Immunovirological response to combined antiretroviral therapy and drug resistance patterns in children: 1- and 2-year outcomes in rural Uganda

Despite the progress made in the last few years, in 2009 only 356,400 of the estimated 2.5 million children currently infected with HIV were receiving combined antiretroviral therapy (ART) in low- and middle-income countries [1]. Ninety percent of children infected with HIV were living in sub-Saharan Africa and the ART coverage in this area was 26% [2]. In the absence of therapy, more than 50% of HIV-infected children die before the age of 2 years [3]. Therefore, there is an urgent need to increase access to treatment and care and to monitor the effectiveness of therapy.

Comprehensive evaluations of the effectiveness of generic fixed-drug ART in children come mainly from studies conducted in high-income countries [4‐8] and, to a lesser extent, from urban areas of resource-poor settings [9, 10]. Assessments conducted in rural, resource-limited settings, where programs face important challenges to provide pediatric HIV care, are needed to adapt and improve existing treatment strategies.

In this study, we evaluated pediatric care provision in an HIV/AIDS program in rural, northwestern Uganda. Specifically, we describe survival and program retention, and, among children alive and on ART, patient adherence to therapy and presence of antiretroviral (ARV)-related toxicity. Also presented are plasma non-nucleoside reverse transcriptase inhibitor (NNRTI) concentrations and CD4 and virological responses, including resistance patterns, observed in children with detectable HIV viral load.

Eighty-seven children had initiated ART 12 ± 2 months (M12 cohort), and 41 children 24 ± 2 months (M24 cohort), before the study inclusion period (Figure 1). Overall, 6 children died, 11 were LFU, and 9 transferred to another program. A total of 102 children (80% of M12 and 79% of M24) were still alive and receiving ART. Of these, 59 (M12) and 27 (M24) children, respectively, participated in the cross-sectional survey (11 patients could not be found and 5 were screened too late).

Of the 6 recorded deaths before the survey, 4 occurred within 6 months of treatment start. Median time to death was 2.3 months [IQR 1.7-7.8]. Probabilities of care retention were 0.91 (95% CI: 0.85-0.95) at 6 months and 0.86 (95% CI: 0.79-0.91) at both 12 and 24 months. Probabilities of survival among children not LFU were 0.97 (95% CI: 0.91-0.99) at 6 months, and 0.95 (95% CI: 0.88-0.98) at both 12 and 24 months.

In these two pediatric cohorts of children followed in rural Uganda, we found retention rates of 86% and sustained immunological responses 1 and 2 years after ART start. Nevertheless, virological responses were suboptimal, as only 59% of M12 and 33% of M24 children achieved HIV viral suppression, and resistant viral strains were found in 25% and 62% of children, respectively.

As in other sub-Saharan African cohorts [25‐28], all children followed in our program were enrolled and started therapy after the first year of life, median age at inclusion being 5 years old. Given that young, untreated children are at high risk of rapid disease progression and death before the age of 2 years [3, 29‐32], the overall impact of HIV/AIDS programs in children living in these settings is likely to be suboptimal. Thus, delay in diagnosis of pediatric HIV infection and lack of availability of integrated HIV care and treatment in maternal and child health services at the time of the survey were likely to be partly responsible for the late start of therapy in our site.

Furthermore, as in other pediatric cohorts in resource-limited settings [26, 27, 33, 34], children in our program started therapy at advanced clinico-immunological stage and the majority of deaths and LFU occurred early in treatment. Delayed diagnosis of HIV infection and failure to diagnose and treat concurrent life-threatening infections such as tuberculosis, pneumonia, or sepsis [35] might be responsible for the early losses reported. Starting ART before 12 weeks of life has recently been associated with a 76% reduction in child mortality compared to deferred therapy until immunological or clinical progression is diagnosed [36]. Therefore, some of the early losses in our cohort could have been prevented if ART was started earlier. Despite this, we observed overall high and sustained survival and retention rates in children treated with ART up to 2 years after therapy start. These findings are consistent with reports from other programs from resource-limited settings [10, 25, 37].

Although direct comparison of immunological responses across studies is not possible because of its high dependence on patient age [38], we observed significant CD4 T-cell responses to ART independent of the virological status of the patient, and, as previously reported [27, 28, 38, 39], greater increases were seen in the first than in the second year of therapy among children aged ≥5 years (gains of 206 vs. 132 cells/mm³).

The small sample size in our survey must be considered when interpreting these findings. The small numbers of patients did not allow investigating risk factors for virological failure. Estimates reported in other studies range from 49% in Abidjan, Côte d'Ivoire, to 80% in 63 children exposed to single-dose NVP in Durban, South Africa, at one year of therapy [9, 27, 40‐42]. In the urban studies in Côte d'Ivoire and South Africa, 49% virological suppression was reported at 2 years of ART [9, 27]. Large differences in virological response rates have been observed between clinical studies among children, and the majority showed lower rates than in adults [38]. Possible explanations for such discrepancies could be differences in patient characteristics at ART initiation, regimens used, pediatric dose formulations, drug pharmacokinetics, and/or inadequate compliance to treatment.

As mentioned before, most children in our cohort started treatment at an advanced stage of disease. Presence of high HIV RNA at therapy start has been associated with slower decay rates of plasma viral levels and longer time to reach undetectable viral levels [42‐45]. Increased risk of virological failure has also been reported in children with CD4 < 5% [40]. Our patients received NNRTI-based therapy, and most were given NVP. Higher rates of virological success have been shown in young patients treated with protease inhibitors than in those using NNRTI regimens in some [9] but not all studies [27, 46]. Furthermore, virological response has also been shown to vary in clinical studies using the same medication [38].

Ensuring adequate administration of ART to children is difficult and requires continuous dose adjustment in response to rapid changes in height and weight related to growth. In our cohorts, 1 in 4 children had subtherapeutic NVP plasma concentrations, especially children in the 20-30 kg weight range, highlighting the need for close monitoring of treatment, clear and simplified treatment guidelines, and availability of appropriate pediatric dose formulations.

Ensuring and maintaining good treatment adherence in children is also challenging, especially in resource-limited settings, since many children are orphans or live in difficult social situations: 1 in 5 patients were orphans in our study, and 43% had a caregiver other than a parent. Furthermore, palatable syrups or appropriate pediatric tablet formulations are expensive and not broadly available. In our study, 13% of children were identified as poorly adherent to ART, but this is likely to be underestimated since it was based on parental or caregiver reports. Four children with virological failure had wild-type virus and had therefore not been taking any treatment for some time. Furthermore, the prevalence of resistance mutations was relatively high but similar to those reported by a previous study in Côte d'Ivoire [26]. A recent review of studies investigating ART adherence in children treated in low- and middle-income countries identified difficult familial situations and low socioeconomic status, absence of parental and/or child HIV status disclosure, complicated regimens, and drug-related adverse events as barriers to treatment adherence [47, 48]. Age-adapted therapeutic education of children and extensive discussions and support to parents/caregivers need to be encouraged to improve ART uptake in this vulnerable group.

As reported by others [38, 49], we did not observe severe adverse drug reactions at the time of the survey, apart from one patient with severe neutropenia. However, 3 of 7 children reported gastrointestinal symptoms, which might interfere with drug absorption and affect treatment adherence [50]. Peripheral neuropathy and morphological disorders were not uncommon (38% and 21% of children, respectively). One longitudinal and one cross-sectional study also reported relatively high rates of lipodystrophy in children treated with d4T or protease inhibitors (29% and 33% of children, respectively), especially in those who started therapy at an advanced stage of disease [51, 52]. This syndrome is frequently associated with metabolic abnormalities such as hyperinsulinemia and dyslipidemia. However, its causal link to ART is to be established, and its long-term consequences for the treatment of children are unknown [52].

Important challenges need to be tackled to improve HIV pediatric care in resource-limited settings. These include increasing early HIV diagnosis through programs for the prevention of mother-to-child HIV transmission, training in pediatric clinical management and adherence counseling, and development of palatable and simplified pediatric drug formulations.