Tukei, Vincent J. MBChB, MMed, MPH*; Asiimwe, Alice MBChB, MSc*; Maganda, Albert BStat, MStat*; Atugonza, Rita MBChB*; Sebuliba, Isaac BStat, MStat*; Bakeera-Kitaka, Sabrina MBChB, MMed†; Musoke, Phillipa MBChB, FAAP†,‡; Kalyesubula, Israel MBChB, MMed, DTCH*; Kekitiinwa, Adeodata MBChB, MMed, DPPM*
The use of antiretroviral therapy (ART) for management of patients infected with HIV has had positive impact on growth, survival, and general wellbeing of children and adults in both resource-rich and resource-poor settings.1–4 ART, however, has been associated with the occurrence of a number of adverse events.5 The adverse events have varied from milder and often transient gastrointestinal symptoms such as nausea, vomiting, and diarrhea to acute life-threatening hypersensitivity reactions, psychiatric, hematologic, renal, and sometimes fatal hepatic injury.6–9 In addition, body fat redistribution, hyperlipidemia, and neuropathies have occurred as a consequence of prolonged ART use.8,10–12 The occurrence of these events directly impacts on patient adherence to medication13 subsequently contributing to poor recovery14 and often creating the need for treatment modification.15
In Africa, studies of adult patients show that ART-related adverse events occur at a frequency comparable with that seen in patients in other parts of the world.16,17 However, recent reports from Medecins Sans Frontieres programs in several parts of Africa indicate a low frequency of occurrence of these events among African children.18
In Uganda, there is still a paucity of information on ART adverse events in children. With the implementation of the World Health Organization (WHO) 2010 ART guidelines that encourage early initiation of treatment for infants and children, the number of children presenting with ART-related adverse events is likely to increase.19 There is therefore need to understand the frequency of occurrence and outcome of these adverse events among cohorts of children in care in resource-constrained settings.
Our objective was to determine the frequency of ART adverse events among a cohort of infants, children, and adolescents being followed up at the Baylor College of Medicine Bristol Myers Squibb Children's Clinical Center of Excellence at Mulago Hospital (Baylor-Uganda) in Kampala, Uganda; and to assess the outcome of these events.
The study was conducted at Baylor-Uganda in Kampala, Uganda. Baylor-Uganda is a donor-funded outpatient pediatric and family–centered clinic involved in prevention and treatment of HIV/AIDS in Uganda. With an average daily attendance of 170 patients and a total clinic enrollment of more than 5000 patients, Baylor-Uganda is one of the largest pediatric HIV clinics in Uganda. Patients enrolling for care at the clinic are referred from hospitals and HIV treatment centers within Kampala city and from the pediatric wards within Mulago Hospital. Up to one-third of children come as self-referrals.
Study Design and Study Participants
We assembled an observational cohort of 408 HIV-infected children and adolescents drawn from a larger pool of patients receiving care and treatment at the Baylor-Uganda Clinic in Kampala. Starting from July 2004, all consecutive HIV-infected patients enrolling for care and treatment at the clinic were assessed for inclusion into the study. To be included, patients had to be: registered for care at the clinic; HIV positive; aged between 6 weeks and 18 years; ART naive; and have an adult caretaker willing to participate in the study. Other criteria required that the patient live within a 20-km radius of the clinic and be willing to return to the clinic for treatment and regular check-up. The number of eligible patients seeking care at the clinic during the study period determined the sample size. Children without parents or guardians were excluded.
For analysis, we included only cohort patients that were followed up and started on ART within the period July 2004 to July 2009.
Antiretroviral Treatment and Follow-Up
All new patients with confirmed laboratory diagnosis of HIV infection were taken through the clinic routine, which involved a medical examination, staging of HIV disease, clinical and laboratory investigation for presence of opportunistic infections and assessment for eligibility and readiness to start ART. Eligibility for ART was based on WHO treatment guidelines current at the time of the visit.
During the study period, first-line ART involved the use of a 3-drug regimen comprising of 2 nucleoside reverse transcriptase inhibitors (NRTI) and 1 nonnucleoside reverse transcriptase inhibitor (NNRTI) drug as recommended by the WHO in its 2003 and 2006 revisions of treatment guidelines.20,21 The main drug combinations used in children were zidovudine (ZDV) or stavudine (D4T), plus lamivudine (3TC), and efavirenz (EFV) or nevirapine (NVP). D4T was preferred for patients who had anemia [hemoglobin (Hb) level <8 g/dL] at baseline or developed it after starting ZDV. NVP was preferred as the NNRTI for children below 3 years of age and for sexually active adolescent girls. Patients on medication for tuberculosis received EFV as the preferred NNRTI; and if EFV was contraindicated, such patients were given a triple NRTI combination consisting of abacavir (ABC), 3TC, and either ZDV or D4T. Patients, who had treatment failure while on first-line medication, were put on a second-line regimen that consisted of a boosted protease inhibitor, lopinavir/ritonavir; didanosine, and ABC. The ART combinations used among older children were mainly generic fixed-dose combinations although younger children were given individual tablets or fixed-dose combinations that were cut to obtain weight-appropriate dozes. Infants and children unable to swallow tablets were put on liquid formulations of the individual antiretroviral (ARV) drugs.
At every visit, clinical information on probable or confirmed adverse events was recorded in the patient's chart and appropriate laboratory investigations were carried out. Laboratory monitoring involved baseline and 6 monthly assessments of CD4 cell counts, complete blood counts, liver function tests (alanine aminotransferase), and renal function tests (serum creatinine). Patients starting ART were scheduled to return to the clinic 2, 4, and 8 weeks after starting ART. Thereafter, routine monthly follow-up at the clinic involved drug refills, assessment for adverse events, and assessment of adherence to medication. In addition, patients were encouraged to return to the clinic any time they developed symptoms of disease or probable drug toxicity. At each visit, a structured questionnaire designed to capture possible adverse events was filled by the physicians. Patients who spent more than 3 months without returning to the clinic were considered lost to follow-up.
Definition of Variables
ART was the exposure variable, and the outcome variable was the occurrence of adverse events. Potentially confounding variables such as age, sex, clinical stage of HIV disease, HIV viral load, and CD4 cell count were recorded. ART was defined as the combined administration of 3 ARV drugs to an HIV-infected patient for any duration. Patients on 1 or 2 ARV drugs were not considered.
An adverse event or reaction to ARV drug was defined as a physician-documented occurrence or worsening of any undesirable symptom or sign (including an abnormal laboratory finding) temporally associated with the use of ARV drugs. These included nausea, vomiting, diarrhea, skin rashes, nail discoloration, central nervous system (CNS) abnormalities, peripheral neuritis, pancreatitis, body fat redistribution, abnormal liver function tests, anemia, and neutropenia. CNS-related events were recorded only in children older than 4 years because infants and young children could not relate the events to the clinicians.
Only events specifically documented as resulting from ARV drugs based on the physician's judgment were considered. Hematologic and biochemical events discovered during routine laboratory checks were analyzed separately.
Abnormal laboratory results were determined for age-appropriate groups using known national and international reference values. Severity of adverse events was assessed using the US National Institute of Allergy and Infectious Diseases Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (grading table) Version 1.0.22
Data Collection and Statistical Analysis
All patient information was recorded in the patient charts by trained physicians during routine clinic visits. This information was then entered into the clinic's database by a team of trained data clerks. The database is designed to check for errors and consistency of the data. The data were subsequently exported to STATA 10.1 (Statacorp. College Station, TX) for analysis.
Descriptive analyses were conducted to assess baseline characteristics of the patients. The proportions of patients with adverse events and the frequency of occurrence of specific adverse events were computed. Pearson χ2 statistic was used to assess associations between relevant categorical variables. Kaplan–Meier analysis was employed to determine the probability of developing adverse events during the period of observation, and where appropriate, the log-rank test was used to assess comparisons in survival distributions between groups. Cox proportional hazards models for univariate and multivariable analysis were developed to identify factors associated with the occurrence of adverse events. The final multivariable model included all variables found to be associated with adverse events in the univariate analysis at a P value <0.2 together with other variables considered to be clinically relevant. For all analyses, the confidence intervals were set at the 95% level with statistical significance set at a P value of less than 0.05.
Written consent to participate in the study was obtained from parents/guardians of the patients. All children older than 8 years were asked to assent to the study before participation could be granted. Written permission to conduct the study was granted by the Makerere University College of Health Sciences' Research and Ethics Committee; Uganda National Council of Science and Technology (UNCST); and Baylor College of Medicine Institutional Review Board.
Of the 408 cohort patients followed up during the study period, 378 (92.6%) were started on ART. Thirty patients who were considered immunologically and clinically stable were not started on ART. These patients however continued to get regular clinical care and antibiotic prophylaxis but were excluded in the analysis because they were not on ART.
The median follow-up time for patients on ART was 170 weeks [interquartile range (IQR): 14–229]. Of the 378 patients who started ART, 299 (79.1%) were children younger than 13 years (Table 1). One hundred ninety-seven (52.1%) patients were female; 297 (83.4%) patients were in WHO clinical stage 3 or stage 4; and at baseline, the median CD4 cell percentage was 10.4 % (IQR: 5.2%–15.2%). Of 310 patients who had baseline plasma HIV RNA viral load tests, 75 (24.2%) had viral loads greater than 750,000 copies per milliliter. Two hundred twenty patients received ZDV and 3TC as their NRTI drugs, 128 patients were on D4T and 3TC, and 30 patients received other NRTI combinations. NVP was given to 171 patients, and EFV was the NNRTI drug for177 patients. More than 95% of the patients were on cotrimoxazole prophylaxis. Three patients who had been treated for cryptococcal meningitis were on daily fluconazole for secondary prophylaxis.
Clinical Adverse Events
There were 126 clinical adverse events reported in 107 (28.3%) patients. Ninety-six of the 107 patients experienced only 1 adverse event; 11 patients had 2 or 3 adverse events, and no patient had more than 3 events. The most common clinically manifest adverse events were dizziness, nausea, vomiting, and diarrhea (Table 2).
One hundred two (81%) adverse events were mild and transient. Modification or change in the ART regimen was made for 24 (19%) patients considered to have developed severe or life-threatening events: All 10 patients with clinically manifest anemia; 1 patient with cardiomyopathy; 1 with amnesia; 1 with hepatitis, and the 11 patients with lipodystropy had a regimen change. All patients received treatment specific to their condition.
Events related to the CNS were not assessed among children younger than 5 years; however, among 243 older children who could relate neurologic events, 39 events were reported. Of these, 25 were from patients on EFV and 13 were from patients on NVP; [Risk ratio = 1.4 (95% confidence interval: 0.75 to 2.59)].
Although on ART, 31 (8.2%) patients died and 8 were lost to follow-up. Only 6 of the 31 patients who died experienced ART-related toxicities during follow-up. None had toxicities at the time of death. Postmortem examination to establish the cause of death was not carried out; however, other diagnoses recorded during the clinic visit preceding death included the following: HIV-associated nephropathy, persistent diarrhea, tuberculosis, and lymphoma.
Probability of Remaining Free of Adverse Events
The median duration from start of ART to detection of clinical adverse event was 12 weeks (IQR: 3–24). This duration varied according to adverse event as follows: anorexia 16.7 (IQR: 2–24) weeks; nausea/vomiting 9.3 (IQR: 2–12.1) weeks; diarrhea 11.9 (IQR: 4.7–13) weeks; abdominal pain 2 weeks; anemia 14.5 (IQR: 5–31) weeks; hepatitis 50.8 (IQR: 3–98.7) weeks; anxiety/nightmares 10 (IQR: 2–12) weeks; drowsiness/somnolence 3 (IQR: 2–8) weeks; cardiomyopathy 35.4 weeks; nail discoloration 24 (IQR: 12–71) weeks; lipodystrophy 207 (IQR: 96–224) weeks; dizziness 9.4 (IQR: 2.6–12) weeks; skin rash 11 (IQR: 4–12) weeks; amnesia 52 weeks; peripheral neuritis 13 weeks; lactic acidosis 50 weeks; and gynaecomastia 52 weeks.
Among children old enough to report neurologic events, the probability of remaining free of adverse events reduced to 66%, 4 years after starting ART (Table 3).
Biochemical and Hematologic Adverse Events
Among 259 patients who had laboratory results for baseline and follow-up tests, 172 (66.4%) patients were on ZDV-based regimen and 87 (33.6%) were on a D4T regimen. Subclinical hematologic and biochemical abnormalities were seen both at baseline and during follow-up. Within the first 6 months of ART, there was a general increase in the mean Hb from a baseline level of 10.9 g/dL to 11.6 g/dL (paired t test, P < 0.001) (Table 4). Among patients on ZDV, mean Hb increased from a baseline level of 11.1 g/dL to11.6 g/dL (paired t test; P < 0.001); Although patients on non–ZDV-based regimen had Hb increase from a baseline mean of 10.3 g/dL to 11.6 g/dL at month 6 of ART (paired t test; P < 0.001).
Among individual patients, the proportion with low Hb (Hb less than 10 g/dL) drastically reduced within the first 6 months of therapy. At the start of ART, 73 (28.2%) patients had low Hb, whereas 186 (71.8%) patients had normal Hb. Of patients with low Hb, 42 were started on ZDV-based regimen and 31 received non-ZDV regimens. By 6 months of ART, only 26 patients (12 on ZDV and 14 on D4T) who had low baseline Hb, continued to have low levels of Hb.
Of 186 patients who had normal baseline Hb levels, 136 were put on ZDV. Of these, 10 (7.4%) developed anemia within the first 6 months of ART. ART regimens were changed, and the anemia successfully treated in all 10 patients. None of the patients on non-ZDV regimen developed anemia.
The proportion of patients with leucopenia did not markedly change in the first 6 months of treatment; neither was there a significant change in the proportion of patients with high alanine aminotransferase or serum creatinine (Table 4).
Factors Associated With Occurrence of Adverse Events
A multivariable Cox regression analysis of data from children old enough to relate all adverse events showed no significant association between baseline factors (age, sex, WHO clinical stage, CD4 cell count, Hb, white blood cell count, ART combination) and the first occurrence of adverse events (Table 5).
In this cohort of Ugandan children and adolescents, 28% of patients developed ART-related clinical adverse events during the 5-year study period. The adverse events, though seen in a number of children, were mild and self-limiting requiring no change of medication. The majority of children in this cohort were able to continue with their treatment, and no deaths were directly attributed to ART.
These results offer reassuring evidence of the safety and tolerability of ART in Ugandan children and are in agreement with results of studies conducted in other parts of Africa and Asia.18,23 As reported in previous studies,9,24 the most common events involved the gastrointestinal system; however, CNS complaints were not uncommon.
Among the NNRTI agents used, EFV has been reported to cause neuropsychiatric events in as many as 50% of adult patients.25,26 Often times, patients experience transient symptoms such as dizziness, drowsiness, and abnormal dreams which resolve within a few weeks of starting treatment. In infants and young children, diagnosis of these neurologic events is hampered by the inability to obtain relevant history from the patient. In our study, we were not able to record these events among infants and young children; however, among older children and adolescents, a smaller proportion of patients on EFV experienced neurologic events. No psychiatric events warranting treatment interruption were recorded. Due to differences in definition, diagnosis, and reporting of adverse events, comparisons of proportions of patients who experience these events across studies are difficult to make.
Hepatitis and hypersensitivity skin reactions, known to occur mainly in patients on NNRTIs, were reported only in a small proportion of patients. Only 1 patient with hepatitis needed treatment change. None of the skin rashes progressed to Steven Johnson syndrome. The small number of complaints related to hepatotoxicity and hypersensitivity skin rashes among these patients coupled with lack of significant increase in liver enzymes during follow-up further emphasize the safety of these drugs.
Adverse events related to NRTI use include hematologic events (anemia and neutropenia) mainly seen in patients on ZDV; lactic acidosis, pancreatitis, peripheral neuropathy, and lipodytrophy commonly seen among patients on D4T.27 In general, our study showed significant increase in the mean Hb levels within the first 6 months of ART. This increase was seen even among patients on ZDV and may indicate a general improvement in patient health after ART initiation. Anemia in HIV-infected patients is often caused by a combination of opportunistic infections, nutritional deficiencies, bone marrow infiltration, ZDV, and general chronic ill health.28–30 With ART initiation, many of these risk factors were either controlled or eliminated subsequently leading to the rise in Hb levels. These results are in agreement with findings of several studies conducted among adult patients.31–33 The higher number of cases of anemia among the ZDV group compared with the non-ZDV group, however, underscores the need for close monitoring of patients on this drug. As seen in many adult studies, anemia in this cohort developed within the first 2–3 months of therapy. Contrary to reports from several studies, neutropenia was not common in this cohort.
Lipodystrophy and peripheral neuropathy occurred 3–4 years after ART initiation and were a major reason for regimen modification. Lipodystrophy was mainly seen among patients on D4T. We did not see many patients with peripheral neuropathy; neither did we see any cases of pancreatitis related to NRTI use. Peripheral neuropathy in infants and young children is often difficult to diagnose. It is possible that this adverse event may have been missed by the clinicians. Milder cases of pancreatitis may equally have gone undiagnosed because serum amylase levels were not routinely determined.
D4T, because of its ability to cause irreversible side effects, is no longer recommended by the WHO.34 It is being phased out of Uganda and in its place; AZT or ABC is recommended for first-line treatment of infants and young children. In older children and adults, the less-toxic tenofovir is preferred.
We were not able to determine the level of dyslipidemia because the clinic does not routinely measure serum lipids; however, hypercholesterolemia, which is a known risk factor for cardio vascular disease, has been reported among children on ART.12,35 As these children grow to adulthood, there is need to determine the lipid profiles of patients because this may have a direct impact on the long-term risk of cardiovascular disease.
With ever increasing evidence showing that clinical monitoring alone as opposed to frequent laboratory testing may be adequate in the management of HIV/AIDS,36 our results underscore the safety of these drugs even when used among infants and children in settings where laboratory monitoring is inadequate.
Our study had several limitations. Being an observational cohort study in which patient recruitment largely depended on consecutive enrolment of all patients that were eligible, selection bias at the time of enrollment could have distorted our results. In addition, information bias leading to misclassification of cases largely as a result of differences in the manner in which clinicians diagnosed or identified the outcomes could have happened. Patients on particular treatments known to cause certain toxicities may have been subjected to more detailed probing by the clinicians and this may have led to reporting bias.
Our analysis must be viewed and interpreted in the context of what is clinically practical for identifying these adverse events in resource-constrained settings. Settings with advanced laboratory monitoring may yield more adverse events such as myopathies, pancreatitis, and metabolic acidosis; all of which were not diagnosed in our clinic.
In summary, our findings provide relevant information on the safety and tolerability of ART among children in Uganda and may guide clinical practice in resource-constrained settings where patient monitoring is largely clinically driven. In addition, these findings indicate that with adequate clinical monitoring and minimal laboratory monitoring, as was done in this study, morbidity and mortality resulting from drug toxicity can be avoided.
The authors appreciate Abbott Fund for providing the HIV test kits; Clinton Foundation and Ministry of Health of Uganda who provided the drugs used; and Baylor International Pediatric AIDS Initiative (BIPAI) for the technical support. The authors thank the children and caregivers of Baylor-Uganda for their participation and corporation; and all the staff of Baylor-Uganda who participated in the data collection process. Special thanks to Moorine Ssekadde, Barbara Asire, Betty Nsangi, Betty Kasule, Aggrey Dhabangi, Grace Kabaniha, Jane Nakimuli, Daniella Migisha, Kahungu Methuselah, Paul Tumbu, Sue Kelly and Robert Iriso for their dedication to patient follow-up and cohort data collection.
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