Abstract
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
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 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.
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
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 the interpretation of all genotypic resistance testing performed by the reference laboratory in 2006 and 2012, including both adults and children.
Data Analysis
Differences between groups and correlates of resistance were evaluated using the Wilcoxon test for continuous and χ2 test for categorical variables. Factors associated with resistance were evaluated using multivariable logistic regression. Because of small numbers, INSTI resistance is described but not further analyzed.
RESULTS
Study Population
Of the 448 participants with an entry visit, 235 (52%) had resistance testing results, of which 144 were obtained from clinical records. Eleven participants had INSTI resistance results including 1 with only INSTI results. This participant was included only in the description of INSTI resistance. The remaining 234 participants with testing results were predominantly black and Hispanic and 57% were female, reflecting the AMP population (Table 1) [10]. The participants were young when first treated, starting ART at a median age of 0.8 years and cART at a median age of 3.1 years. Sixty-five percent received single or dual ARV for a median of 2.1 years before starting cART, and most (58%) started protease inhibitor (PI)-containing cART.
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) | Resistance (n = 175) | No Resistance (n = 59) | P Valuea |
|---|---|---|---|---|
| Female sex | 134 (57) | 98 (56) | 36 (61) | .50 |
| Race/ethnicity | ||||
| White/other non-Hispanic | 11 (5) | 7 (4) | 4 (7) | .53 |
| Black non-Hispanic | 164 (70) | 126 (72) | 38 (64) | |
| Hispanic | 58 (25) | 42 (24) | 16 (27) | |
| Missing | 1 (0) | 0 | 1 (2) | |
| Age at ART initiation, y | ||||
| Median (IQR) | 0.8 (0.3–2.4) | 0.7 (0.3–2.1) | 1.2 (0.4–2.7) | .12 |
| Never on ART | 3 (1) | 0 | 3 (5) | |
| Parameters measured at time of cART initiation | ||||
| Age, y | ||||
| Median (IQR) | 3.1 (1.1–5.8) | 2.7 (1.0–5.5) | 4.3 (2.0–6.3) | .08 |
| Never on cART | 15 (6) | 5 (3) | 10 (17) | |
| NS-ART prior to cART | ||||
| Yes | 153 (65) | 120 (69) | 33 (56) | .66 |
| No | 66 (28) | 50 (29) | 16 (27) | |
| Never on cART | 15 (6) | 5 (3) | 10 (17) | |
| 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) | .32 |
| Never on NS-ART prior to cART or cART | 81 (35) | 55 (31) | 26 (44) | |
| Initial cART type | ||||
| PI-based | 135 (58) | 104 (59) | 31 (53) | .91 |
| NNRTI-based | 45 (19) | 36 (21) | 9 (15) | |
| PI + NNRTI-based | 39 (17) | 30 (17) | 9 (15) | |
| Never on cART | 15 (6) | 5 (3) | 10 (17) | |
| Log10 viral load, copies/mLb | ||||
| Median (IQR) | 4.9 (4.2–5.5) | 5 (4.3–5.6) | 4.7 (3.7–5.1) | .005 |
| Missing or never on cART | 73 (31) | 53 (30) | 20 (34) | |
| Viral load, copies/mLb | ||||
| <400 | 6 (3) | 3 (2) | 3 (5) | .01 |
| 400–5000 | 15 (6) | 7 (4) | 8 (14) | |
| >5000 | 140 (60) | 112 (64) | 28 (47) | |
| Missing or never on cART | 73 (31) | 53 (30) | 20 (34) | |
| Log10 peak viral load, copies/mL | ||||
| Median (IQR) | 5.5 (4.9–5.9) | 5.6 (5.1–5.9) | 5.2 (4.7–5.7) | .02 |
| Missing or never on cART | 44 (19) | 27 (15) | 17 (29) | |
| CD4%b | ||||
| <15 | 21 (9) | 17 (10) | 4 (7) | .08 |
| 15–24 | 45 (19) | 39 (22) | 6 (10) | |
| ≥25 | 92 (39) | 64 (37) | 28 (47) | |
| Missing or never on cART | 76 (32) | 55 (31) | 21 (36) | |
| Nadir CD4% | ||||
| Median (IQR) | 19 (14–27) | 19 (14–27) | 21 (17–27) | .20 |
| Missing or never on cART | 42 (18) | 25 (14) | 17 (29) | |
| CDC classification | ||||
| Category C | 47 (20) | 39 (22) | 8 (14) | .32 |
| Never on cART | 15 (6) | 5 (3) | 10 (17) | |
| Parameters at time of most recent resistance result | ||||
| Age, y, median (IQR) | 15.1 (13.2–17.0) | 14.9 (13.0–16.9) | 15.6 (13.5–17.6) | .18 |
| Ever use of ART | 231 (99) | 175 (100) | 56 (95) | .003 |
| Ever use of cART | 219 (94) | 170 (97) | 49 (83) | <.001 |
| Ever use of NNRTI | 162 (69) | 131 (75) | 31 (53) | .001 |
| Ever use of PI | 210 (90) | 163 (93) | 47 (80) | .003 |
| No. of cART regimens | ||||
| Median (IQR)c | 4 (2–6) | 4 (2–6) | 4 (2–5) | .24 |
| Never on cART | 15 (6) | 5 (3) | 10 (17) | |
| Cumulative duration of cART, yc | ||||
| Median (IQR) | 10.2 (7.4–12.1) | 10.4 (7.5–12.2) | 9.5 (7.1–11.6) | .29 |
| Never on cART | 15 (6) | 5 (3) | 10 (17) | |
| Years spent on cART while VL > 1000 copies/mLc | ||||
| Median (IQR) | 3.9 (1.8–7.0) | 4.5 (2.5–7.3) | 1.8 (0.9–4.8) | <.001 |
| Never on cART | 15 (6) | 5 (3) | 10 (17) | |
| Current ART regimend | ||||
| NRTI alone | 18 (8) | 16 (9) | 2 (3) | <.001 |
| PI + INSTI | 18 (8) | 16 (9) | 2 (3) | |
| PI + EI/FI | 5 (2) | 5 (3) | 0 (0) | |
| PI + NNRTI | 13 (6) | 12 (7) | 1 (2) | |
| PI alone | 111 (47) | 89 (51) | 22 (37) | |
| NNRTI + INSTI | 2 (1) | 2 (1) | 0 (0) | |
| NNRTI alone | 19 (8) | 16 (9) | 3 (5) | |
| INSTI alone | 5 (2) | 5 (3) | 0 (0) | |
| No ART | 43 (18) | 14 (8) | 29 (49) | |
| Years on current regimen, median (IQR) | 1.8 (0.6–4.3) | 1.7 (0.7–3.9) | 1.9 (0.4–5.4) | .98 |
| Log10 viral load, copies/mLb | ||||
| Median (IQR) | 3.6 (3.0–4.4) | 3.5 (3.0–4.2) | 4.1 (3.6–4.8) | <.001 |
| Missing | 19 (8) | 11 (6) | 8 (14) | |
| Viral load, copies/mLb | ||||
| <400 | 18 (8) | 17 (10) | 1 (2) | .003 |
| 400–5000 | 93 (40) | 78 (45) | 15 (25) | |
| >5000 | 104 (44) | 69 (39) | 35 (59) | |
| Missing | 19 (8) | 11 (6) | 8 (14) | |
| Log10 peak viral load, copies/mL, median (IQR) | 5.6 (5.1–5.9) | 5.7 (5.2–5.9) | 5.5 (4.9–5.9) | .13 |
| CD4 count, cells/µLb | ||||
| <200 | 30 (13) | 20 (11) | 10 (17) | .32 |
| 200–500 | 80 (34) | 59 (34) | 21 (36) | |
| >500 | 107 (46) | 85 (49) | 22 (37) | |
| Missing | 17 (7) | 11 (6) | 6 (10) | |
| Nadir CD4%, median (IQR) | 16 (9–23) | 16 (9–22) | 18 (13–24) | .04 |
| CDC category C | 70 (30) | 58 (33) | 12 (20) | .06 |
| ART adherence | ||||
| 100% | 93 (40) | 77 (44) | 16 (27) | .08 |
| Missing | 56 (24) | 37 (21) | 19 (32) | |
Data are presented as No. (%) unless otherwise specified.
Abbreviations: ART, antiretroviral therapy; cART, combination antiretroviral therapy; CDC, Centers for Disease Control and Prevention; EI/FI, entry inhibitor/fusion inhibitor; INSTI, integrase inhibitor; IQR, interquartile range; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor; NS-ART, nonsuppressive ART that does not meet the definition of cART; PI, protease inhibitor; VL, viral load.
a Wilcoxon test for continuous variables, and χ2 test for categorical variables. Excludes missing values.
b Window of ≤60 days was allowed.
c Based on cumulative assessment.
d Plus NRTI backbone.
The median age of the participants at the time of their most recent resistance testing (included in this analysis) was 15.1 years. They had received a median of 4 different cART regimens with a mean duration of cART of 10.2 years, including a median of 3.9 years of cART while their VL was >1000 copies/mL.
Prevalence of Resistance by ARV and ARV Class
Among the 234 participants with resistance results, 44 (19%) had fully susceptible virus while 15 (6%) had low-level resistance, 6 (3%) intermediate resistance, and 169 (72%) high-level resistance to at least 1 ARV (Table 2). Sixty-one percent had resistance to at least 1 nucleoside/nucleotide reverse transcriptase inhibitor (NRTI), 45% to at least 1 nonnucleoside reverse transcriptase inhibitor (NNRTI), and 34% to at least 1 PI; 18% had resistance in all 3 classes. Resistance to all drugs in a class was uncommon, with only 12% having resistance to all NRTIs, 19% to all NNRTIs, and 5% to all PIs. Only 1 participant was resistant to all drugs in all 3 classes. The rates of resistance for the reference laboratory were substantially lower than those of AMP participants, and, except for all NRTIs + PIs, were less than the lower bounds of the 95% confidence interval (CI) for AMP participants (Table 2). For example, their prevalence of any ARV resistance was 36% in 2012.
Table 2.
Prevalence of Intermediate or High-Level Human Immunodeficiency Virus Resistance by Drug Class and Combinations of Classesa
| PHACS AMP Subjects (N = 234) |
Reference Laboratory (n > 10 000) |
||||
|---|---|---|---|---|---|
| Year of Report | |||||
| 2007–2015 |
2006 |
2012 |
|||
| Type of Resistance | No. | Prevalence, % | 95% CI | Prevalence, % | |
| Any ARV | 175 | 75 | 69–80 | 44 | 36 |
| At least 1 class | |||||
| NRTI | |||||
| Anyb | 142 | 61 | 54–67 | 33 | 21 |
| Allc | 27 | 12 | 8–16 | 6 | 2 |
| NNRTI | |||||
| Any | 105 | 45 | 38–51 | 28 | 26 |
| All | 45 | 19 | 14–25 | 0.9 | 1 |
| PI | |||||
| Any | 80 | 34 | 28–41 | 17 | 7 |
| All | 11 | 5 | 2–8 | 1 | 0.4 |
| At least 2 classes | |||||
| NRTI + NNRTI | |||||
| Any | 77 | 33 | 27–39 | 18 | 12 |
| All | 10 | 4 | 2–8 | 0.4 | 0.2 |
| NRTI + PI | |||||
| Any | 71 | 30 | 25–37 | 15 | 5 |
| All | 4 | 2 | 0.5–4 | 0.6 | 0.2 |
| At least 3 classes | |||||
| Any | 43 | 18 | 14–24 | 8 | 3 |
| All | 1 | 0.4 | 0.01–2 | 0 | 0.1 |
Abbreviations: ARV, antiretroviral drug; CI, confidence interval; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor; PHACS AMP, Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol; PI, protease inhibitor.
a Excludes 1 subject with only integrase strand transfer inhibitor testing results.
b Any drug in class or any in each class.
c All drugs in class or all in each class.
The prevalence of resistance to individual ARVs is shown in Supplementary Table 1. In general, the prevalence was lower for newer drugs in each class. Of the 11 participants with INSTI resistance testing results, 3 (27% [95% CI, 6%–61%]) were resistant to both raltegravir and elvitegravir but none to dolutegravir.
Factors Associated With Resistance
Participants with resistance had a higher median VL and peak VL when starting cART than those without resistance (Table 1). At the time of resistance testing, those with resistance were more likely to have ever received cART, an NNRTI, and a PI; had a lower median VL; had a longer duration of cART with a VL > 1000 copies/mL; and had a lower median nadir CD4 percentage. Only 51% of those without resistance but 92% with resistance were receiving ART at the time of resistance testing. Those with resistance were more likely to be receiving a regimen containing an INSTI (13% vs 3%; P < .001). Factors not significantly associated with resistance included the use of and the duration of nonsuppressive ART prior to cART and the CD4 count at the time of resistance testing.
In a multivariable analysis considering factors present before or when starting cART, only peak VL was independently associated with the future development of resistance, with an odds ratio of 1.76 for every 1 log10 increase in the peak VL (95% CI, 1.00–3.09; P = .048).
DISCUSSION
Among a cohort of children and youth with PHIV infection and virologic failure, 75% had intermediate- or high-level resistance to at least 1 ARV, approximately twice the prevalence of all individuals tested at the reference laboratory during the same time period. Resistance was most common to the NRTIs, with 61% of participants having resistance to at least 1 drug, followed by the NNRTIs (45%) and PIs (34%). Resistance to all drugs in a class was less common, although 19% of participants were resistant to all NNRTIs.
The only independent correlate of future resistance was a higher peak VL prior to starting cART, with the risk of developing resistance nearly doubling with every log increase in peak VL. It is interesting that neither the use of nonsuppressive ART prior to cART nor age nor CD4 percentage when starting cART was associated with resistance.
At the time of resistance testing, only 51% of those without resistance were receiving ART, although nearly all (95%) had previously received ART. This likely accounts for the higher VL at testing among those without resistance. It is also likely that they had fully sensitive virus despite prior ART because of poor adherence, resulting in ARV concentrations too low to select for resistant virus [5]. Poor adherence is the principal cause of virologic failure, whether or not viral resistance is present, and is particularly common among HIV-infected youth [11].
A limitation of the study is the unavailability of resistance results for 21% of participants with a detectable VL. An additional limitation is the infrequency of INSTI resistance testing.
In conclusion, ARV resistance is common among US children and youth with PHIV, including resistance to multiple ARV classes, with a prevalence of resistance substantially higher than that of the US HIV-infected population. As these young people transition to adult care, it is important that providers be aware of their high rate of viral resistance. Fortunately, resistance to newer ARVs is uncommon, and effective treatment regimens are available for most youth with resistant virus.
Supplementary Data
Supplementary materials are available at http://cid.oxfordjournals.org. Consisting of data provided by the author to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the author, so questions or comments should be addressed to the author.
Notes
Acknowledgments. We thank the children and families for their participation in Pediatric HIV/AIDS Cohort Study (PHACS), and the individuals and institutions involved in the conduct of PHACS. The following institutions, clinical site investigators, and staff participated in conducting PHACS Adolescent Master Protocol in 2014, in alphabetical order: Ann & Robert H. Lurie Children's Hospital of Chicago: Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter; Baylor College of Medicine: William Shearer, Mary Paul, Norma Cooper, Lynnette Harris; Bronx Lebanon Hospital Center: Murli Purswani, Mahboobullah Baig, Anna Cintron; Children's Diagnostic and Treatment Center: Ana Puga, Sandra Navarro, Patricia Garvie, James Blood; Children's Hospital, Boston: Sandra Burchett, Nancy Karthas, Betsy Kammerer; Jacobi Medical Center: Andrew Wiznia, Marlene Burey, Molly Nozyce; Rutgers–New Jersey Medical School: Arry Dieudonne, Linda Bettica, Susan Adubato; St Christopher's Hospital for Children: Janet Chen, Maria Garcia Bulkley, Latreaca Ivey, Mitzie Grant; St Jude Children's Research Hospital: Katherine Knapp, Kim Allison, Megan Wilkins; San Juan Hospital/Department of Pediatrics: Midnela Acevedo-Flores, Heida Rios, Vivian Olivera; Tulane University Health Sciences Center: Margarita Silio, Medea Jones, Patricia Sirois; University of California, San Diego: Stephen Spector, Kim Norris, Sharon Nichols; University of Colorado Denver Health Sciences Center: Elizabeth McFarland, Alisa Katai, Jennifer Dunn, Suzanne Paul; University of Miami: Gwendolyn Scott, Patricia Bryan, Elizabeth Willen.
Author contributions. Conception and design of the study: R. B. V. D., K. P., and G. R. S. All authors participated in acquisition of data, analysis and interpretation of data, and drafting or revision of the manuscript.
Disclaimer. The conclusions and opinions expressed in this article are those of the authors and do not necessarily reflect those of the National Institutes of Health or US Department of Health and Human Services.
Financial support. This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart, Lung, and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism through cooperative agreements with the Harvard T.H. Chan School of Public Health (HD052102) (Principal Investigator [PI]: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104) (PI: Russell Van Dyke; Co-PI: Kenneth Rich; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (PI: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (PI: Julie Davidson).
Potential conflicts of interest. R. M. K. and W. A. M. are employees of Quest Diagnostics, which performed resistance testing for the study. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Contributor Information
Collaborators: for the Pediatric HIV/AIDS Cohort Study (PHACS), Robert H. Lurie, Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter, William Shearer, Mary Paul, Norma Cooper, Lynnette Harris, Murli Purswani, Mahboobullah Baig, Anna Cintron, Ana Puga, Sandra Navarro, Patricia Garvie, James Blood, Sandra Burchett, Nancy Karthas, Betsy Kammerer, Andrew Wiznia, Marlene Burey, Molly Nozyce, Arry Dieudonne, Linda Bettica, Susan Adubato, Janet Chen, Maria Garcia Bulkley, Latreaca Ivey, Mitzie Grant, Katherine Knapp, Kim Allison, Megan Wilkins, Midnela Acevedo-Flores, Heida Rios, Vivian Olivera, Margarita Silio, Medea Jones, Patricia Sirois, Stephen Spector, Kim Norris, Sharon Nichols, Elizabeth McFarland, Alisa Katai, Jennifer Dunn, Suzanne Paul, Gwendolyn Scott, Patricia Bryan, and Elizabeth Willen
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