Clinical Infectious Diseases BRIEF REPORT HIV/AIDS
Antiretroviral Drug Resistance Among Children and Youth in the United States With Perinatal HIV Russell B. Van Dyke,1 Kunjal Patel,2 Ron M. Kagan,3 Brad Karalius,2 Shirley Traite,4 William A. Meyer III,5 Katherine K. Tassiopoulos,2 George R. Seage III,2 Lorna M. Seybolt,6 Sandra Burchett,7 and Rohan Hazra8; for the Pediatric HIV/AIDS Cohort Study (PHACS) 1
Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; 3Focus Diagnostics, a Quest Diagnostics Subsidiary, San Juan Capistrano, California; 4Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; 5Quest Diagnostics, Baltimore, Maryland; 6Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans; 7Department of Pediatrics, Harvard Medical School, Boston, Massachusetts; and 8Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland
virologic failure, 22%–86% have viral resistance to their current therapy [6, 8]. Virologic failure with sensitive virus is likely due to poor adherence [9]. Herein we present the prevalence of ARV-resistant virus among a cohort of US children and youth with PHIV, compare the prevalence to that of national data, describe the patterns of drug resistance, and identify factors associated with ARV resistance.
2
Among 234 US youths with perinatal human immunodeficiency virus, 75% had antiretroviral resistance, substantially higher than that of the reference laboratory overall (36%–44%). Resistance to newer antiretrovirals and to all antiretrovirals in a class was uncommon. The only factor independently associated with future resistance was a higher peak viral load. Keywords. human immunodeficiency virus; antiviral resistance; children; adolescents; perinatal infection.
METHODS
The Adolescent Master Protocol (AMP) of the Pediatric HIV/ AIDS Cohort Study is a prospective cohort study evaluating the outcomes of PHIV and ART [10]. Between March 2007 and November 2009, we enrolled 451 children with PHIV between 7 and 16 years of age at 15 sites across the United States, including Puerto Rico. The protocol was approved by the institutional review board at each site and at the Harvard T.H. Chan School of Public Health. Written informed consent was obtained from the parent or legal guardian and assent was obtained from participants according to local institutional review board guidelines. Data Collection
Children and youth with perinatal human immunodeficiency virus (HIV) infection (PHIV) are at risk for acquired antiretroviral (ARV) drug resistance [1]. ARV resistance is associated with an increased risk of subsequent virologic failure [2] and death [3]. Causes of resistance include unpalatable drug formulations, poor adherence to antiretroviral therapy (ART), poor absorption of ARVs, and nonsuppressive regimens, all resulting in viral replication in the presence of low blood ARV concentrations [4, 5]. In adults, starting ART at lower CD4+ T-lymphocyte (CD4) counts or higher plasma HIV RNA concentrations (viral load [VL]) are associated with an increased risk of viral resistance and virologic failure [6]. Viral resistance testing is recommended prior to initiation of ART and when changing therapy because of treatment failure, and is cost-effective and improves virologic, immunologic, and clinical outcomes [2, 7]. Among children and adults with
Received 13 January 2016; accepted 28 March 2016; published online 7 April 2016. Presented in part: 21st Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts, 3–6 March 2014. Abstract 897. Correspondence: R. B. Van Dyke, Department of Pediatrics, 8408, Tulane University School of Medicine, 1440 Canal St, Ste 1600, New Orleans, LA 70112 ([email protected]). Clinical Infectious Diseases® 2016;63(1):133–7 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail [email protected]. DOI: 10.1093/cid/ciw213
Clinical and laboratory data were collected through self-report and medical chart abstraction, including the Centers for Disease Control and Prevention clinical classification and a lifetime history of ART, VL, and CD4+ lymphocyte measurements [10]. The peak LV and nadir CD4 were the highest and lowest values documented, respectively, since birth. Because many VL results were obtained prior to the general availability of ultrasensitive assays, we used a VL < 400 copies/mL to indicate viral suppression. Self-reported ARV adherence was obtained from the caregiver or participant as the proportion of ARV doses taken in the prior 7 days [11]. Combination antiretroviral therapy (cART) was defined as ≥3 ARVs from ≥2 classes. All other regimens were considered nonsuppressive. Viral Resistance Testing
The most recent genotypic resistance laboratory reports from the clinical sites as of 1 April 2015 were reinterpreted centrally using the Stanford HIVdb algorithm, version 7.0.1 [12]. Participants without results and with a VL ≥ 400 copies/mL while on study had their most recent plasma sample (as of 1 January 2013) tested for genotypic resistance at a reference laboratory (Quest Diagnostics) and interpreted centrally as above. ARV resistance was defined as intermediate- or high-level resistance. Because integrase strand transfer inhibitor (INSTI) use was uncommon, we did not test for INSTI resistance but collected testing results from the sites. As a comparison group, we obtained HIV/AIDS
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Table 1.
Characteristics of Participants With Resistance Testing Results Overall and by the Presence or Absence of Intermediate or High-Level Resistance
Characteristic
Total (N = 234)
Female sex
134 (57)
Resistance (n = 175) 98 (56)
No Resistance (n = 59)
P Valuea
36 (61)
.50 .53
Race/ethnicity White/other non-Hispanic
11 (5)
7 (4)
4 (7)
164 (70)
126 (72)
38 (64)
Hispanic
58 (25)
42 (24)
16 (27)
Missing
1 (0)
Black non-Hispanic
0
1 (2)
Age at ART initiation, y Median (IQR)
0.8 (0.3–2.4)
Never on ART
3 (1)
0.7 (0.3–2.1) 0
1.2 (0.4–2.7)
.12
3 (5)
Parameters measured at time of cART initiation Age, y Median (IQR)
3.1 (1.1–5.8)
Never on cART
15 (6)
2.7 (1.0–5.5) 5 (3)
4.3 (2.0–6.3)
Yes
153 (65)
120 (69)
33 (56)
No
66 (28)
50 (29)
16 (27)
Never on cART
15 (6)
5 (3)
10 (17)
.08
10 (17)
NS-ART prior to cART .66
Years on NS-ART prior to cART Median (IQR)
2.1 (0.7–4.4)
1.9 (0.7–3.7)
2.5 (1.5–5.3)
Never on NS-ART prior to cART or cART
81 (35)
55 (31)
26 (44)
135 (58)
104 (59)
31 (53)
45 (19)
36 (21)
9 (15)
PI + NNRTI-based
39 (17)
30 (17)
9 (15)
Never on cART
15 (6)
5 (3)
10 (17)
5 (4.3–5.6)
4.7 (3.7–5.1)
.32
Initial cART type PI-based NNRTI-based
.91
Log10 viral load, copies/mLb Median (IQR)
4.9 (4.2–5.5)
Missing or never on cART
73 (31)
53 (30)
.005
20 (34)
Viral load, copies/mLb 5000 Missing or never on cART
.01
Log10 peak viral load, copies/mL .02
CD4%b
Antiretroviral Drug Resistance Among Children and Youth in the United States With Perinatal HIV Russell B. Van Dyke,1 Kunjal Patel,2 Ron M. Kagan,3 Brad Karalius,2 Shirley Traite,4 William A. Meyer III,5 Katherine K. Tassiopoulos,2 George R. Seage III,2 Lorna M. Seybolt,6 Sandra Burchett,7 and Rohan Hazra8; for the Pediatric HIV/AIDS Cohort Study (PHACS) 1
Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; 3Focus Diagnostics, a Quest Diagnostics Subsidiary, San Juan Capistrano, California; 4Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; 5Quest Diagnostics, Baltimore, Maryland; 6Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans; 7Department of Pediatrics, Harvard Medical School, Boston, Massachusetts; and 8Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland
virologic failure, 22%–86% have viral resistance to their current therapy [6, 8]. Virologic failure with sensitive virus is likely due to poor adherence [9]. Herein we present the prevalence of ARV-resistant virus among a cohort of US children and youth with PHIV, compare the prevalence to that of national data, describe the patterns of drug resistance, and identify factors associated with ARV resistance.
2
Among 234 US youths with perinatal human immunodeficiency virus, 75% had antiretroviral resistance, substantially higher than that of the reference laboratory overall (36%–44%). Resistance to newer antiretrovirals and to all antiretrovirals in a class was uncommon. The only factor independently associated with future resistance was a higher peak viral load. Keywords. human immunodeficiency virus; antiviral resistance; children; adolescents; perinatal infection.
METHODS
The Adolescent Master Protocol (AMP) of the Pediatric HIV/ AIDS Cohort Study is a prospective cohort study evaluating the outcomes of PHIV and ART [10]. Between March 2007 and November 2009, we enrolled 451 children with PHIV between 7 and 16 years of age at 15 sites across the United States, including Puerto Rico. The protocol was approved by the institutional review board at each site and at the Harvard T.H. Chan School of Public Health. Written informed consent was obtained from the parent or legal guardian and assent was obtained from participants according to local institutional review board guidelines. Data Collection
Children and youth with perinatal human immunodeficiency virus (HIV) infection (PHIV) are at risk for acquired antiretroviral (ARV) drug resistance [1]. ARV resistance is associated with an increased risk of subsequent virologic failure [2] and death [3]. Causes of resistance include unpalatable drug formulations, poor adherence to antiretroviral therapy (ART), poor absorption of ARVs, and nonsuppressive regimens, all resulting in viral replication in the presence of low blood ARV concentrations [4, 5]. In adults, starting ART at lower CD4+ T-lymphocyte (CD4) counts or higher plasma HIV RNA concentrations (viral load [VL]) are associated with an increased risk of viral resistance and virologic failure [6]. Viral resistance testing is recommended prior to initiation of ART and when changing therapy because of treatment failure, and is cost-effective and improves virologic, immunologic, and clinical outcomes [2, 7]. Among children and adults with
Received 13 January 2016; accepted 28 March 2016; published online 7 April 2016. Presented in part: 21st Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts, 3–6 March 2014. Abstract 897. Correspondence: R. B. Van Dyke, Department of Pediatrics, 8408, Tulane University School of Medicine, 1440 Canal St, Ste 1600, New Orleans, LA 70112 ([email protected]). Clinical Infectious Diseases® 2016;63(1):133–7 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail [email protected]. DOI: 10.1093/cid/ciw213
Clinical and laboratory data were collected through self-report and medical chart abstraction, including the Centers for Disease Control and Prevention clinical classification and a lifetime history of ART, VL, and CD4+ lymphocyte measurements [10]. The peak LV and nadir CD4 were the highest and lowest values documented, respectively, since birth. Because many VL results were obtained prior to the general availability of ultrasensitive assays, we used a VL < 400 copies/mL to indicate viral suppression. Self-reported ARV adherence was obtained from the caregiver or participant as the proportion of ARV doses taken in the prior 7 days [11]. Combination antiretroviral therapy (cART) was defined as ≥3 ARVs from ≥2 classes. All other regimens were considered nonsuppressive. Viral Resistance Testing
The most recent genotypic resistance laboratory reports from the clinical sites as of 1 April 2015 were reinterpreted centrally using the Stanford HIVdb algorithm, version 7.0.1 [12]. Participants without results and with a VL ≥ 400 copies/mL while on study had their most recent plasma sample (as of 1 January 2013) tested for genotypic resistance at a reference laboratory (Quest Diagnostics) and interpreted centrally as above. ARV resistance was defined as intermediate- or high-level resistance. Because integrase strand transfer inhibitor (INSTI) use was uncommon, we did not test for INSTI resistance but collected testing results from the sites. As a comparison group, we obtained HIV/AIDS
•
CID 2016:63 (1 July)
•
133
Table 1.
Characteristics of Participants With Resistance Testing Results Overall and by the Presence or Absence of Intermediate or High-Level Resistance
Characteristic
Total (N = 234)
Female sex
134 (57)
Resistance (n = 175) 98 (56)
No Resistance (n = 59)
P Valuea
36 (61)
.50 .53
Race/ethnicity White/other non-Hispanic
11 (5)
7 (4)
4 (7)
164 (70)
126 (72)
38 (64)
Hispanic
58 (25)
42 (24)
16 (27)
Missing
1 (0)
Black non-Hispanic
0
1 (2)
Age at ART initiation, y Median (IQR)
0.8 (0.3–2.4)
Never on ART
3 (1)
0.7 (0.3–2.1) 0
1.2 (0.4–2.7)
.12
3 (5)
Parameters measured at time of cART initiation Age, y Median (IQR)
3.1 (1.1–5.8)
Never on cART
15 (6)
2.7 (1.0–5.5) 5 (3)
4.3 (2.0–6.3)
Yes
153 (65)
120 (69)
33 (56)
No
66 (28)
50 (29)
16 (27)
Never on cART
15 (6)
5 (3)
10 (17)
.08
10 (17)
NS-ART prior to cART .66
Years on NS-ART prior to cART Median (IQR)
2.1 (0.7–4.4)
1.9 (0.7–3.7)
2.5 (1.5–5.3)
Never on NS-ART prior to cART or cART
81 (35)
55 (31)
26 (44)
135 (58)
104 (59)
31 (53)
45 (19)
36 (21)
9 (15)
PI + NNRTI-based
39 (17)
30 (17)
9 (15)
Never on cART
15 (6)
5 (3)
10 (17)
5 (4.3–5.6)
4.7 (3.7–5.1)
.32
Initial cART type PI-based NNRTI-based
.91
Log10 viral load, copies/mLb Median (IQR)
4.9 (4.2–5.5)
Missing or never on cART
73 (31)
53 (30)
.005
20 (34)
Viral load, copies/mLb 5000 Missing or never on cART
.01
Log10 peak viral load, copies/mL .02
CD4%b
