¶ Membership of the Madrid Cohort of HIV-Infected Children is provided in the Acknowledgments
The authors have declared that no competing interests exist.
Conceived and designed the experiments: MDM GY AN JTR AH. Performed the experiments: MDM. Analyzed the data: MDM GY AN AH JTR. Wrote the paper: MDM AH GY AN. Provided clinical records of the study population: MIDJ MDG MIGT MJM JSL. Provided clinical samples from HIV-1 biobank: MAMF. Provided statistical analysis and cohort data: SJDO.
Antiretroviral treatment (ART) has contributed to increased life expectancy of HIV-1 infected children. In developed countries, an increasing number of children reaching adulthood are transferred to adult units. The objectives were to describe the demographic and clinical features, ART history, antiviral drug resistance and drug susceptibility in HIV-1 perinatally infected adolescents transferred to adult care units in Spain from the Madrid Cohort of HIV-1 infected children.
Clinical, virological and immunological features of HIV-1 vertically infected patients in the Madrid Cohort of HIV-infected children were analyzed at the time of transfer.
One hundred twelve infected patients were transferred to adult units between 1997 and 2011. They were mainly perinatally infected (93.7%), with a mean nadir CD4+-T-cells count of 10% and presented moderate or severe clinical symptoms (75%). By the time of transfer, the mean age was 18.9 years, the mean CD4+T-cells count was 627.5 cells/ml, 64.2% presented more than 350 CD4+T-cells/ml and 47.3% had ≤200 RNA-copies/ml. Most (97.3%) were ART experienced receiving Highly Active ART (HAART) (84.8%). Resistance prevalence among pretreated was 50.9%, 76.9% and 36.5% for Protease Inhibitors (PI), Nucleoside Reverse Transcriptase Inhibitors (NRTI) and Non-NRTI (NNRTI), respectively. Resistance mutations were significantly higher among transferred patients compared to non-transferred for the PI+NRTI combination (19%
Despite a good immunological and virological control before transfer, we found high levels of resistance to PI, NRTI and triple drug resistance in HIV-1 infected adolescents transferred to adult units.
By the end of 2010, of the 34 million people living with human immunodeficiency virus (HIV), there were 3.4 million children below the age of 15 years
Due to the expanded access to highly active antiretroviral treatment (HAART) and prevention efforts in HIV testing, prenatal care, formula feeding, elective Caesarean and pregnancy monitoring
In developed settings with access to HAART, perinatally acquired HIV-1 infection has become a chronic disease of childhood with increasing numbers of adolescents surviving to adulthood and transitioning from pediatric to adult services. Perinatally infected adolescents have been heavily pretreated, have a long history of treatment with many switches and variable levels of adherence to the treatment have been reported. Sub-optimal treatments and non-complete compliance can increase the prevalence of drug resistance mutations in HIV thus, compromising the success of present and future treatment options.
Successful transition to adult services has become a necessity in these heavily pretreated patients. Teenagers growing up with HIV/AIDS have common problems related to social difficulties and to side-effects of HIV and HAART which play an impact on their growth and development. The objectives of this study were to describe the demographic and clinical features, antiretroviral therapy (ART) history, antiviral drug resistance and susceptibility to drugs in HIV-1 perinatally infected adolescents transferred to adult units in Spain from the Madrid Cohort of HIV-1 infected children.
Since the beginning of the HIV epidemic in Spain, a total of 534 patients have been registered in the Madrid cohort of HIV-infected children established in 2003. By the end of December 2011, 175 of them still remained under clinical follow-up in pediatric units, 112 had been transferred to adult units, 62 had been lost to follow-up and 185 had died. In this study we selected the 112 patients from the cohort that had reached adolescence and been transferred to adult units in 8 public hospitals from 1997 to December 2011. Clinical and epidemiological features of all transferred patients were recorded from the database of the cohort.
An additional cohort of HIV-1 infected patients was used to compare results on drug resistance and drug sensitivity. The selected cohort consisted of the HIV Madrid cohort of non-transferred perinatally infected patients previously described
This study was part of a project approved by the review board of the Hospital Universitario Ramón y Cajal Clinical Research Ethical Committee. It was designed to protect the right of all subjects involved under the appropriate local regulations. To maintain subject confidentiality, a unique number was assigned to each specimen, and written consent obtained for each patient by clinicians.
For the drug resistance study, we selected those transferred patients according to
Previously reported genotypes were performed from infected samples (immortalized DNA, plasma or peripheral blood mononuclear cells, PBMCs) kindly provided by the HIV BioBank integrated in the Spanish AIDS Research Network (RIS)
The prevalence of transmitted drug resistance among naïve patients was defined according to the list of mutations for Transmitted Drug Resistances (TDR) surveillance, as recommended by the WHO
Prevalence was expressed in percentage with a 95% confidence interval (CI). CI tests were performed with Epidat 3.1 (Pan American Health Organization). Statistical significance was set at p<0.05.
A total of 112 patients of the Madrid cohort of HIV-infected children transferred from pediatric services to adult units in different hospitals in Madrid between 1997 and December 2011 were selected for this study. Baseline characteristics of the non-transferred (n = 131), total transferred (n = 112), and transferred patients with available genotypic profile (n = 63) are summarized in
Features | Non-transferred n = 131 | Transferred n = 112 | Transferred with genotype |
[n (%)] | [n (%)] | [n (%)] | |
Adopted | 31 (23.7) | 14 (12.5) | 8 (12.7) |
Female gender | 76 (58) | 60 (53.6) | 34 (54) |
Median age until diagnosis (years) | 0.5 | 2 | 1.4 |
Non-B variants prevalence (%) | 11.6 | – | 1.9 |
|
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Caucasian | 100 (76.3) | 98 (87.5) | 59 (93.6) |
Hispanic | 6 (4.6) | 4 (3.5) | 2 (3.2) |
Romani | 4 (3.1) | 3 (2.7) | 1 (1.6) |
African |
18 (13.7) | 2 (1.8) | – |
Other | 2 (1.5) | 2 (1.8) | 1 (1.6) |
Unknown | 1 (0.8) | 3 (2.7) | – |
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Europe | 112 (85.5) | 105 (93.7) | 61 (96.8) |
North America | 1 (0.8) | – | – |
South and Central America | 8 (6.1) | 5 (4.5) | 2 (3.2) |
North Africa | 2 (1.5) | – | – |
Sub-Saharan Africa | 7 (5.3) | 2 (1.8) | – |
Asia | 1 (0.8) | – | – |
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1985–1989 |
1 (0.8) | 31 (27.7) | 16 (25.4) |
1990–1994 |
37 (28.2) | 60 (53.6) | 39 (61.9) |
1995–1999 |
54 (41.2) | 18 (16) | 7 (11.1) |
2000–2004 |
28 (21.4) | 3 (2.7) | 1 (1.6) |
2005–2009 | 10 (7.6) | – | – |
Unknown | 1 (0.8) | – | – |
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Perinatally | 127 (96.9) | 105 (93.7) | 61 (96.8) |
Transfusion | 3 (2.3) | 5 (4.5) | 2 (3.2) |
Unknown | 1 (0.8) | 2 (1.8) | – |
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1997–1999 | – | 3 (2.7) | – |
2000–2002 | – | 9 (8) | 1 (1.6) |
2003–2005 | – | 27 (24.1) | 13 (20.7) |
2006–2008 | – | 33 (29.5) | 21 (33.3) |
2009–2011 | – | 40 (35.7) | 28 (44.4) |
|
Mean 10% | Mean 11% | |
<15% | 67 (51.1) | 75 (67) | 43 (68.3) |
15–24% | 42 (32.1) | 24 (21.4) | 13 (20.6) |
≥25% | 19 (14.5) | 13 (11.6) | 7 (11.1) |
Unknown | 3 (2.3) | – | – |
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<200 |
35 (26.7) | 64 (57.1) | 31 (52.4) |
200–499 | 63 (48.1) | 37 (33) | 26 (38.1) |
≥500 |
30 (22.9) | 11 (9.9) | 6 (9.5) |
Unknown | 3 (2.3) | – | – |
Origin of patients by country: Spain (n = 103), Portugal (n = 1), Romania (n = 1), Honduras (n = 2), Argentina (n = 1), Mexico (n = 1), Peru (n = 1), Cape Verde (n = 1), Equatorial Guinea (n = 1).
Transferred to adult units with available resistance genotyping profile.
Statistical differences (p<0.05) have been found between transferred and non-transferred patients for these features. HIV-1 non-B variants include HIV-1 non-B subtypes and recombinants.
Advanced stages of immunosuppression were observed as a result of the long term infection and scarce effective antiretroviral availability before 1996. Over two thirds of transferred patients reached less than 15% CD4+ cell counts and half (57.1%) reached <200 cells/mm3. The mean nadir CD4+ T-cells count was 10%. Monotherapy was the first ARV treatment in 59.8%, mainly with AZT (79.1%), 23.2% started with combined therapy (including AZT backbone in 88.4% of them) and only 14.3% with HAART.
In the transferred cohort compared to the non-transferred, a statistical significant lower number of African patients were found (1.8%
Characteristics of the study population at the time of transfer to adult units are shown in
Features | Non-transferred n = 131 | Transferred n = 112 | Transferred with genotype |
|
14.7 | 18.9 | 18.5 |
|
1 (0.8) | 5 (4.5) | 2 (3.2) |
|
12 (4.5) | 11.5 (4.8) | 13.5 (4.1) |
|
13.2 (5.2) | 15.6 (4.5) | 16.7 (3.6) |
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1 | 8 (6.1) | 4 (3.6) | 2 (3.2) |
2 | 41 (31.3) | 31 (27.7) | 18 (28.5) |
3 | 79 (60.3) | 75 (66.9) | 43 (68.3) |
Unknown | 3 (2.3) | 2 (1.8) | - |
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N | - | 2 (1.8) | 1 (1.6) |
A |
49 (37.4) | 26 (23.2) | 14 (22.2) |
B |
35 (26.7) | 45 (40.2) | 23 (36.5) |
C | 43 (32.8) | 39 (34.8) | 25 (39.7) |
Unknown | 4 (3.1) | - | - |
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<15% | 3 (2.3) | 6 (5.4) | 3 (4.8) |
15–24% | 18 (13.7) | 26 (23.2) | 15 (23.8) |
≥25% |
105 (80.2) | 74 (66) | 43 (68.2) |
Unknown | 5 (3.8) | 6 (5.4) | 2 (3.2) |
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Mean 770.5 cells/ml | Mean 627.5 cells/ml | Mean 654 cells/ml | |
≤200 | 3 (2.3) | 4 (3.6) | 1 (1.6) |
201–350 | 6 (4.6) | 7 (6.3) | 5 (7.9) |
351–500 | 13 (9.9) | 10 (8.9) | 4 (6.4) |
>500 |
99 (75.6) | 62 (55.3) | 36 (57.1) |
Unknown | 10 (7.6) | 29 (25.9) | 17 (27) |
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≤20 |
41 (31.3) | 12 (10.7) | 9 (14.2) |
21–50 | 44 (33.6) | 31 (27.7) | 23 (36.5) |
51–200 | 10 (7.6) | 10 (8.9) | 4 (6.4) |
201–500 | 7 (5.3) | 10 (8.9) | 2 (3.2) |
501–1,000 | - | 4 (3.6) | 3 (4.8) |
1,001–10,000 | 12 (9.2) | 19 (17) | 9 (14.3) |
>10,000 | 13 (9.9) | 16 (14.3) | 11 (17.4) |
Unknown | 4 (3.1) | 10 (8.9) | 2 (3.2) |
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Drug naive | 1 (0.8) | 3 (2.7) | 2 (3.2) |
PI-experienced | 116 (88.6) | 95 (84.8) | 54 (85.7) |
NRTI-experienced |
130 (99.2) | 106 (94.6) | 59 (93.6) |
NNRTI-experienced | 99 (75.6) | 81 (72.3) | 47 (74.6) |
FI-experienced | - | 3 (2.7) | 1 (1.6) |
InI-experienced | - | 1 (0.9) | 1 (1.6) |
PI+NRTI+NNRTI-experienced | 88 (67.2) | 72 (64.3) | 42 (66.7) |
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HAART |
124 (94.6) | 95 (84.8) | 54 (85.7) |
Stopped-treatment | 3 (2.3) | 11 (9.8) | 6 (9.5) |
Naive | 1 (0.8) | 3 (2.7) | 2 (3.2) |
Monotherapy | 1 (0.8) | ||
Combined | 2 (1.5) | 3 (2.7) | 1 (1.6) |
SD, standard deviation; ART, antiretroviral therapy; PI, protease inhibitors; NRTI, nucleoside reverse transcriptase inhibitors; NNRTI, non-NRTI; FI, fusion inhibitors, InI; integrase inhibitors.
Transferred to adult units with available resistance genotyping profile.
Statistical differences (p<0.05) have been found between transferred and non-transferred patients for these features.
Comparison among transferred and non-transferred patients by December 2011 revealed that transferred patients had a worst immunological-virological profile comparing to the non-transferred group. A lower number of transferred patients were categorized in clinical status A (23.2%
The transferred cohort started any type of ART with a median age of 5.6 years (SD 3.5 years) and the median duration of ART was 11.5 years (SD 4.8 years). Only 3 (2.7%) of the 112 transferred individuals remained drug naïve at transfer and the rest (97.3%) were ART experienced. Most (84.8%) were receiving HAART, 9.8% had stopped treatment and 2.7% were receiving combined therapy at the transfer time according to clinical reports. The most commonly used HAART combinations in our cohort were 2NRTI+1NNRTI (32.6%) and 2NRTI+1PI (28.4%). The pretreated patients presented a long treatment history and had experienced several different ART combinations; the mean number of regimens was five, with at least 3 HAART regimens in 48% of them. The main ART families were NRTI, PI and NNRTI, 94.6%, 84.8%, and 72.3% respectively (
Among the 112 patients transferred before the end of December 2011, only in 63 (56.2%) subjects drug resistance genotypes could be analyzed. Among them, in 48 (76.2%) cases the
Among the 63 transferred patients of the Madrid cohort of HIV-infected children with available
Global resistance prevalence among the 58 transferred ARV-exposed pretreated patients with available
Transferred patients |
Non-transferred children |
|
Patients with available PR | 51 | 125 |
Patients with available RT | 52 | 116 |
Prevalence of drug resistance mutations (%) [95% CI] |
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Global (to any class) | 81.0 [70.1–92] | 69.5 [61.2–77.7] |
To PIs | 50.9 [36.3–65.7] | 36.8 [27.9–45.7] |
To NRTIs | 76.9 [64.5–89.3] | 62.1 [52.8–71.3] |
To NNRTIs | 36.5 [22.5–50.6] | 40.5 [31.2–49.9] |
To NRTI+NNRTI | 12.1 [2.8–21.3] | 12.2 [6.2–18.2] |
To PI+NRTI |
19 [8–29.9] | 8.4 [3.3–13.5] |
To PI+NNRTI | – | 0.8 [0.02–4.2] |
To PI+NRTI+NNRTI | 17.3 [6.7–27.8] | 17.6 [10.7–24.5] |
Selected patients from the Madrid cohort of HIV-1 infected children that have been transferred to adult units by December 2011.
Pretreated patients selected from the Madrid cohort of HIV-1 infected children excluding those transferred to adult units.
Prevalence of drug resistance mutations was determined following the IAS-USA 2011 list
Statistical difference (p<0.05) has been found between transferred and non-transferred patients for this feature.
Besides assessing the global prevalence of DRM in the 58 pretreated patients of the transferred cohort, prevalence of DRM was also compared to the non-transferred cohort. The first included the 58 transferred and pretreated patients with available genotypic data compared to the 131 non-transferred pretreated pediatric patients from the Madrid cohort of HIV-1 infected children (
Transferred patients tended to present higher DRM prevalence when compared to non-transferred children (
Resistance level was estimated according to the HIVdb Interpretation Algorithm (Stanford University, Palo Alto, CA, USA)
Most (98.1%) of the transferred patients were infected by subtype B, the most prevalent HIV-1 variant in North America and Western Europe, including Spain
Due to the low number of new cases of HIV infection caused by MTCT in developed countries
Features of the transferred patients from the Madrid cohort of HIV-1 infected children have been scarcely studied
The emergence of drug resistance due to incomplete viral suppression and incomplete adherence are the major obstacle for an effective ART
Interestingly, DRM prevalence to all 3 drug classes among transferred patients was higher than for non-transferred infected children. This fact could be caused by regimen switches due to therapeutic failure or because of the availability of new drugs during the infection period. As a consequence of their long treatment history and the treatment switches they have experimented, 81% of the patients transferred to adult units harboured resistant virus to at least one of the drug classes, higher than in non-transferred children (69.5%) mainly for NRTI, the first available drug class for clinical use, and for PI. This high rate of resistance could have compromised the susceptibility found in our data from both the PI and NRTI families.
In fact, the pediatric population (transferred and non-transferred) infected by viruses carrying triple resistance mutations was significantly higher than in pretreated adults from Madrid (17%
Treatment failure in children during ART is frequent, develops fast and with more extensive drug resistance than in adults, leading to detectable viral loads and immunological damage
Epidemiological differences related to the nature of HIV-1 infecting variants were found between the non-transferred cohort of HIV infected children (11.4%) and with those transferred to adult units (1.9%). Pediatric patients that reached adulthood and were transferred to adult units were mainly infected by subtype B (98.2%). This fact is explained by the long term infection of our patients (mean age of 18.9 years), reflecting the local epidemiological situation in Spain at the time in which circulating variants other than B had not yet been detected in Spain.
Previous studies in the Madrid cohort of HIV-1 infected children and adolescents reported a non-B prevalence of 10%
Understanding the progress of HIV-1 infected children through pediatric care until they reach adolescence in developed countries could help to improve and plan adequate clinical and psychological transitioning services for the HIV-1 infected children that will reach adolescence
We thank all the members of the Madrid cohort of HIV-infected children: Navarro ML, Delgado R, Martín-Fontelos P, Guillén S, Martínez J, Roa MA, Beceiro J, Blázquez D, Fernández-Silveira L, Medín G, Rojo P, Prieto L, García-Hortelano M, Jiménez B, Calvo C, Rubio B, Gonzalez-Granado I, Bellón-Cano JM, Penin-Antón JM, García I and Medin G.