Background
The advent of antiretroviral therapy (ART) has reduced HIV-associated morbidity and mortality in HIV-infected individuals. The benefits of ART have been substantial in sub-Saharan Africa, home to over 90 % of children living with HIV/AIDS [
1]. Unfortunately, with the unprecedented scale-up of ART in resource-limited countries and the success of prevention of mother to child transmission (PMTCT) of HIV, pediatric HIV ART coverage still lags behind that of adults. At the end of December 2013, only 23 % of the 3.2 million children estimated to be living with HIV were receiving ART [
2]. The World Health Organization (WHO) recently revised its recommendation on when to start ART in children; ART should be initiated among all children (<10 years of age) and adolescents (10 to 19 years) living with HIV, regardless of WHO clinical stage or CD4 cell count [
3]. Based on this new recommendation, ART coverage in children living with HIV will increase sharply in the next couple of years.
Increase in ART coverage will exacerbate the existing challenges with laboratory monitoring of ART in resource-limited countries. In resource-rich countries, ART is monitored routinely with laboratory measures such as blood chemistry, HIV viral load, and CD4 count for early detection of medication side-effects and drug-resistant viruses [
4,
5]. The WHO recommendation for ART monitoring has evolved over time from CD4 monitoring every six months and viral load testing only when the capacity exists [
6] to viral load being recommended as the preferred monitoring approach to diagnose and confirm treatment failure [
3]. However, if viral load is not routinely available, CD4 count and clinical monitoring should be used to diagnose treatment failure [
3]. This compromise is due to the fact that routine laboratory monitoring is not feasible in most resource-limited countries due to cost, lack of technical expertise, and lack of infrastructure [
7]. Several studies from sub-Saharan Africa have reiterated the need for universal access to viral load monitoring of ART as clinical and immunologic monitoring of treatment failure are not sensitive enough [
8‐
12]. We recently reported that the rate of virological treatment failure after at least 24 weeks on first-line regimen was 16.7 % in our pediatric HIV cohort in Ghana [
13]. The virological treatment failure rate in HIV-infected children receiving ART in sub-Saharan ranges from 13 % to 44 % [
14‐
16].
In many resource-limited settings, clinicians rely on clinical and immunologic criteria to identify children failing first-line therapy. These criteria have low sensitivity and positive predictive value of detecting virological failure [
11,
17]. Thus without viral load monitoring of ART, HIV-infected children in sub-Saharan Africa may be at increased risk of staying on a failing first-line regimen and developing drug-resistant HIV variants [
18‐
20]. Viral load is therefore an essential complementary test to CD4 cell count [
21] in monitoring treatment. The question, therefore, is not whether to do viral load testing in resource-limited countries but what is the most cost-effective way of monitoring viral load. Routine viral load monitoring (every 3–4 months) in resource-rich countries over 20 years was found to have limited additional health benefit considering the cost [
22]. Taken together, there is a need to explore different cost-effective viral load measures such as less frequent, targeted, viral load measurements (based on clinical and immune response to ART) and cumulative viral load.
Given the grave consequences of virological treatment failure both at the individual and population level, we designed an exploratory prospective observational study of HIV-infected children receiving care at Korle-Bu Teaching Hospital in Accra, Ghana, to study biomarkers for monitoring ART in children [
13,
23]. The main objectives of the current study were: (1) to evaluate the association between cross-sectional viral load and frequency of morbidity while on ART; and (2) to explore whether cumulative viral load, measured as viremia copy-years (VCY) [
24], could predict morbidity in a setting where viral load is not routinely monitored.
Discussion
Forty-four percent of our study participants (62 of 140) had >4 log
10 VCY. Interestingly, only 6.5 % of the participants with >4 log
10 VCY were identified as meeting the WHO criteria for clinical and immunological treatment failures [
25]. Moreover, participants with >4 log
10 VCY had statistically significant increased outpatient encounters compared with participants with <4 log
10 VCY. We found poor sensitivity of clinical and immunologic assessments in determining treatment failure, consistent with other pediatric studies from sub-Saharan Africa [
8,
10,
11]. Taken together, our study validates the need for viral load monitoring as part of pediatric HIV care in resource-limited setting. Although implementation of viral load monitoring will continue to be constrained by budgetary and technical constraints in a resource-limited setting, there is an urgent need for innovative and cost-effective algorithms to include viral load monitoring for accurate and timely diagnosis of treatment failure.
We did not find statistically significant associations between cumulative viremia and frequency of opportunistic infections or hospitalizations during the study period. However, persistent viremia may have deleterious consequences with time. Interestingly, there are reports of an association between transient viremia and virological failure [
26‐
28], depletion of CD4+ T-cells [
29], and emergence of HIV drug resistant viruses [
30,
31]. The hallmark of HIV infection is progressive depletion of CD4 T-cells leading to development of opportunistic infections (OIs), AIDS, and death [
32]. HIV viral load has been found in several studies to be the main determinant of HIV disease progression [
4,
33‐
35]. In a resource-limited setting, the two immediate deleterious effects of persistent viremia will be virological treatment failure and evolution of HIV drug resistant variants. Since the reported sensitivity of clinical/immunological monitoring in detecting treatment failure is low, 29 %-33 % [
36], many of these children will continue to be on failing first-line regimens. Several studies have shown that delayed detection of virological failure to first-line therapy often leads to development of drug resistance, jeopardizing potential second-line treatments [
11,
37,
38].
There is a paucity of data on the use of VCY, a measure of cumulative viremia, in monitoring ART in HIV-infected children. Two earlier pediatric studies found no association between cumulative viremia and virological failure or drug resistance [
39,
40]. However, two recent studies reported findings consistent with our findings [
41,
42]. Thorvaldsson et al. reported that for every 10-fold increase in viremia copy-years, there was about 8.5-fold increase in the risk of morbidity and mortality among a cohort of perinatally HIV-infected children in New Haven, CT, USA [
41]. Rossouw et al. found that cumulative viremia in children on protease inhibitor (PI)-based ART was associated with development of PI resistant mutations [
42]. In HIV-infected adults, there are several reports of significant association between VCY and morbidity and mortality [
10‐
14]. Cole et al. reported that each log
10 increase in VCY was associated with 1.70-fold increased hazard of AIDS or death among HIV seroconvertors, independent of duration of infection, age, race, CD4 cell count, viral load set-point, peak viral load, or most recent vial load [
24]. The authors concluded that VCY is a better prognostic indicator of HIV disease progression than traditional single measures of viremia. Reports from other cohorts have reiterated that VCY is a better predictor of HIV all-cause mortality [
43‐
45]. Taken together, viral load monitoring irrespective of the approach taken is critical for any HIV program. Therefore, the WHO in 2013 recommended viral load monitoring as the preferred approach in evaluating treatment failure [
25].
The rationale for the new recommendation is to: (1) provide an early and more accurate detection of treatment failure and guide appropriate switch from first to second-line drugs to reduce the accumulation of drug-resistance mutations; and (2) help to differentiate between treatment failure and non-adherence [
46]. However, there are several challenges involved in implementing these recommendations in resource-limited settings including costs of the test, costs of second-line drug regimens, accessibility to centers who offer the tests, and lack of laboratory infrastructure [
47,
48]. For example, during our study period, we faced several occasions where there were no reagents to run viral load, breakdown of the equipment, technical problems, or power outages. These obstacles led to rescheduling patients for blood draws for viral load, and most patients subsequently failed to attend the rescheduled appointments due to lack of time or transportation. Despite the myriad of constraints in performing routine viral load monitoring in resource-limited settings, there is a need for countries to invest in innovative and cost-effective monitoring of HIV treatment. VCY may be a good alternate to routine viral load measurement or part of clinical/immunological criteria to improve sensitivity of detecting treatment failure. It also appears to be a good surrogate for persistent viremia, a determinant of HIV disease progression and non-AIDS-associated clinical events. To adopt VCY as part of treatment monitoring, there will be a need for studies to establish the “set-point” for VCY and how often to determine VCY. It may be possible to have multiple viral loads during the first year on therapy to determine one’s VCY “set-point” and thereafter the frequency could be personalized. Less frequent viral load determination might be cost-saving in the long-term.
Even though our study is one of the first studies to investigate the utility of VCY in monitoring ART in HIV-infected children, it has several limitations. First, this is a single tertiary center study and, therefore, one has to be cautious in generalization of our findings to all HIV care centers in resource-limited settings. Also, the small sample size limits the generalization of our findings. Moreover, viral load was not ascertained at regular interval so we could not adjust for transient viremia in the analysis. Due to periodic shortage of reagents or technical problems, viral load measurements were not available at each clinic visit or on scheduled dates. Since the viral loads were not uniformly missing at random among study participants we could not use any statistical test to account for data missing at random. Furthermore, data on adherence was not uniformly available in participants’ medical records so we could not model adherence in our analyses. Most of these limitations reflect the realities of carrying out observational cohort studies in a resource-limited setting. Our findings suggest potential utility of VCY in pediatrics, and this warrants further investigations in resource-limited settings.
Competing interest
The authors declare that they have no competing interest.
Author’s contributions
OK participated in the study design, data collection and analysis and drafted the manuscript. LR participated data collection and analysis and drafting of the manuscript. JP participated in the study design, data collection and analysis. OB participated in the study design, data collection and analysis. MP participated in the study design, data collection and analysis. JK participated data collection, coordination and analysis. XC participated in the design of the study and performed the statistical analysis. EP conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.