Predictors of loss to follow-up among children on long-term antiretroviral therapy in Zambia (2003–2015)

We conducted a retrospective cohort study of infants and children who received ART at the Pediatric Center of Excellence clinic (PCOE), an outpatient children’s clinic at LCH in Southern Province, Zambia. Livingstone Central Hospital serves over 200,000 people in the Southern Province and parts of the Western Province of Zambia. Pediatric HIV treatment at LCH was started in 2003 in line with national policy and in 2006 the PCOE clinic was established through a collaborative agreement between the Ministry of Health in Zambia and the Centers for Diseases Control and prevention country office (CDC) [10].

We analyzed data for children with confirmed HIV infection and receiving ART at the PCOE between January 2003 and December 2015. The inclusion criteria were: 1) children aged from birth to 15 years at the time of ART initiation who commenced ART between January 1st 2003 and December 31st 2015, 2) children who had taken ART for at least 6 months or more, 3) children who had received at least three ARVs. Children who received one ARV for PMTCT were excluded from the study because we considered ART to be a combination of at least three antiretroviral drugs. We excluded children who started ART on or after June 30th, 2015 because data collection was closed on December 31st, 2015 and we included only children who took ART for at least 6 months.

The date of entry into the cohort was the date the child began taking ARVs as recorded on the medical chart. Children who were transferred out of the clinic and children who died were censored on the date the outcomes were ascertained. All the children who were lost to follow-up were censored at least 90 days after they missed their last clinic visit. Children who were active in care were censored on December 31st, 2015 when the study was closed. Adolescents who transitioned to adult care were censored on the date of their last visit and were recorded as transferred out of the clinic.

The main outcome was LTFU which was defined as no clinical and pharmacy contact for at least 90 days after the child missed their last scheduled clinical visit. The exposure was ART. Since this was a retrospective cohort study, the decision to initiate ART was made by the treating physician and the child’s caregivers and not influenced by the study investigators.

Clinical management of the study population was based on the Ministry of Health in Zambia pediatric HIV treatment guidelines. The 2007 pediatric HIV testing and treatment guidelines recommended virologic testing where available and presumptive HIV diagnosis and treatment of HIV exposed infants and children under 18 months of age who presented with WHO stage 3 and 4 conditions or had low CD4% [11]. The 2013 pediatric HIV testing and treatment guidelines recommended collection of dried blood spots (DBS) cards for DNA-PCR from all HIV-exposed infants at 6 weeks and 6 months of age followed by serologic testing at 12 months, 18 months and 3 months after cessation of breastfeeding [12]. Routine provider initiated counseling and testing was recommended for all hospitalized children. All children who were confirmed HIV seropositive were initiated on ART. Prior to 2012, pediatric HIV treatment guidelines recommended ART based on clinical and immunological criteria. First line ART regimens comprised of three antiretroviral medicines including two Nucleoside reverse transcriptase inhibitors (NRTI’s): Azidothymidine, Stavudine, Abacavir, (Tenofovir for children above 10 years old) and Lamivudine, plus one Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), either Nevirapine or Efavirenz for ART naïve infants and children. Infants who took ART prophylaxis after delivery were commenced on Protease inhibitors (PI) based regimens (Lopinavir boosted with Ritonavir) in addition to two NRTIs. Triple NRTI based regimens were recommended for children below 3 months of age who were co-infected with Tuberculosis at baseline [12].

Children who tested positive for HIV were enrolled into care by trained nurse counsellors at the PCOE clinic using standardized forms. The data collected included; sex, date of birth, birth history, mother’s gestational history including date of HIV test and whether the mother took ARVs. The child’s caregivers contact information (phone numbers and home address, directions on how to get to the house using landmarks) were collected. Oral and written consent to contact the family in case they missed appointments was obtained and documented in the medical record. This information was updated by the registry clerks at every clinic visit. Once the patient was commenced on ART, they were scheduled to come back to the clinic after 2 weeks. Following the 2 weeks’ clinical visit, the patient was scheduled for monthly clinical visits for 6 months after which they could be scheduled for 3 monthly clinical visits if they were clinically stable and adherence was observed to be satisfactory. During the counseling process, the caregivers were informed that they could bring the child back for sick visits without a prior appointment. At each visit, the child’s weight, height, head circumference was measured and recorded in the medical chart. Developmental milestones were monitored and recorded in the medical charts for young children.

The PCOE had an outreach team comprised of nurse counsellors, social worker and community volunteers. The clinic nurses kept a list of patients who did not come for their scheduled appointments every day and contacted those whom they could call by phone. At the end of the week, the outreach team collected the list of patients with missed appointments and tried to contact them either by phone or home visits. Attempts to contact the caregivers and re-engage the children were made over a period of 3 months. If the outreach team was not able to trace the child within a period of 3 months, the tracing outcome was classified as “LFTU” and the child’s medical chart was flagged and kept in a separate registry folder. Tracing was successful when the outreach team found a child and determined their outcome.

For this study, we collected all the medical charts in the “LFTU” registry folder and attempted to trace the children. When a child was traced and their caregivers decided not to continue with medical treatment despite the interventions, the child’s tracing outcome was classified as “Defaulter”. When a child was found, and they had continued taking ART at another facility the tracing outcome was “on ART at other facility”. If the child had a period when they were not taking ART but came back to the clinic and continued treatment, the tracing outcome was “on ART with gaps”. And if the child was traced but had died, the tracing outcome was “dead”. Children who were not found were classified as “unknown status”.

For all the children who were traced with outcomes “dead”, “defaulted”, “On ART at other facility”, “on ART with treatment gaps” and “unknown status” the exact date the outcome occurred was not available and we used the date the outcome was ascertained by the outreach team as documented on the medical records.

We examined the medical records of all the patients at the clinic and compared with the outreach team’s registers to ensure that we did not miss any additional patients who were lost to follow-up. We looked for patients who had been lost to follow-up but silently returned to care by comparing the medical records with the outreach team’s registers and the clinic registers.

Patient data were abstracted from the medical records of children who received ART. We created a Microsoft Access database with the following variables; date of birth, gender, date of ART initiation, weight, height, WHO stage, CD4 count, hemoglobin, viral load, mother’s PMTCT history, delivery history, medical history, ART regimens, adherence history, social economic indicators of the care giver including occupation, income, phone ownership, visit dates and treatment outcome. We assigned unique study identification numbers to each patient record. Data abstraction was done independently by two data entry clerks and their entries were verified at random intervals by a supervisor.

Baseline demographics and clinical features were described by estimating medians and interquartile ranges for continuous variables and frequencies and proportions for categorical variables. Non-parametric competing risks models were used to estimate the incidence of death, transfer and LTFU [13]. We estimated the cumulative incidence at 3 months, 6 months, 1 year, 3 years, 5 years and 10 years of observation in the competing risks model. Our event of interest in the analysis was the initial LTFU because most of the patients had been lost for more than 90 days before we traced them for the purpose of our study. Cause-specific Cox Proportional Hazards regression was used to estimate the hazard ratios of the risk factors of loss to follow-up. All statistically significant variables (p < 0.05) in the univariable analysis were included in the multivariable analysis. We evaluated the proportional hazards assumption using log-log plots and plots of Schoenfeld’s residuals and no violations of the assumption were found. The dataset was almost complete as we had very few missing variables.

Data analysis was done using R statistical software version 3.4 [14]. We used the cmprsk package for the competing risks analysis [15].

The median duration of follow-up was 3.8 years (95% CI: 1.2–6.5) and the median age at baseline was 3.6 years (IQR: 1.3–8.6). At the time of ART initiation, 520 (49%) children were female and 721 (69%) were cared for by their biological mothers. A total of 179 (17%) commenced treatment during their first year of life. In total, 49% (512) of children commenced ART between 2006 and 2009 but this declined to 29% (305) of children between 2010 and 2012 and 14% (151) between (2013–2015). At least 304 (29%) were diagnosed during hospital admission and 30 (3%) were diagnosed at the time of birth, while their mothers were still admitted to the delivery wards (Table 1). At least 68% of the caregivers owned phones. HIV status was only disclosed to children aged 7 years old and above as recommended by national guidelines and HIV disclosure had been completed for 18% (n = 191) of children at the time of ART initiation (Table 1).

The median baseline CD4+ count for children 6 to 15 years old was 505 (IQR: 243–948). Whereas for children between 1 and 5 years the median CD4% was 19.4% (IQR: 12.4–25.6), children aged less than 1 year had median CD4% of 16.7% (IQR: 11.3–21.5). At least 1002 (97%) took Cotrimoxazole at baseline and 301 (30%) had a diagnosis of clinical Tuberculosis (TB) at ART initiation. Overall, 472 (46%) were WHO stage 3 and 177 (17%) were WHO stage 4 (Table 2).

The first line regimen for 907 (87%) children was two NRTIs and one NNRTI, and 54 (5%) were commenced on two NRTIs and a Protease Inhibitor (Lopinavir boosted with Ritonavir) while 78 (8%) children took triple NRTIs at baseline, (Azidothymidine or Stavudine, Lamivudine and Abacavir) (Table 2).

Among LTFU children, 13% continued treatment with gaps and reported that they did not take pills for at least 2 weeks. The reported reasons for not taking pills included; distance from the health facilities, change of caregiver, unexpected travel for a prolonged period and the caregiver was busy with other activities. At least 13% of children were found to have continued treatment at another facility without informing the health facility staff. The reported reasons for the silent transfer were similar to those reported for treatment with gaps.

In the competing risks analysis, the cumulative incidence of LFTU for the entire cohort was 2.7% (95% CI: 1.9–3.9) at 3 months, 4.1% (95% CI: 2.9–5.4) at 6 months and continued to increase over time to 14.1% (95% CI: 12.4–16.9) and 21.1% (95% CI: 17.6–24.9) after 5 and 10 years on ART respectively (Fig. 2 and Table 3).

Loss to follow-up differed significantly across key baseline demographic, clinical and treatment variables. Cumulative incidence of LTFU increased over time for all age groups and was consistently higher among children who started ART at < 1 year of age: after 3 months of treatment cumulative incidence was 5% (95% CI: 2.5–8.9) for < 1 year, 3.6% (95% CI: 2.0–5.8) for children 1–5 years and 1.3% (95% CI: 0.5–2.6) for children 6–15 years, the p-value for difference across age strata was statistically significant (p < 0.0001) (Fig. 2, Table 4). Likewise, cumulative incidence of LTFU was higher among children acutely malnourished at baseline compared to children who were not acutely malnourished 5.0% (95% CI:2.4–8.8) after 3 months, (p = 0.0107). Children who commenced triple NRTIs had higher cumulative incidence of LTFU [10.3% (95% CI: 4.7–18.3)] after 3 months compared to those who were on standard first line ARV regimens (1NNRTI + 2NRTI) [2.2% (95% CI: 1.3–3.3)], and protease inhibitor based regimens [1.8% (95% CI: 0.1–8.7)] (p < 0.0001).

Children who commenced ART in recent years (2013–2015) had higher cumulative incidence of LTFU [11.5%% (95% CI:6.8–17.4)] after 1 year, compared to those who begun treatment from 2010 to 2012 [6.2% (95% CI: 3.9–9.4)] and those who begun treatment from 2006 to 2009 [5.9% (95% CI: 4.1–8.2)] (p < 0.0001) during the same period of time. Lack of access to a phone resulted in higher cumulative incidence of 10.1% (95% CI: 7.1–13.7) compared to those whose caregivers owned phones [4.6% (95% CI: 3.2–6.3)], (p < 0.0001). Older children aged 7 years and above who did not know their HIV status had higher cumulative incidence of 7.7% (95% CI: 6.0–9.6) compared to those who knew their HIV status [0.5% (95% CI: 0.04–2.7) [16]], (p = 0.0266) (Fig. 2, Table 4).

After adjusting for age, baseline CD4, baseline hemoglobin, HIV disclosure status, nutritional status and WHO clinical stage, children who started treatment between 2013 and 2015, had the highest hazard ratio of loss LTFU, (aHR = 5.6; 95% CI:2.2–14.1), compared to those who started treatment between 2003 and 2005 (Table 5). Compared to children whose care givers owned phones, children without phones were 80% more likely to be LTFU (aHR = 1.8; 95% CI: 1.3–2.5). Among children above the age of 7, those who did not know their HIV status had 90% higher hazard of loss to follow-up in the univariable analysis when compared to their counterparts who knew their HIV status at baseline (HR = 1.9; 95% CI:1.2–2.9). However, this was not statistically significant in the multivariable analysis (Table 5).