INTRODUCTION
To improve antiretroviral therapy (ART) coverage and help reach the UNAIDS 90-90-90 targets, differentiated approaches to care are necessary.1–3 3 4,5 6–9
There have been reservations about adapting DSD models such as MMP for children and adolescents living with HIV (ALHIV).10 2,10 11
In partnership with respective Ministries of Health, the Baylor International Pediatric AIDS Initiative (BIPAI) has centers of excellence (COEs) in 6 African countries. Our main objective was to evaluate the feasibility and describe 5-year patient outcomes among children and adolescents on ART who transitioned to MMP at the BIPAI COEs.
METHODS
Ethical Approval
The study protocol was approved, with waiver of the requirement for individual consent/assent, by relevant local Internal Review Boards (IRBs) in each country and by the IRB of Baylor College of Medicine, in Houston, TX.
Study Design, Population, and Eligibility
In partnership with respective Ministries of Health, BIPAI operates COEs in Botswana, Lesotho, Swaziland, Malawi, Uganda, and Tanzania (Mbeya and Mwanza). These COEs provide free, comprehensive HIV care for HIV-infected infants, children, and adolescents in alignment with national guidelines. We conducted an analysis of deidentified patient data from standardized electronic medical records at these 7 COEs in 6 African countries. This analysis included all patients aged 0–19 years who transitioned to MMP from January 1, 2003, to June 30, 2015.
MMP was introduced in each country in accordance with national policy. There were no established, standardized criteria across the clinical network to determine patient eligibility for transition to MMP. The decision to switch to MMP was made on an individual basis and varied by provider and facility. In general, patients were transitioned to MMP when deemed to be clinically stable and ART adherent, typically after 6–9 months of monthly prescriptions (MPs). Clinically stable was defined as improving CD4+ cell count/CD4% or viral load (VL) suppression, or minimal HIV-associated morbidity. Patients were considered ART adherent if the pill count was measured at 95%–105%. Patients receiving second-line ART regimens were also eligible for MMP.
ART regimens prescribed at each COE were in-line with contemporary local ART guidelines based on WHO guidance (Table 1 ). These guidelines generally recommended non-nucleoside reverse transcriptase inhibitor (NNRTI)–based regimens although lopinavir/ritonavir (LPV/r) became available for those <3 years in some countries, especially after 2014. Adherence measurement at each COE was mandated from 2008 onward and was assessed through pill count at each refill visit. CD4+ testing was typically conducted every 6 months contingent on availability of testing capacity. VL assessment became routine in most COEs from 2014 onward (Table 1 ) and was conducted annually in most countries. The exception to this was Botswana, which implemented routine VL measurements with the launch of its ART program in 2003, and conducted VL monitoring every 3 months.
TABLE 1.: National and COE Policies and Practices Related to First-Line ART, ART Dispensing Policy, and Routine VL
Patients were considered to have transitioned to MMP if they had 3 consecutive visits that occurred between 56 and 180 days of each other. The date of the first MMP-qualifying visit was the MMP start date. Patients who transitioned to MMP < 12 months before the end of the observation period, June 30, 2016, were excluded from the analysis. Patients were analyzed in the MMP group if they ever started MMP.
At all COEs except Lesotho, when a patient was moved to MMP, they received fewer clinical visits and extended ART refills (sufficient ART until their next scheduled appointment). In Lesotho, when a patient was considered stable, clinical visits were spaced beyond 1 month, but until 2016, they continued to return to the clinic monthly to pickup medication. During these monthly visits, they only saw a pharmacist (and received additional ART).
Variables and Definitions
Baseline characteristics included demographics (age and sex), WHO stage, age at ART initiation, and transition to MMP. Outcome measures were mortality, lost to follow-up (LTFU), ART adherence assessment, immunosuppression as measured by CD4+ , and VL. Mortality was determined by a chart status of “died,” and the date that the electronic chart was closed. If the status was “died” and the chart had not been closed, then the last visit date was used as the date of death. LTFU was determined by a chart status of “LTFU,” and the date the electronic chart was closed. If the status was “LTFU” and the chart was not closed, then the date after the most recent visit was used. In practice, a patient was classified as LTFU if he/she had not returned for any scheduled visit and could thereafter not be contacted or was unwilling to return for care. LTFU rates were calculated based on the number of patients whose chart status was “LTFU” within the timeframe of the examined visits. Transferred out was determined by a chart status of “transfer out.” In practice, a patient was classified as transferred out if it was documented that the patient transferred to other facilities for care. Patients on ART at their most recent clinic visit were classified as active.
Patients were classified as attaining acceptable immunological response or not, acceptable being CD4+ cell count >350 for patients aged 5 years or older and reaching CD4+ percentage >25% for children younger than 5 years. Patients were classified as having good adherence when the recorded pharmacy pill count was between 95% and 105%. VL measurements were categorized as suppressed or unsuppressed with suppressed defined as <400 copies per milliliter.
Statistical Analysis
All patient data were deidentified before analysis. Statistical analysis was performed using IBM SPSS Statistics 24 (IBM, Chicago, IL). In keeping with an intent-to-treat analysis, patients once allocated to the MMP group were maintained in that group for the duration of their follow-up, even if they subsequently reverted to MPs.
Patient characteristics were described using measures of central tendency [medians and interquartile ranges (IQRs) because they were non-Gaussian] if they were continuous (age at ART initiation, age at MMP initiation, ART duration, and MMP duration) and frequencies if they were categorical (sex, WHO stages, and patient status). In addition to description with medians, age at ART and MMP initiation were categorized and described using frequencies. Patient characteristics were described for the entire patient population and stratified by COE.
Survival analysis was performed to describe patient survival and LTFU. Five-year survival rates were estimated for all study patients and stratified by COE and age of MMP initiation. Kaplan–Meier (KM) curves were created for 5 years of MMP follow-up for the combined study population. Because LTFU patients may have died, separate survival curves were created for the patient status as categorized (only patients categorized as died are dead) and assuming the worst-case scenario that all LTFU patients also died. Right-censored categories included active, LTFU, and transferred out. In creating the survival curves, time to event (death and LTFU) was estimated from the date of MMP initiation to the date of chart closure or the date of last clinic visit if there was no date of chart closure. Time to right-censoring was estimated from the date of MMP initiation to the date of last clinic visit. KM curves for time to death were also stratified by COE, and age of MMP initiation and comparisons were made between survival using log-rank tests.
The frequencies of clinical outcomes (adherence, CD4, and VL) were evaluated over time using repeated-measures analysis. Outcomes were grouped into measures taken at 6-month intervals for adherence and CD4+ and 12-month intervals for VL. Because measures were not performed on all patients at exact 6- and 12-month intervals, measures taken closest to the 6- or 12-month intervals, but within 3-month to less than 9-month or 6-month to less than 18-month intervals, respectively, were used. Some patients did not have measurements for all 6- or 12-month intervals; the frequency of these missing values is described for each outcome as the number of patients tested divided by the number of patients followed at that follow-up interval.
For each outcome, the results are presented visually as outcome frequencies (acceptable immunologic response, ART adherent, and VL suppression) at baseline (MMP start) and 6- or 12-month intervals (depending on the outcome) up to 5 years of MMP, for all patients and stratified by COE and age group. Statistical comparisons were made using general estimating equations.
Sensitivity analysis was performed examining key outcomes between non-Lesotho and Lesotho COE patients. KM curves for time to death were stratified by non-Lesotho and Lesotho COEs, and comparisons were made between survival and LTFU using log-rank tests for all groups and stratified by at MMP initiation. Frequencies of VL suppression at baseline (MMP start) and 12-month intervals up to 5 years of MMP, for all patients, were stratified by non-Lesotho and Lesotho COEs.
RESULTS
Patient Characteristics
There was a total of 22,658 patients aged 0–19 years receiving ART and potentially eligible for inclusion in the analysis (Fig. 1 ). Of the 5245 patients who received MP but were not transitioned to MMP, 708 patients were LTFU and 870 died. Overall, 17,413 patients were transitioned to MMP, 14,932 of them between January 1, 2003, and June 30, 2015 (Table 2 ). The largest number of patients was enrolled in the Uganda COE (37.7%), followed by Malawi (16.5%), Botswana (13.2%), Lesotho (13.0%), Swaziland (9.6%), Mbeya, Tanzania (5.6%), and Mwanza, Tanzania (4.4%). The median age at ART initiation was 5.4 years (IQR: 2.0–9.6 years). Over the period of observation, patients took ART for a median of 5.8 years (IQR: 3.7–8.4 years). The median time on ART before transition from MP to MPP was 1.1 year (IQR: 0.4–2.5 years), and median age at transition was 7.5 years (IQR: 3.8–11.5 years). The median duration on MMP was 3.9 years (IQR: 2.2–5.9 years) for all participants and was longest at 5.9 (IQR: 2.9–8.9 years) in Botswana.
FIGURE 1.: Study flow diagram.
TABLE 2.: Patient Characteristics for 14,932 MMP Patients, Stratified by COE
Outcomes
Death and LTFU
Overall, after transition to MMP, 293 patients died and 385 were classified as LTFU. Of the 293 who died during the study, 187 died in the first 2 years and 263 in the first 5 years. Of the 385 who were LTFU over the study, 258 were lost in the first 2 years and 366 in the first 5 years.
The 5-year KM curve for known deaths (Fig. 2A ), LTFU (Fig. 2B ), and combined deaths and LTFU (Fig. 2C ) indicates an even distribution of deaths and LTFU over time. However, there were significant differences in survival (P < 0.0001) and LTFU (P < 0.0001) between age groups (Figs. 2A, B ). For both mortality and LTFU, the youngest (<1 year) and oldest (15–19 years) age groups had the least favorable KM curves.
FIGURE 2.: KM curves for known deaths (A), LTFU (B), and known deaths and LTFU (C).
Subanalyses by COE (see Figure 1, Supplemental Digital Content, https://links.lww.com/QAI/B169 P value = 0.014) and LTFU (P value < 0.0001) by center, with Botswana having the most favorable outcomes. The 5-year KM curves for known deaths (see Figure 4a, Supplemental Digital Content, https://links.lww.com/QAI/B169 Fig. 4B ) indicate similar distributions of deaths (log-rank P value = 0.375) and LTFU (log-rank P value = 0.083) over time for non-Lesotho and Lesotho COEs.
Adherence, CD4+ , and VL
Over the period of observation, CD4+ testing frequency did not change substantially, ranging from 79% to 86% of children and adolescents undergoing CD4+ testing at each 6-month visit interval. There was a steady increase in the proportion of patients receiving adherence assessment at MMP visits, from a baseline of 79% clients at transition to MMP, to 87% after 5 years of MMP. VL testing also increased considerably, from 23% of children and adolescents receiving a VL test at baseline to 66% at 5 years, consistent with the eventual introduction of routine VL measurements (see Figure 2, Supplemental Digital Content, https://links.lww.com/QAI/B169
The frequency of favorable clinical endpoints (ART adherence, acceptable immunologic status, and VL < 400) was high and relatively stable throughout the first 5 years of MMP follow-up (Fig. 4A ). Using the last nonmissing result for each patient, 93.1% (13,688/14,701) had normal CD4+ levels, 76.1% (10,976/14,428) had good adherence, and 82.3% (9199/11,179) had VL <400. Stratifying each of these endpoints by COE and age at MMP initiation revealed significant differences by age, but significant differences by COE were only observed for VL and not for CD4+ or adherence (see Figure 2, Supplemental Digital Content, https://links.lww.com/QAI/B169 https://links.lww.com/QAI/B169
Adherence remained favorable but was statistically (P value < 0.0001) different between age groups (Fig. 4C ). In the first 36 months after transition to MMP, adherence was lowest in patients who started MMP younger than 1 year; after 36 of MMP months, the pattern changed and adherence was similar across all age groups, except the oldest group for whom adherence data were lacking. Patients who transitioned to MMP after the age of 14 years had 81.7% adherence when they started and 81.4% at last testing. Patients who transitioned to MMP younger than 14 years had 79.8% adherence when they started and 78.8% adherence when last tested older than 14 years. Reported adherence among MMP patients did not differ by COE (see Figure 3, Supplemental Digital Content, https://links.lww.com/QAI/B169
The frequency of favorable immunologic response remained positive but differed significantly (P value < 0.0001) by age at MMP initiation (Fig. 3B ) but not COE (see Figure 1, Supplemental Digital Content, https://links.lww.com/QAI/B169 Fig. 3B ).
FIGURE 3.: Survival Function for (A) known deaths and (B) LTFU, stratified by age at MMP initiation.
The frequency of VL suppression also remained favorable but was significantly (P value < 0.0001) different between age groups (Fig. 4D ). In the first 24 months after MMP transition, the frequency of VL suppression was lowest for the youngest patients (<1 years old), after which it was lower for patients in the older age groups (10–14 and 15–19 years old). There were significant differences between study centers in the frequencies of VL suppression (see Figure 3, Supplemental Digital Content, https://links.lww.com/QAI/B169
FIGURE 4.: A, Frequency of favorable immunologic status, adherence assessment, and VL results among participants with available results. B, Frequency of acceptable immunologic response levels by age at MMP initiation. C, Frequency of treatment adherence by age at MMP initiation. D, Frequency of VL <400 copies per milliliter by age at MMP initiation.
DISCUSSION
This analysis of close to 23,000 children and adolescents from 6 African countries demonstrates that transition from MP to MMP schedules was feasible and provides evidence of ongoing favorable health outcomes in terms of mortality, retention, ART adherence, viral suppression, and immunologic status. These results, therefore, may provide reassurance to clinicians that implementing reduced frequency of clinical visits and extending ART refills are doable and can work for these populations. To the best of our knowledge, this is the first study examining the potential impact of MMP on clinical outcomes among children and ALHIV.
Patients transitioned to MMP were, by definition, those who had survived, been retained, were clinically stable and ART adherent. Therefore, it is perhaps not surprising that their outcomes remained favorable by all the measures we were able to assess over time as well as across diverse countries, COEs, and ages. Most patients at the COEs transitioned to MMP. Of those who transitioned to MMP, only 2.6% of patients were LTFU and 2.0% died over the course of the study. Most LTFUs and deaths occurred in the first 5 years after MMP initiation. Throughout the first 5 years, ART adherence and viral suppression remained high.
Although outcomes remained favorable for each age group and country, there were some noteworthy differences. Patients 15–19 years old or younger than 1 year at the time of transition to MMP were at higher risk of LTFU and mortality compared with other age groups. Although this finding was not surprising, given the known higher mortality among these age groups,4,12,13 14 15
Comparisons between COEs revealed that participants enrolled in care at the Botswana COE had better survival, LTFU, and VL suppression. Botswana's COE has been better resourced with earlier access to more robust drug regimens, CD4+ , and VL monitoring. However, it is reassuring that outcomes among patients from the COEs with fewer resources who transitioned to MMP remained relatively stable.
Successful implementation of MMP required clinical criteria for assessing adherence to ART and/or clinical progress such as adherence measurement (pill count), CD4+ and VL measurements, as well as clinical determination of HIV associated morbidity. Importantly, staff was trained to interpret measurements and make these clinical assessments. Barriers to MMP may include forecasting and supply chain limitations, such as insufficient supply of antiretrovirals at the facility level. Although not formally assessed, anecdotally, these were issues that arose during implementation of MMP. To some extent, this may be mitigated through training of pharmacy staff and the use of good commodity management systems. Furthermore, pharmacy pill counts and CD4+ were used as measures of adherence and response to treatment; however, viral suppression is a better indicator of response to treatment and nonadherence10,16,17 18–25
A significant benefit of MMP is likely to be time-saving for both health care providers and patients. In this study, we did not specifically explore the impact of MMP on provider and patient time. Anecdotally, the most common provider-reported benefit of MMP at all countries was the consequent reduction in patient load. Other studies have explicitly explored the relationship between MMP and time-savings. A recent study from Myanmar reported that implementing decreased physician visits and fast-track refills demonstrated an increase in the average number of patients 1 medical team could care for—from 745 patients in 2011 to 1627 in 2014—and thus, a reduction in the number of teams needed.26
Several potential study limitations should be kept in mind when reviewing the results. The COEs are relatively well staffed, and these personnel may have had more training and resultant confidence with managing pediatric HIV than their peers at primary health centers in many sub-Saharan African countries. Moreover, the centers have staff to provide counseling and support for adherence as well as personnel designated to track patients missing clinic visits. Tracking of patients missing appointments is performed both through telephone and home visits. Adherence was only measured by pharmacy pill count. Therefore, adherence measurements among infants started on liquid formulations or split tablet dose formulations may be less accurate. In the early years at the COEs, VL availability was more limited. Therefore, there may have been biased/differential testing of VL early in the study years. Because testing was not uniform and because sicker patients may have been more likely to be tested, differences between age groups and centers could reflect a bias in testing rather than true differences in VL. Finally, this is a descriptive study of routinely collected patient data, and we did not use a clearly defined and uniform set of criteria to judge eligibility for MMP, and there was no MP comparison group. Therefore, although the results are reassuring, we cannot make definitive conclusions on the impact of MMP that might be possible through a prospective clinical trial. The MMP group was analyzed as MMP even if they might have gone back to MP. If we assume that patients “went back” to MP because they became more ill, our analysis may be biased toward MMP results appearing less good than they actually were. To date, we are not aware of other evidence regarding the impact of MMP on clinical outcomes among children and ALHIV.
CONCLUSIONS
Overall, this analysis of close to 23,0000 children and adolescents from 6 African countries demonstrates that a transition to MMP schedules with less-frequent clinical visits and extended ART refills was feasible and provides evidence of ongoing favorable health outcomes in terms of immunologic status, ART adherence, viral suppression, retention, and mortality.
ACKNOWLEDGMENTS
The authors thank the Ministry of Health in all participating countries for their partnership in this endeavor. They thank the BIPAI Network including Dr. Peter N. Kazembe (Malawi), Dr. Edith Mohapi (Lesotho), Dr. Khosie Hlatshwayo (Swaziland), Dr. Lumumba Mwita (Tanzania), Dr. Adeodata Kekitinwa (Uganda), Prof. Gabriel Anabwani (Botswana), and Drs. Mark Kline and Gordon Schutze. They are very grateful to the children, adolescents, and families who inspire us with their perseverance and courage. They appreciate the support rendered from the USAID Regional HIV AIDS Program, USAID Washington, and the Technical Support to PEPFAR Programs (TSP) team.
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