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Abstract
Objectives The goal of the authors was to determine the epidemiological and clinical characteristics of all HIV-positive children and adolescents infected by vertical transmission.
Methods A descriptive, cross-sectional and retrospective study was conducted that included all HIV-positive patients infected by vertical transmission who attended the referral services of the municipality of Campo Grande from 1993 to 2009, and who used antiretrovirals (ARV). The data were collected from medical records after local institutional review board approval.
Results 78 patients were included, and almost half of the living patients (75) in 2009 were 11–15 years of age. The average age at diagnosis was 38.8 months, treatment was most often initiated from 12 to 35 months of age, and HAART was the most common treatment. Most patients (51.3%) were hospitalised between one and five times, and the first regimen was not associated with hospitalisation (p=0.2). The majority of patients did not exhibit virological suppression at the last examination, and genotyping revealed the presence of resistance mutations. Failure of therapy was often the result of non-adherence to therapy. Five patients died, and the causes of death were pneumonia, sepsis, cerebral cryptococcosis and myocarditis.
Conclusions Despite the availability of drugs and appropriate laboratory tests, a significant number of paediatric patients were failing ARV therapy due to non-adherence. Further interventions to enhance adherence in this population are needed.
- AIDS
- paediatric
- antiretroviral therapy
- resistance
- children
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Introduction
Increasing rates of HIV infection among women favours perinatal infections.1 Due to Brazilian national guidelines, HIV-positive children were treated with dual therapy for many years, and this treatment often resulted in virological failure. In this article, we report the epidemiological, laboratory and therapeutic characteristics of HIV-positive patients infected by vertical transmission in Campo Grande, Brazil.
Materials and methods
This descriptive, cross-sectional and retrospective study included all HIV-positive patients infected by vertical transmission who used antiretrovirals (ARV) and attended the referral services of Campo Grande, State of Mato Grosso do Sul, Brazil, from 1993 to 2009. Patients were managed in longitudinal-care paediatric clinics. Paediatricians followed the updated Brazilian Ministry of Health guidelines for the management of HIV-infected children.
The data were collected from medical records after local institutional review board approval which waived the need for consent. Only hospitalisations related to immunological deficiency were considered.
ARV drugs including, protease inhibitors (PI), have been provided free of charge to Brazilian citizens through public pharmacies since 1997. Viral load (VL) and CD4 cell count testing became available in 1999, and the results presented are related to the first quantitative measure performed to evaluate HIV-positive patients. Resistance was evaluated using genomic sequencing of HIV, and this test became available in 2003. Only major classes of resistance were investigated.
Statistical analyses were performed using BioEstat version 5.0. The associations between variables were assessed using the χ2 test for trend.
Results
Ninety HIV-positive patients infected by vertical transmission were identified, and 78 were eligible for inclusion. Twelve patients were excluded because they did not use ARV therapy at any time between 1993 and 2009 despite having the indication and the access to treatment. The patient data are shown in table 1, and the medical records of one patient did not contain data about CD4 and viral load count.
Epidemiological, laboratory and therapeutic characteristics of HIV-positive patients infected by vertical transmission, Campo Grande—MS, Brazil, 1993–2009
The highest rates of vertical transmission were observed in 1997 (12/5.8%) and 1998 (16/7.6%). The age at diagnosis of HIV infection ranged from 2 to 132 months, with an average of 37.3 months (SD ±33.3 months) (95% CI 31.1 to 46.6).
Most HIV-infected patients initiated ARV therapy between ≥1 and <3 years of age (27/78, 34.6%) and required two ARV regimens (21/78, 26.9%). The maximum age at the start of ARV therapy was 11 years 6 months.
Initial ARV therapy consisted of one ARV agent as initial therapy in two of 78 patients (2.6%), two ARV agents in 37 of 78 patients (47.4%) and on highly active ARV therapy (HAART) in 39 of 78 patients (50.0%), most commonly non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens (26/78, 33.3%).
In 2009, 30 (40.0%) patients had been taking ARV for more than 10 years but only 10 of these had HIV RNA <50 copies/ml. Of the 20 patients who did not achieve a suppressed HIV RNA non-adherence accounted for 90.0%. The most common ART regimens were PI-based regimens (37/73, 50.7%), represented by zidovudine, lamivudine, lopinavir and ritonavir (13/37, 35.1%).
Forty patients (51.3%) were hospitalised between one and five times, and one patient (1.3%) was hospitalised 11 times. The average number of patient hospitalisations was 1.7±2.4 (±SD).
The viruses of 32/78 (41.0%) patients were submitted for genotyping, and 28/32 (87.5%) patients harboured viruses that exhibited resistance. These patients were 4 years old or younger at the time of ARV initiation; had been treated with ARV for more than 5 years; and had used four regimens or more.
The presence of thymidine analogue mutations were identified in 20 of the 27 patients: M41L (16/27), D67N (13/27), K70R (9/27), L210W (10/27), T215Y (15/27), K219Q (8/27), V75M (1/27), Q151M (2/27). The most frequent primary mutation to NNRTI was K103N (10/19), PI resistance mutations were M46I (6/21), L90M (6/21), V82A (5/21), and D30N (2/21). M184V mutations were observed in 15 children.
Of the five patients who died, three were male. The first patient died of bronchopneumonia and sepsis at the age of 5 years. At the time of death, his CD4 count and HIV RNA levels were 18 mm3 and 810 000 copies/ml, respectively. The second patient died of cerebral cryptococosis at the age of 11 years. At the time of death, his CD4 count and HIV RNA levels were 8 mm3 and 24 525 copies/ml, respectively. The third patient died of pneumonia and sepsis at the age of 10 years. At the time of death, her CD4 count and HIV RNA levels were 109 mm3 and 140 428 copies/ml, respectively. The fourth patient died of bronchopneumonia and sepsis at the age of 4 years. At the time of death, his CD4 count and HIV RNA levels were 1404 mm3 and 2 700 000 copies/ml, respectively. The fifth patient died of myocarditis at the age of 4 years. At the time of death, her CD4 count and HIV RNA levels were 2704 mm3 and 100 copies/ml, respectively. Treatment failure was observed in all five patients before they died.
Discussion
It has recently been recommended that all Brazilian children less than 1 year in age be treated regardless of clinical symptoms, immunological classification or HIV RNA counts. These recommendations differ from those of European countries.2 This is significant in light of our findings that a majority of children with vertically transmitted HIV who had been treated for at least 10 years with ARV did not achieve undetectable HIV RNA levels. The main reason for lack of viral suppression was non-adherence.
The baseline CD4 count of our patients was similar to that reported by other studies,3–5 whereas, the baseline HIV RNA was higher than that found by Resino et al.6
In this study, most children were initiated on HAART and used two drug regimens, and this was documented by other studies.4 ,5 ,7 Chearskul et al 8 reported that 67% of children starting ARVs were treated with mono or dual therapy.
Patients who were initiated on monotherapy were switched to treatment with dual therapy as soon as the government approved new ARV agents. Switching a patient to HAART was dependent on the patient's health status, and was not performed in response to the availability of medicines. Currently, the Brazilian National Guidelines recommend that the initial drug regimen for HIV-infected children consist of three ARV agents. The preferred regimens are 2 NRTIs (zidovudine and lamivudine) associated to one NNRTI (nevirapine to children less than than 3 years of age, and efavirenz to children more than 3 years of age). The alternative regimen is 2 RNTIs (zidovudine and lamivudine) associated to PI (lopinavir/ritonavir). Children co-infected with tuberculosis are indicated to initiate on zidovudine, lamivudine and abacavir.
ARV resistance testing was performed at various times in treatment-experienced patients who were failing therapy. The genotyping results of this study were similar to those reported by Machado et al 4 that found 90% of children harboured viruses with viral mutations. Bunupuradah et al 9 described lower ARV resistance.
Finally, the mortality rates in our case series were similar to that described by other investigators.2 ,5 ,8
ARV access has not been a problem in Brazil. However, CD4, HIV RNA and genotype testing became available subsequently. For many years, physician judgement was the single resource used to determine the best treatment for patients. Whether the availability of these tests will improve outcomes is not clear given that a significant number of paediatric patients being treated with appropriate ARV were failing therapy due to non-adherence. Further interventions to enhance ARV adherence among paediatric patients with HIV are needed.
Key messages
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Despite the success of antiretroviral prophylaxis in pregnant women, vertical transmission is still a reality.
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HAART is the best ARV treatment, and increases survival.
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CD4 count and viral load testing, genotyping and physician judgement are valuable resources that, when used together, improve treatment outcomes.
Footnotes
Competing interests None.
Ethics approval Ethics approval was provided by Institutional Review Board of Federal University of Mato Grosso do Sul.
Provenance and peer review Not commissioned; externally peer reviewed.