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Systematic review of retention of pediatric patients on HIV treatment in low and middle-income countries 2008–2013

Fox, Matthew P.a,b,c; Rosen, Sydneya,c

doi: 10.1097/QAD.0000000000000559
EPIDEMIOLOGY AND SOCIAL
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Objectives: There are several published systematic reviews of adult retention in care after antiretroviral therapy (ART) initiation among adults, but limited information on pediatric retention.

Design: Systematic review of pediatric retention on ART in low and middle-income countries during 2008–2013.

Methods: We estimated all-cause attrition (death and loss to follow-up) and retention for pediatric patients receiving first-line ART in routine settings. We searched PubMed, Embase, Cochrane Register, and ISI Web of Science (January 2008–January 2014) and abstracts from AIDS and IAS (2008–2013). We estimated mean retention across cohorts using simple averages; interpolated any time period not reported to, up to the last period reported; summarized total retention in the population using Kaplan–Meier survival curves; and compared pediatric to adult retention.

Results: We found 39 reports of retention in 45 patient cohorts and 55 904 patients in 23 countries. Among them, 37% of patients not retained in care were known to have died and 63% were lost to follow-up. Unweighted averages of reported retention were 85, 81, and 81% at 12, 24, and 36 months after ART initiation. From life-table analysis, we estimated retention at 12, 24, and 36 months at 88, 72, and 67%. We estimated 36-month retention at 66% in Africa and 74% in Asia.

Conclusion: Pediatric ART retention was similar to that among adults. There were limited data from Asia, only one study from Latin America and the Caribbean, and no data from Eastern Europe, Central Asia, or the Middle East.

aCenter for Global Health & Development, Boston University

bDepartment of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA

cHealth Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Correspondence to Matthew P. Fox, Crosstown Center, 3rd Floor, 801 Massachusetts Ave, Boston, MA 02118, USA.Tel: +1 617 414 1270; e-mail: mfox@bu.edu

Received 19 June, 2014

Revised 28 November, 2014

Accepted 3 December, 2014

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).

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Introduction

While the success of programs for prevention of mother-to-child transmission of HIV has meant that fewer children are being infected over time, a substantial number of children are still being born infected or are infected after birth through breastfeeding. The WHO estimates that under 300 000 children were newly infected with HIV in 2012, down from a high of over 500 000 in the early 2000 [1]. With current treatment guidelines recommending earlier treatment for HIV-infected children [2], substantial resources will continue to be needed to be invested in pediatric HIV care and treatment programs over the coming decades. For children who initiate antiretroviral therapy (ART), treatment has been demonstrated to be highly effective, with substantially increased survival, in particular when treatment is started early [3–6].

Retention in HIV care both before and after treatment initiation has received a great deal of attention in recent years [1]. For ART programs to achieve long-term success, both mortality and loss to follow-up, for any reason, must be minimized. In two reviews up to 2009 of retention in care of adult patients in sub-Saharan Africa, which were conducted in 2007 [7] and 2010 [8], we found that overall retention in care at 24 months averaged 60–75%. These reviews excluded children for two main reasons: we suspected that factors influencing retention in pediatric treatment programs differ from those affecting adult retention; and, more practically, few reports on pediatric retention had been published at the time of those reviews.

Realizing that retention in adult treatment programs was poorer than expected led many researchers to investigate pediatric retention as well. The result has been a small flurry of papers published since 2008 that consider this issue amongst children. With data now available, we conducted a systematic review of retention in pediatric ART programs in all low and middle-income countries (LMICs) to help policy makers and program managers make informed decisions about pediatric treatment program design and resource allocation and provide other researchers with estimates of pediatric retention that were drawn from all available data.

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Methods

We conducted this analysis of pediatric ART retention as a component of a broader systematic review of retention in all populations in LMICs. As with our previous reviews, we sought to estimate attrition (defined as death and loss to follow-up) and retention for patients receiving first-line ART in routine service delivery settings in World Bank defined LMICs. For this analysis, we included any cohorts where the reported mean or median age was below 18 years. When possible, we excluded transfers to other treatment sites from both the numerator and denominator of our estimates, as the outcomes of patients who transfer care are unknown. Patients who stopped treatment but remained in care were counted as retained.

We included observational studies describing retention in HIV treatment programs published in 2008 or later. We included cohorts receiving standard first-line ART at any type or level of facility that followed prevailing national treatment guidelines. We excluded clinical trials, intervention evaluations, and studies that provided care that patients would not have received under usual care. We included standard-of-care arms from studies evaluating interventions in nonrandomized trials.

When multiple reports described a single cohort of patients, we chose the one with the most complete data and/or the longest duration of follow-up. If a report provided data on multiple cohorts, we included it only if the data could be stratified by country and there was no other report of any of the cohorts individually. If such a report disaggregated the data by cohort, only cohorts that were also reported in other sources were excluded, whereas the remaining cohorts were included. We required the report follow patients from ART initiation to a mean or median of at least 6 full months of follow-up. Studies had to report or provide enough information to estimate all-cause attrition (death and loss to follow-up) for one or more of the following endpoints: 6, 12, or 18 months, or a later 12-month interval after treatment initiation. We placed no restrictions on how a cohort assessed mortality among patients lost.

To identify studies, we searched PubMed, Embase, the Cochrane Register, and ISI Web of Science from 1 January 2008 to 28 July 2013. We searched conference abstracts from AIDS and IAS conferences from 2008 to 2013. We did not search the Conference on Retroviruses and Opportunistic Infections as its website archives were unavailable. We did not review data from prior to 2007 as so much has changed in the care and treatment of pediatric HIV patients since then that we believed the data would not be relevant to current policy debates on how to address retention in care.

Within each index, we combined ‘antiretroviral’ and any of ‘Africa’/’Asia’/’Central America’/‘Mexico’/'South America’/’Middle East’/’Eastern Europe’/’Caribbean Region’, with any of the following: ‘retention’/’attrition’/’adherence’/‘mortality’/’loss to follow-up’/’efficacy’/or ‘evaluation’. Conference abstracts were searched using ‘attrition,’ ‘retention’, or ‘loss to follow-up’.

We then conducted three secondary searches. First, to capture journals that are not Medical Subject Headings (MeSH)-indexed, we searched again in PubMed, substituting region names with individual country names for all LMICs for which we did not initially include at least two adult or pediatric cohorts. Second, we searched PubMed to determine if any conference abstracts identified in the primary search had been published as full-text articles. Finally, we repeated each search in PubMed for the period from 1 August 2013 to 9 January 2014, when the database for the search was closed.

M.F. supervised the search that was performed by two graduate research assistants, as well as determination of eligibility. After excluding those whose titles were not relevant, abstracts were read to determine eligibility. Full-text articles were then reviewed to confirm eligibility. S.R. confirmed the eligibility of sources for inclusion, and uncertainties were resolved through consensus of both authors.

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Statistical analysis

We defined retention in care as follows: for cohorts reporting retention to a particular time point (either as a proportion or Kaplan–Meier estimate), retention at each point was defined as the cohort's report of all cause retention; for cohorts that did not report retention at specific time points, but provided data on the number of patients lost and who died, we defined retention as the proportion alive and in care and assigned this estimate to the time closest to the median follow-up. We accepted each report's own definition of loss to follow-up.

For analysis, countries were grouped into four regions: Africa (including North Africa); Asia (including Pacific island states and the Middle East); Europe and Central Asia (ECA); and Latin America and the Caribbean (LAC) (including South and Central America and Caribbean island states).

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Analysis of retention proportions as reported

We estimated mean retention across cohorts using simple averages unweighted by sample size. As each cohort reported to different time periods, we also interpolated any time period not reported to, up to the last time period reported. For example, if a cohort reported 12 and 24-month retention, we interpolated 6 and 18-month retention, assuming a linear decline between the two points. To look for potential reporting bias, we plotted the mean values of retention over time by period reported to, weighted by its sample size. This allowed us to assess whether cohorts reporting to longer time periods were more likely to report higher retention at earlier time periods than cohorts that reported to shorter time periods. We also conducted a linear regression of retention at 12 and 24 months by cohort level factors, but as no important or significant associations were identified, we do not present these results.

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Meta-analysis of retention rates

To synthesize the data, we conducted a meta-analysis stratified by last time period reported to. We plotted each retention estimate and its 95% confidence interval (CI) in a forest plot and combined estimates using a random-effects regression with a Freeman and Tukey arcsine transformation [9]. We then created a patient-level dataset for each study with all attrition occurring at the time period attrition was reported. We then summarized total retention using Kaplan–Meier survival curves and estimated retention at each time period using life-table analysis. We do not report CIs for this specific set of estimates as the sample size creates misleadingly narrow intervals.

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Sensitivity analysis

We then plotted mean retention by last time period reported to assess whether cohorts reporting to longer time periods were more likely to report higher retention at earlier time periods than cohorts that reported to shorter time periods. To suggest upper and lower bounds on true retention rates given the varying time periods reported to, we conducted a sensitivity analysis to consider the best and worst case scenarios for retention. In the best-case scenario, we assume no additional attrition from the last period reported to through 60 months. In the worst-case scenario, we assumed retention continued along the same linear trend to what was observed between baseline and the last time period reported to.

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Results

Our primary search for the overall review (all populations) identified 3517 potentially relevant articles and 6846 abstract citations. Our secondary search added 1236 more citations. Of these, 39 sources met the inclusion criteria for this analysis of pediatric retention (30 articles, 9 abstracts) (Appendix 1, http://links.lww.com/QAD/A624). The citations reported on 55 904 patients enrolled in 45 separate cohorts, as described in Table 1. The various definitions used by each cohort are provided in Appendix 2 (http://links.lww.com/QAD/A624).

Table 1

Table 1

The eligible studies came from 23 countries in three of the four regions: 17 from Africa (37 cohorts), five from Southern and Eastern Asia (7 cohorts), and one from Latin America and the Caribbean (LAC) (1 cohort). No study was reported from Europe or Central Asia, so this region will not be included in further analysis. Because we only found one cohort from Latin America and the Caribbean, disaggregation by region will include only Africa and Asia. Most cohorts (82%) were from Africa. Within Africa, 32% of the cohorts, and just over one-quarter of all cohorts in the review, were from South Africa. The distribution of individual patient numbers was not quite as skewed: South Africa contributed just over 13 000 patients, or 27% of the total from Africa, but Kenya and Mozambique were also well represented, with 8000–9000 patients (17–19%) each. In Asia, two cohorts each were identified from Thailand and Vietnam, with Thailand contributing half of all participants from Asia.

The average patient age was 5.2 years at ART initiation. There was no evidence of a trend toward starting ART at younger ages over calendar time; average age at initiation was between 5 and 8 years in every year from 2002 to 2009. The average CD4+ percentage at initiation was 12.7%. About half of the patients were female, with almost no variation by region. Most (60%) cohorts reported to less than 2 years after ART initiation (n = 24).

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Retention on antiretroviral therapy

Table 2 details the proportion of patients who died or were lost to follow-up from each cohort by the end of that cohort's follow-up period. For cohorts that reported both deaths and losses to follow-up (n = 33), a simple average (not weighted by cohort size) of 37% of all patients not retained in care were known to have died, whereas the remaining 63% were lost to follow-up.

Table 2

Table 2

Retention in care at each time period reported to, by country, is presented in Table 3, and Appendix 3 (http://links.lww.com/QAD/A624) illustrates retention rates and 95% CIs at 12, 24, and 36 months using forest plots. Simple average retention over time for select time points is plotted in Appendix 4 (http://links.lww.com/QAD/A624). Simple average retention rates with no interpolation of missing values across all regions averaged 85% at 12 months, 81% at 24 months, and 81% at 36 months. Because different cohorts reported to different time periods, however, retention can increase over time as happens at months 12 and 24 for Asian cohorts. Reported retention rates were higher at later time periods in Asia compared to Africa.

Table 3

Table 3

To assess publication bias, we plotted weighted average attrition rates stratified by last time point reported to. As Appendix 5 (http://links.lww.com/QAD/A624) shows, studies with shorter periods of follow-up also reported higher attrition at any given time point than did studies with longer follow-up. Studies reporting only to 12 months, for example, retained an average of 85% of their patients at 12 months, whereas those reporting to 36 months retained an average of 90% of their patients at 12 months, suggesting that actual retention at later time points would be lower than the averages shown, had all studies followed their cohorts to those later time points.

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Meta-analysis of antiretroviral therapy retention

To pool the data from all time points, we plotted Kaplan–Meier survival curves using the interpolated data by age group and region, as shown in Fig. 1a–c. We regard these as our most accurate estimates of retention, as they take into account the different time periods that studies reported to. Using life-table analysis, we estimate that 1, 2, and 3-year retention rates at 88, 72, and 67%, respectively, similar to what we observed in adults, for whom our estimates for the same time periods were 83, 74, and 68%, respectively [49]. Estimates for the pediatric cohorts did vary by region, with 3-year retention averaging 74% in Asia and 66% in Africa.

Figure

Figure

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Sensitivity analysis

Because of the potential for publication bias identified above, simple averages at each time point may overestimate true retention in care. We thus also undertook a sensitivity analysis in which we modeled expected attrition under best-case and worst-case scenarios, and a midpoint scenario as the average of the two (Fig. 2). As we also see with adults, there is little variation among the three scenarios up to 24 months on ART. By 36 months, the difference widens, and it continues to expand for the duration of the period analyzed. The midpoint estimate of retention at 36 months is 71%. The worst and best-case estimates at the same time point are 66 and 77%, respectively. These estimates are slightly higher than those for adults, for whom we estimated midpoint, worst, and best-case retention at 36 months of 67, 62, and 72%, respectively.

Fig. 2

Fig. 2

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Discussion

This review of retention in care among pediatric patients included 55 904 patients from 45 cohorts in 23 LMICs between 2008 and 2013. It found that average retention in care across all the cohorts, using life-table analysis (our best estimate of overall programmatic retention), was 88, 72, and 67% at 12, 24, and 36 months after ART initiation. In a sensitivity analysis that estimated the best and worst-case scenarios for long-term outcomes, 36-month retention did not vary dramatically, ranging from 66% in the worst case to 77% in the best case. We did find some variation in retention across regions, with 36-month retention estimated by life-table analysis in Asia at 74% and only 66% in Africa.

There are no other reviews with which to compare our findings, but pooled pediatric cohorts from Africa and Asia have been published. In 2008, the Kids Antiretroviral Therapy in Lower Income Countries (KIDS ART-LINC) cohort reported outcomes from a pooled cohort of roughly 2400 children in sub-Saharan Africa who initiated ART in 2006 or earlier. They found that 2-year mortality and loss to follow-up was 6.9 and 10.3% respectively, summing to 2-year retention of 83%, which is somewhat better than our estimate of 72% at 24 months for African cohorts. Whether this difference reflects a worsening of retention over calendar time or is merely an artifact of the specific cohorts included in our review and in the pooled KIDS ART-LINC cohort is unclear. For Asia, in contrast, the Therapeutics Research, Education, and AIDS Training (TREAT) Asia Pediatric HIV Observational Database – a pooled cohort of 1655 children in seven Asian countries – reported 5% mortality and 4% loss to follow-up, or 91% retention at 12 months after initiation [3], at which point we estimated 97% for Asian cohorts. In both the TREAT Asia study and our review, however, attrition increased substantially in later years, with TREAT Asia reporting retention of 68% at 5 years after initiation, which is nearly identical to our life-table estimate of 67% at 5 years.

Retention rates for children appear very similar to those found in our recent review of adults in LMICs over the same time, among whom retention averaged 83, 74, and 68% at 12, 24, and 36 months, respectively [49]. Unlike for adults, however, we could not accurately estimate retention beyond 36 months due to the limited sample size. We identified only seven reports in this review that presented retention beyond 36 months, and only about 10 000 patients still in care beyond 36 months. Among adults, attrition is generally high in the first 1–2 years after treatment initiation; then it slows dramatically. Here, we see that same high rate of early attrition, but trends in later years are unclear. Both our review and the TREAT Asia study described above found continuing high rates of attrition in later years, whereas the KIDS ART-LINC cohort saw attrition fall dramatically from year 1 to year 2. Future research should aim for more long-term reports on pediatric outcomes, to help guide allocation of resources toward the time when retention support is needed most.

The reports included in this review were published between 2008 and 2013. Because of delays in publication, the data generally reflect cohorts that began enrolling in or after 2004 and ended in or before 2009. These data can thus serve as a baseline against which future research can measure the impact of changes in guidelines for care of pediatric patients. For example, in this review, the median age at initiation of therapy was 5 years. In 2010, the WHO, acting on the results of the Children with HIV Early Antiretroviral Therapy (CHER) trial [50], called for immediate initiation of treatment as soon as HIV was detected in pediatric patients [2]. It will be important to examine in future reviews if the median age at initiation drops as more countries enact this recommendation. Our review identified significant gaps in the literature about retention in care for pediatric patients. We identified only 39 studies eligible for inclusion, covering just 23 countries of the nearly 140 that fall into the low or middle-income categories. As with adults, we identified no study that met our inclusion criteria from the Middle East, Central Asia, or Eastern Europe, and only one from Latin America and the Caribbean. In addition, most of the cohorts in our review stopped enrolling in or before 2010. More studies from more countries, longer follow-up, and more recent data are needed to improve the validity and precision of estimates.

Unlike for adult attrition, when a substantial body of work has demonstrated that many patients who are lost to follow-up have either died or sought care at other facilities [51–54], very little empirical work has been done to investigate the true outcomes of pediatric patients who are lost follow-up. Studies tracing lost pediatric patients are needed to determine this. As such, the findings of any individual study included in the review are likely upper bounds on attrition, as some patients may be self-transfers (sometimes referred to as ‘silent transfers’) and would have been excluded from the analysis had we had more accurate data. At the same time, they are likely lower bounds on mortality, as some patients who are recorded as lost to follow-up would have been recorded as deaths had we had more accurate data. Still the high rate of attrition seen in pediatric cohorts is concerning given that pediatric disease progression tends to occur faster than for adults in the absence of treatment and therefore likely means that the distribution of mortality among those lost may be higher than in adults. Interventions to reduce attrition from pediatric care are urgently needed, as are studies that trace the true outcomes of lost pediatric patients.

In addition to the limited geographic coverage and small sample sizes of the studies included, this review has several limitations that should be kept in mind when interpreting the results. First, as for adults, we do find evidence of publication bias that may influence our results. Studies in our review which report to shorter time periods (e.g. 12 months) show worse retention at that time period than do studies that report retention at the same time period but then continue to follow patients for longer durations. This suggests that if studies that only report to shorter time periods were to report to longer time periods, overall attrition at later time periods would be lower than what we report. Second, meta-analyses like ours are susceptible to the influence of large cohorts. In this review, while there were no extremely large cohorts, we included several cohorts of over 5000 patients each, representing more than 10% of the entire study population. These studies can have undue influence on overall study results. We also note that our analysis excluded patients who transferred out of care. Transferring could be seen as a competing risk for attrition, and our estimates may have differed if transfer was considered a competing risk. The studies did not contain sufficient data on time to transfer to allow us to do this analysis, however. In addition, we did not have sufficient data to comment on whether the procedures used to prepare patients for ART influenced retention. Future studies should be encouraged to provide this information to allow assessment of its impact. Also, the studies reviewed each reported to differing time points and used different definition of loss to follow-up. Definitions of loss that use the date of dataset closure give patients time to become lost, but then return to care. This can artificially inflate retention estimates. Also we did not extract data in duplicate. This could have led to missing studies that could have been relevant. Finally, as with adults, mortality in observational cohorts is frequently under-reported and appears as loss to follow-up. Our results cannot accurately distinguish between patients who are lost and those who died, though this does not affect our primary outcome of total attrition from death or loss to follow up.

In conclusion, we found in this review of roughly 56 000 pediatric HIV treatment patients from 23 LMICs that retention in care was 88, 72, and 67% in the 12, 24, and 36 months, respectively, after ART initiation. Future efforts to estimate changes in retention over time would benefit from more cohorts that are representative of pediatric treatment populations throughout LMICs and longer duration of follow-up for existing and new cohorts.

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Acknowledgements

Author contributions: M.F. supervised the primary search and S.R. conducted the secondary searches. M.F. and S.R. conducted the primary analyses. M.F. drafted the initial manuscript and S.R. reviewed and edited it.

Funding: WHO, National Institutes of Health (K01AI083097), US Agency for International Development (AID 674-A-12-00029).

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Conflicts of interest

There are no conflicts of interest.

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                                    Keywords:

                                    antiretroviral therapy; attrition; HIV; loss to follow-up; low and middle-income countries; meta-analysis; pediatric; retention; systematic review

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