P = 0.121
15.0
19992003
P = 0.024
19992003
891
431
20042008
624
20042008
1,292
20092013
251
399
2,202
581
2,275
4,230
807
5,023
20092013
P < 0.001
PI
10
10
10
Fig. 3. Prevalence of transmitted HIV drug resistance in HIV-infected antiretroviral-naive MSM, people who inject drugs and
heterosexual people by time periods. (a) and (b) present prevalence levels in low/middle-income and high-income countries,
respectively, in which P values were obtained from Q tests. (ce) present prevalence of resistance to antiretroviral drug classes.
Each column chart series represents the prevalence trends of resistance to a certain antiretroviral drug class (NRTI, NNRTI and PI)
among MSM [represented in (c)], people who inject drugs [PWID, represented in (d)] and heterosexual people [represented in (e)]
using data from three periods (19992003, 20042008 and 20092013). P values were obtained from meta-regression analysis
examining the slopes of resistance prevalence levels over three time periods. Sample size for each meta-analysis is presented at the
bottom of each column. NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor;
PI, protease inhibitor.
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1.35
1.38
1.24
1.28
0.91
0.97
1.49
1.42
22/204
260/3333
968/10 808
1250/14 345
15/172
19/446
147/2688
181/3306
Heterosexuals
(0.342.44)a, n/a
(0.412.28), 0.0%
(1.131.99)b, 5.1%
(1.111.82)c, 0.0%
(0.702.58), 0.0%
(1.121.70)b, 25.7%
(1.081.42)b,e, 49.0%
(1.141.42)d,e,h, 38.4%
OR (95% CI), I2
6/75
75/934
81/1009
4/17
678/5474
1890/15 754
2572/21 245
MSM
0/14
12/172
12/186
5/25
107/1176
279/3161
391/4 362
PWID
(0.285.45)a, n/a
(1.061.70)b, 0.0%
(0.991.72)f,h, 51.2%
(1.101.58)c,f,h, 33.1%
1.23
1.34
1.31
1.32
OR (95% CI), I2
0/14
1/66
27/470
28/550
16/96
101/1121
272/3029
389/4 246
PWID
15/172
8/229
91/2267
114/2668
9/54
219/2641
808/8945
1036/11 640
Heterosexuals
0.35
0.41
1.66
1.45
1.07
1.08
0.97
1.01
(0.026.16)a, n/a
(0.053.13), 0.0%
(0.982.78), 0.0%
(0.892.39), 0.0%
(0.392.94), 0.0%
(0.811.43), 0.0%
(0.791.19)g, 25.1%
(0.881.17)g, 5.9%
OR (95% CI), I2
CI, confidence interval; n/a, not applicable; OR, odds ratio; PWID, people who inject drugs; TDR, transmitted HIV drug resistance.
a
Estimate was obtained from a single study.
b
P value < 0.05.
c
P value < 0.01.
d
P-value < 0.001.
e
This also included four studies (1601 MSM and 1557 heterosexual people) reporting only crude odds ratios and its 95% confidence intervals.
f
This also included two studies (361 MSM and 42 PWID) reporting only crude odds ratios and its 95% confidence intervals.
g
This also included two studies (413 PWID and 1445 heterosexual people) reporting only crude odds ratios and its 95% confidence intervals.
h
Signficant potential presence of publication bias: MSM versus heterosexuals over the entire study period (Eggers test, P 0.006; Begg and Mazumdar test, P 0.138) and MSM versus PWID over
20092013 (Eggers test, P 0.027; Begg and Mazumdar test, P 0.134), as well as the entire study period (Eggers test, P 0.003; Begg and Mazumdar test, P 0.125) in high-income countries.
High-income countries
19992003
24/194
20032008
755/6418
20092013 2094/18 766
Overall
2873/25 378
Low/middle-income countries
19992003
6/75
20032008
10/228
20092013
182/2130
Overall
198/2433
MSM
AIDS
Table 2. Comparison of pooled odds ratios of transmitted HIV drug resistance infection across HIV-infected antiretroviral-nave MSM, people who inject drugs and heterosexual populations by
country-income category and published period.
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Acknowledgements
The authors wish to thank Louisa Wright for assistance
with English language editing and proofreading, and
Conflicts of interest
The authors declare that there is no conflict of interest.
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