The Open AIDS Journal




ISSN: 1874-6136 ― Volume 12, 2018
SHORT COMMUNICATION

Modification of Initial Highly Active Antiretroviral Therapy (HAART) Regimen in Paediatric HIV Patients



Yee Shan Low1, Farida Islahudin1, *, Kamarul Azahar Mohd Razali2, Shafnah Adnan2
1 Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia
2 Hospital Kuala Lumpur, Jalan Pahang, 50586 Kuala Lumpur, Malaysia

Abstract

Background:

Treatment options among Human Immunodeficiency Virus (HIV)-infected children are limited as only a few Highly Active Antiretroviral Therapy (HAART) are approved worldwide for paediatric use. Among children, frequent changes in HAART regimen can rapidly exhaust treatment options, and information addressing this issue is scarce.

Objective:

The aim of the study was to determine factors associated with the modification of initial HAART regimen modification among HIV-infected children.

Method:

A retrospective study was performed among HIV-infected children aged 18 and below, that received HAART for at least six months in a tertiary hospital in Malaysia. Factors associated with modification of initial HAART regimen were investigated.

Results:

Out of 99 patients, 71.1% (n=71) required initial HAART regime modification. The most common reason for HAART modification was treatment failure (n=39, 54.9%). Other reasons included drug toxicity (n=14, 19.7%), change to fixed-dose products (n=11, 15.5%), product discontinuation (n=4, 5.6%) and intolerable taste (n=3, 4.2%). The overall mean time retention on initial HAART before regimen modification was 3.32 year ± 2.24 years (95% CI, 2.79–3.85). Patient's adherence was the only factor associated with initial regimen modification in this study. Participants with poor adherence showed a five-fold risk of having their initial HAART regimen modified compared to those with good adherence (adjusted OR [95% CI], 5.250 [1.614 – 17.076], p = 0.006).

Conclusion:

Poor adherence was significantly associated with initial regimen modification, intervention to improve patient's adherence is necessary to prevent multiple regimen modification among HIV-infected children.

Keywords: Paediatric, HIV, Regimen modification, Highly active antiretroviral therapy, HAART, Malaysia, Intolerable taste.


Article Information


Identifiers and Pagination:

Year: 2018
Volume: 12
First Page: 11
Last Page: 19
Publisher Id: TOAIDJ-12-11
DOI: 10.2174/1874613601812010011

Article History:

Received Date: 17/09/2017
Revision Received Date: 11/10/2017
Acceptance Date: 30/01/2018
Electronic publication date: 12/03/2018
Collection year: 2018

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© 2018 Low et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300, Kuala Lumpur, Malaysia; Tel: 6(03) 92897689; E-mail: faridaislahudin@yahoo.com




1. INTRODUCTION

Approximately 2.1 million children worldwide are living with Human Immunodeficiency Virus (HIV) in 2016 [1UNAIDS. Fact Sheet 2016.]. This number accounts for about 9% of total people infected with HIV around the world [1UNAIDS. Fact Sheet 2016.]. Unfortunately, an estimated 43% of children infected with HIV have access to antiretroviral treatment [1UNAIDS. Fact Sheet 2016.]. In Malaysia, it is estimated that 92,895 people are living with HIV, with children contributing to approximately 1% of the total number of cases [2Global AIDS response progress report. country responses to HIV/AIDS HIV/STI Section, Disease Control Division 2016.].

Although there is no safe and effective cure for human immunodeficiency virus (HIV) infection [3Mocroft A, Ledergerber B, Katlama C, et al. Decline in the AIDS and death rates in the EuroSIDA study: An observational study. Lancet 2003; 362(9377): 22-9.[http://dx.doi.org/10.1016/S0140-6736(03)13802-0] [PMID: 12853195] ], the use of Highly Active Antiretroviral Therapy (HAART) in the treatment of HIV has substantially reduced the morbidity and mortality associated with HIV infection [3Mocroft A, Ledergerber B, Katlama C, et al. Decline in the AIDS and death rates in the EuroSIDA study: An observational study. Lancet 2003; 362(9377): 22-9.[http://dx.doi.org/10.1016/S0140-6736(03)13802-0] [PMID: 12853195] ]. Fortunately, the introduction of HAART has revolutionized the management and prognosis of HIV infection in children, making it medically manageable [4Colvin CJ. HIV/AIDS, chronic diseases and globalisation. Global Health 2011; 7: 31.[http://dx.doi.org/10.1186/1744-8603-7-31] [PMID: 21871074] ]. The increased life expectancy for HIV-infected children in the era of HAART has led to challenges in selecting successive new antiretroviral drug regimens. Given the fact that children may require longer treatment periods, maintaining efficacy is vital. However, despite the advance in drug discovery research and development, there are only a few antiretrovirals approved worldwide for the treatment of HIV infection in children [5Waning B, Diedrichsen E, Jambert E, et al. The global pediatric antiretroviral market: analyses of product availability and utilization reveal challenges for development of pediatric formulations and HIV/AIDS treatment in children. BMC Pediatr 2010; 10: 74.[http://dx.doi.org/10.1186/1471-2431-10-74] [PMID: 20950492] , 6Schlatter AF, Deathe AR, Vreeman RC. The need for pediatric formulations to treat children with HIV. AIDS Res Treat 2016.[http://dx.doi.org/10.1155/2016/1654938] ]. In developing countries, treatment choice is further restricted by accessibility and cost.

Multiple or frequent regimen modification may rapidly exhaust treatment options among paediatric HIV patients [5Waning B, Diedrichsen E, Jambert E, et al. The global pediatric antiretroviral market: analyses of product availability and utilization reveal challenges for development of pediatric formulations and HIV/AIDS treatment in children. BMC Pediatr 2010; 10: 74.[http://dx.doi.org/10.1186/1471-2431-10-74] [PMID: 20950492] , 6Schlatter AF, Deathe AR, Vreeman RC. The need for pediatric formulations to treat children with HIV. AIDS Res Treat 2016.[http://dx.doi.org/10.1155/2016/1654938] ]. This is evident as fewer treatment and formulations are available for paediatric HIV patients compared to adults [5Waning B, Diedrichsen E, Jambert E, et al. The global pediatric antiretroviral market: analyses of product availability and utilization reveal challenges for development of pediatric formulations and HIV/AIDS treatment in children. BMC Pediatr 2010; 10: 74.[http://dx.doi.org/10.1186/1471-2431-10-74] [PMID: 20950492] , 6Schlatter AF, Deathe AR, Vreeman RC. The need for pediatric formulations to treat children with HIV. AIDS Res Treat 2016.[http://dx.doi.org/10.1155/2016/1654938] ]. Poor clinical outcome and the successive regimen are often more complex, less tolerable, and generally inferior to that of first line regimens with a higher risk of treatment failure, and is associated with early HAART modification [7Park WB, Choe PG, Kim SH, et al. Early modification of initial HAART regimen associated with poor clinical outcome in HIV patients. AIDS Res Hum Retroviruses 2007; 23(6): 794-800.[http://dx.doi.org/10.1089/aid.2006.0255] [PMID: 17604542] ]. Nevertheless, the incidence of initial HAART regimen modification or discontinuation was found to be frequent [8Cesar C, Shepherd BE, Krolewiecki AJ, et al. Caribbean, Central and South America network for HIV Research (CCASAnet) Collaboration of the International Epidemiologic Databases to Evaluate AIDS (IeDEA) Program. rates and reasons for early change of first HAART in HIV-1-infected patients in 7 sites throughout the Caribbean and Latin America. PLoS One 2010; 5(6): e10490.[http://dx.doi.org/10.1371/journal.pone.0010490] [PMID: 20531956] -10Takuva S, Louwagie G, Zuma K, Okello V. Durability of first line antiretroviral therapy: Reasons and predictive factors for modifications in a Swaziland cohort. J Antivir Antiretrovir 2012; 4: 14-20.[http://dx.doi.org/10.4172/jaa.1000040] ]. Reasons reported for initial HAART regimen modification included treatment failure, antiretroviral toxicity, new drug available, cost, suboptimal regimen, and presence of comorbidities [8Cesar C, Shepherd BE, Krolewiecki AJ, et al. Caribbean, Central and South America network for HIV Research (CCASAnet) Collaboration of the International Epidemiologic Databases to Evaluate AIDS (IeDEA) Program. rates and reasons for early change of first HAART in HIV-1-infected patients in 7 sites throughout the Caribbean and Latin America. PLoS One 2010; 5(6): e10490.[http://dx.doi.org/10.1371/journal.pone.0010490] [PMID: 20531956] -10Takuva S, Louwagie G, Zuma K, Okello V. Durability of first line antiretroviral therapy: Reasons and predictive factors for modifications in a Swaziland cohort. J Antivir Antiretrovir 2012; 4: 14-20.[http://dx.doi.org/10.4172/jaa.1000040] ]. Risk factors such as poor patient adherence, development of drug resistance, low baseline CD4 count on HAART initiation, gender, and age have also been attributed to HAART regimen modification [10Takuva S, Louwagie G, Zuma K, Okello V. Durability of first line antiretroviral therapy: Reasons and predictive factors for modifications in a Swaziland cohort. J Antivir Antiretrovir 2012; 4: 14-20.[http://dx.doi.org/10.4172/jaa.1000040] , 11Sebunya R, Musiime V, Kitaka SB, Ndeezi G. Incidence and risk factors for first line anti retroviral treatment failure among Ugandan children attending an urban HIV clinic. AIDS Res Ther 2013; 10(1): 25.[http://dx.doi.org/10.1186/1742-6405-10-25] [PMID: 24215971] ]. However, most published studies involve adult HIV patients.

There is a lack of data addressing the reasons and factors associated with initial HAART regimen modification among paediatric HIV patients in the Malaysian clinical setting. It is crucial to understand the factors that lead to the initial HAART regimen modification. This is especially true in the paediatric population in order to assist in better decision making of first HAART choice. Optimization of initial HAART in younger patients could lead to better interventions, as well as reduced risk of abrupt HAART interruption. The aim of this study was thus, to determine the factors associated with initial HAART regimen modification among paediatric HIV patients who receive HAART treatment in Malaysia.

2. MATERIALS AND METHODS

2.1. Study Design

This was a retrospective study, performed in a Malaysian paediatric infectious disease referral centre in Hospital Kuala Lumpur, Kuala Lumpur, Malaysia. HIV-infected children, aged 18 and below, that had received HAART (a combination of three antiretrovirals) for at least 6 months from January 2008 to December 2015, were included. The HAART regimen included in the study were two Nucleoside Reverse Transcriptase Inhibitors (NRTI) - zidovudine and lamivudine, and a Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) or Protease Inhibitor (PI).

2.2. Data Collection

Patient's information was collected by using a standardized patient data collection sheet. The information included patient's age on HAART initiation, gender, race, main carer during HAART treatment, World Health Organization (WHO) clinical disease staging at HAART initiation, baseline immunodeficiency staging using CD4 count at HAART initiation, baseline viral load, initial HAART regimen used, any regimen modification, reason for modification if occurred, the new HAART regimen used, follow up viral load and immunodeficiency staging using CD4 count at the time of regimen modification, history of previous antiretroviral exposure before HAART initiation and patients’ adherence level to HAART treatment.

2.3. Study Definition

In this study, HAART was defined as: a regimen that consists of at least three antiretroviral drugs from at least two drug classes that were approved for HIV infection based on international and national guidelines [11Sebunya R, Musiime V, Kitaka SB, Ndeezi G. Incidence and risk factors for first line anti retroviral treatment failure among Ugandan children attending an urban HIV clinic. AIDS Res Ther 2013; 10(1): 25.[http://dx.doi.org/10.1186/1742-6405-10-25] [PMID: 24215971] , 12World Health Organization. WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children 2007. Available from: http://www.who.int/hiv/pub/guidelines/HIVstaging150307.pdf]. Regimen modification was defined as: a switch or substitution of at least one drug from the original HAART regimen [12World Health Organization. WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children 2007. Available from: http://www.who.int/hiv/pub/guidelines/HIVstaging150307.pdf, 13World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach 2016. Available from: http://www.who.int/hiv/pub/arv/arv-2016/en/]. Clinical staging and baseline immunodeficiency staging using CD4 count were classified according to the WHO guidelines [12World Health Organization. WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children 2007. Available from: http://www.who.int/hiv/pub/guidelines/HIVstaging150307.pdf]. The baseline CD4 counts were divided into four categories: not significant, mild, advanced and severe [12World Health Organization. WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children 2007. Available from: http://www.who.int/hiv/pub/guidelines/HIVstaging150307.pdf, 13World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach 2016. Available from: http://www.who.int/hiv/pub/arv/arv-2016/en/]. CD4-based assessment of immune suppression in children is age-dependent (Table 1) [12World Health Organization. WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children 2007. Available from: http://www.who.int/hiv/pub/guidelines/HIVstaging150307.pdf, 13World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach 2016. Available from: http://www.who.int/hiv/pub/arv/arv-2016/en/]. Treatment failure was defined as: either clinical failure, immunological failure or virological failure in accordance with WHO definition [13World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach 2016. Available from: http://www.who.int/hiv/pub/arv/arv-2016/en/]. Previous antiretroviral exposure was defined as: the use of mono- or dual antiretroviral agent for the purpose of neonatal post-exposure prophylaxis. Adherence to HAART was defined into two categories; good adherence (an adherence pill count/ liquid volume assessment of ≥ 95%, or physician-medical reports of good compliance), and poor adherence (an adherence pill count/ liquid volume assessment < 95%, or physician medical-reports of poor compliance). Pill counts/ liquid volume assessment and adherence counselling is performed by the pharmacist during each clinic session. Physician-medical reports are based on interview-based assessments on whether the patient admitted to non-adherence (missing more than 1 dose) or full adherence since the previous follow-up. The age group of the patient was classified according to the WHO classification to ensure consistency with WHO guidelines in the management of HIV in children [13World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach 2016. Available from: http://www.who.int/hiv/pub/arv/arv-2016/en/].



Table 1
Patient demographics and clinical characteristics at HAART initiation.


2.4. Data Analyses

Data was analysed using SPSS (Statistical Package for the Social Sciences, SPSS Inc., Chicago IL) version 23. Descriptive statistics were used to determine overall frequency of initial HAART regimen modification and to identify the most common reason for regimen modification. Univariate and multivariate logistic regression analysis was conducted to determine factors associated with initial HAART regimen modification. Factors tested in the univariate analysis were gender, ethnicity, age on HAART initiation, main carer, adherence, antiretroviral exposure before HAART, initial HAART regimen, baseline immunodeficiency at HAART initiation and WHO clinical stage at HAART initiation. Crude and adjusted odd ratios (OR), 95% confidence interval (CI) and p-value were presented for regression. The mean duration of retention on initial HAART before regimen modification was analysed using ANOVA or T-test. A p-value ≤ 0.05 was considered significant.

3. RESULTS

3.1. Demographics

Demographic characteristics of the patients (age, gender, ethnicity, and type of school area) are shown in Table 1. A total of 110 paediatric HIV infected patient records were screened from January 1, 2008 to December 31, 2015. A total of eleven patients were excluded as HAART was initiated for less than six months. Patient's demographic profiles and clinical characteristic are shown in Table 1. All patients were diagnosed as mother-to-child transmission patients. Among the 99 patients, 53.5% (n = 53) were male. The ethnicity of more than half of the participants were Malay (n=51, 51.1%), followed by Chinese (n=19, 19.2%), Indian (n=6, 6.1%), indigenous (n=6, 6.1%) and others (n=17, 17.2%). Other ethnicities were patients mainly from Myanmar and Thailand.

3.2. Modification of Initial HAART Regimen

The overall percentage of HIV-infected children that required initial HAART regimen modification in this study was 71.1% (n = 71). Modification of two or more agents (treatment failure and drug toxicity) occurred in 53 (52.5%) patients. Treatment failure defined as virological or clinical or immunological failure was the most common reason for initial HAART regimen modification within the studied population (54.9%, n = 39), whilst drug toxicity occurred in 14 (19.7%) patients. Modification of one agent occurred in 18 (17.8%) patients and accounted for the remaining cases that required initial HAART regimen modification: a change to fixed-dose products (n=11, 15.5%), product discontinuation (n=4, 5.6%) and intolerable taste (n=3, 4.2%).

The median duration of retention time on initial HAART before a regimen modification among the study population was 3 years (IQR 2). The time taken for modification of two or more agents was a median of 3.3 years (IQR 2), whilst it took a median of 2.5 years (IQR 0.2) for modification of one agent (p >0.05). Patients with good adherence showed a significantly longer mean retention time on initial HAART (median 4 years, IQR 2.19) compared to patients with poor adherence (median 2.7 years, IQR 1.8) (p = 0.013). No other significant findings were observed.

3.3. Factors Associated with Modification of Initial HAART Regimen

In order to assess factors affecting modification in initial HAART regimens, a univariable analysis was performed (Table 2). It was demonstrated that the factors affecting initial HAART regimen modification were previous antiretroviral exposure (χ2 = 5.6, p = 0.018), adherence (χ2 = 10.3, p = 0.001), and WHO clinical stage at HAART initiation (χ2 = 8.6, p = 0.036). Patients with a previous exposure to antiretroviral were 8.5-fold more likely to modify initial HAART regimen compared to those that were not exposed. Poor adherence increased the risk of modification of initial HAART by 5.8-fold compared to good adherence.

Table 2
Logistic regression analysis describing correlates of patient's demographic and clinical characteristic with occurrence of initial HAART regimen modification among HIV-infected children.


Multivariable logistic regression analysis was conducted to determine the factors associated with initial HAART regimen modification when adjusting for potential confounders (Table 2). Results showed that only patients' adherence level remained associated with initial HAART regimen modification in the studied population in a logistic multivariate analysis. Patients with poor adherence demonstrated were 5.2-fold more likely to have their initial HAART regimen modified compared to those with good adherence (adjusted OR [95% CI], 5.250 [1.614 – 17.076], p = 0.006).

4. DISCUSSION

As in most parts of the world, the younger population in Malaysia remains vulnerable to HIV. In the current work, the ethnic balance of HIV paediatric patients observed, clearly represents the Malaysian population [14Ministry of health malaysia. Global aids response progress 2015 2015.]. Free HAART treatment for paediatric HIV patients are currently provided as part of the Ministry of Health, Malaysia initiative in expanding the availability and accessibility of treatment in the country [14Ministry of health malaysia. Global aids response progress 2015 2015.].

HAART is vital for maximal clinical benefit in HIV-infected paediatric patients [12World Health Organization. WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children 2007. Available from: http://www.who.int/hiv/pub/guidelines/HIVstaging150307.pdf]. Despite this, initial HAART regimen modification is found to be common in clinical practice [8Cesar C, Shepherd BE, Krolewiecki AJ, et al. Caribbean, Central and South America network for HIV Research (CCASAnet) Collaboration of the International Epidemiologic Databases to Evaluate AIDS (IeDEA) Program. rates and reasons for early change of first HAART in HIV-1-infected patients in 7 sites throughout the Caribbean and Latin America. PLoS One 2010; 5(6): e10490.[http://dx.doi.org/10.1371/journal.pone.0010490] [PMID: 20531956] -10Takuva S, Louwagie G, Zuma K, Okello V. Durability of first line antiretroviral therapy: Reasons and predictive factors for modifications in a Swaziland cohort. J Antivir Antiretrovir 2012; 4: 14-20.[http://dx.doi.org/10.4172/jaa.1000040] , 15Panel on antiretroviral therapy and medical management of HIV-Infected children. Guidelines for the use of antiretroviral agents in pediatric HIV infection 2016. Available from: https://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf]. In this current study, results revealed initial HAART regimen modification occurred in the majority of the paediatric HIV patients. Early modification of initial HAART however, has been associated with poor clinical outcome [16Bunupuradah T, Puthanakit T, Kosalaraksa P, et al. Immunologic and virologic failure after first-line NNRTI-based antiretroviral therapy in Thai HIV-infected children. AIDS Res Ther 2011; 8: 40.[http://dx.doi.org/10.1186/1742-6405-8-40] [PMID: 22026962] ]. In instances where modification involves two or more agents as observed in more than half of the study population, the succeeding regimen is always more complex, less tolerable and is associated with a higher risk of treatment failure [7Park WB, Choe PG, Kim SH, et al. Early modification of initial HAART regimen associated with poor clinical outcome in HIV patients. AIDS Res Hum Retroviruses 2007; 23(6): 794-800.[http://dx.doi.org/10.1089/aid.2006.0255] [PMID: 17604542] , 16Bunupuradah T, Puthanakit T, Kosalaraksa P, et al. Immunologic and virologic failure after first-line NNRTI-based antiretroviral therapy in Thai HIV-infected children. AIDS Res Ther 2011; 8: 40.[http://dx.doi.org/10.1186/1742-6405-8-40] [PMID: 22026962] ]. Changes of more than one agent usually occurs in treatment failure [7Park WB, Choe PG, Kim SH, et al. Early modification of initial HAART regimen associated with poor clinical outcome in HIV patients. AIDS Res Hum Retroviruses 2007; 23(6): 794-800.[http://dx.doi.org/10.1089/aid.2006.0255] [PMID: 17604542] , 16Bunupuradah T, Puthanakit T, Kosalaraksa P, et al. Immunologic and virologic failure after first-line NNRTI-based antiretroviral therapy in Thai HIV-infected children. AIDS Res Ther 2011; 8: 40.[http://dx.doi.org/10.1186/1742-6405-8-40] [PMID: 22026962] ], similarly observed in the current work. In children, studies have reported a 34% treatment failure rate that led to a first-line regimen modification in a five-year follow up [11Sebunya R, Musiime V, Kitaka SB, Ndeezi G. Incidence and risk factors for first line anti retroviral treatment failure among Ugandan children attending an urban HIV clinic. AIDS Res Ther 2013; 10(1): 25.[http://dx.doi.org/10.1186/1742-6405-10-25] [PMID: 24215971] ]. HIV-children in Thailand demonstrated a 33% treatment failure and HAART modification on first-line HAART within 96 weeks of follow up [16Bunupuradah T, Puthanakit T, Kosalaraksa P, et al. Immunologic and virologic failure after first-line NNRTI-based antiretroviral therapy in Thai HIV-infected children. AIDS Res Ther 2011; 8: 40.[http://dx.doi.org/10.1186/1742-6405-8-40] [PMID: 22026962] ]. Similarly, the main reason for initial HAART modification in this current work was treatment failure that occurred within an average of three years. Treatment failure has been accounted for majority of the cases that require HAART regimen modification in both children and adults [17Owuor AO, Lule GN, Otieno CF, Omonge EO, Maritim MC, Memiah P. Modification of antiretroviral therapy in a cohort study of HIV-infected patients attending an urban teaching hospital in Kenya. Int J Virol AIDS 2014; 1: 1.[http://dx.doi.org/10.23937/2469-567X/1510003] -19Oumar AA, Diallo K, Dembélé JP, et al. Adverse drug reactions to antiretroviral therapy: Prospective study in children in sikasso (mali). J Pediatr Pharmacol Ther 2012; 17(4): 382-8.[http://dx.doi.org/10.5863/1551-6776-17.4.382] [PMID: 23411444] ]. However, other reasons include drug toxicity, previous antiretroviral exposure, clinical stage and non-adherence [9Sun J, Liu L, Shen J, et al. Reasons and risk factors for the initial regimen modification in Chinese treatment-naive patients with HIV infection: A retrospective cohort analysis. PLoS One 2015; 10(7): e0133242.[http://dx.doi.org/10.1371/journal.pone.0133242] [PMID: 26207639] , 17Owuor AO, Lule GN, Otieno CF, Omonge EO, Maritim MC, Memiah P. Modification of antiretroviral therapy in a cohort study of HIV-infected patients attending an urban teaching hospital in Kenya. Int J Virol AIDS 2014; 1: 1.[http://dx.doi.org/10.23937/2469-567X/1510003] , 18Woldemedhin B, Wabe NT. The reason for regimen change among HIV/AIDS patients initiated on first line highly active antiretroviral therapy in Southern Ethiopia. N Am J Med Sci 2012; 4(1): 19-23.[http://dx.doi.org/10.4103/1947-2714.92898] [PMID: 22393543] ], similarly observed in the present study.

Various factors have led to initial HAART modification [11Sebunya R, Musiime V, Kitaka SB, Ndeezi G. Incidence and risk factors for first line anti retroviral treatment failure among Ugandan children attending an urban HIV clinic. AIDS Res Ther 2013; 10(1): 25.[http://dx.doi.org/10.1186/1742-6405-10-25] [PMID: 24215971] ]. Among factors that have been identified are poor adherence, antiretroviral drug resistance, poor absorption, exposure to a single dose nevirapine, low baseline CD4 count at HAART initiation and demographic data such as age, gender and main carer [11Sebunya R, Musiime V, Kitaka SB, Ndeezi G. Incidence and risk factors for first line anti retroviral treatment failure among Ugandan children attending an urban HIV clinic. AIDS Res Ther 2013; 10(1): 25.[http://dx.doi.org/10.1186/1742-6405-10-25] [PMID: 24215971] , 15Panel on antiretroviral therapy and medical management of HIV-Infected children. Guidelines for the use of antiretroviral agents in pediatric HIV infection 2016. Available from: https://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf, 20Bacha T, Tilahun B, Worku A. Predictors of treatment failure and time to detection and switching in HIV-infected Ethiopian children receiving first line anti-retroviral therapy. BMC Infect Dis 2012; 12: 197.[http://dx.doi.org/10.1186/1471-2334-12-197] [PMID: 22916836] -22Adjé-Touré C, Hanson DL, Talla-Nzussouo N, et al. Virologic and immunologic response to antiretroviral therapy and predictors of HIV type 1 drug resistance in children receiving treatment in Abidjan, Côte d’Ivoire. AIDS Res Hum Retroviruses 2008; 24(7): 911-7.[http://dx.doi.org/10.1089/aid.2007.0264] [PMID: 18593341] ]. In this current work, poor adherence was the single factor that significantly led to modification of initial HAART regimen. The current study further demonstrated that patients with poor adherence were found to be five-times more likely to have their initial HAART regimen modified compared to those with good adherence. Adherence plays a vital role in the treatment of HIV infection [23Romanelli RM, Pinto JA, Melo LJ, Vasconcelos MA, Pereira RdeM. Effectiveness of dual and triple antiretroviral therapy in the treatment of HIV-infected children. J Pediatr (Rio J) 2006; 82(4): 260-5.[PMID: 16881008] -27Kwobah CM, Mwangi AW, Koech JK, Simiyu GN, Siika AM. Factors associated with first-line antiretroviral therapy failure amongst HIV-infected African patient: A case-control study. World J AIDS 2012; 2: 271-8.[http://dx.doi.org/10.4236/wja.2012.24036] ]. Nonetheless, poor adherence continues to be a predominant factor for both HAART modification and treatment failure in both adult and children HIV patients [11Sebunya R, Musiime V, Kitaka SB, Ndeezi G. Incidence and risk factors for first line anti retroviral treatment failure among Ugandan children attending an urban HIV clinic. AIDS Res Ther 2013; 10(1): 25.[http://dx.doi.org/10.1186/1742-6405-10-25] [PMID: 24215971] , 16Bunupuradah T, Puthanakit T, Kosalaraksa P, et al. Immunologic and virologic failure after first-line NNRTI-based antiretroviral therapy in Thai HIV-infected children. AIDS Res Ther 2011; 8: 40.[http://dx.doi.org/10.1186/1742-6405-8-40] [PMID: 22026962] , 23Romanelli RM, Pinto JA, Melo LJ, Vasconcelos MA, Pereira RdeM. Effectiveness of dual and triple antiretroviral therapy in the treatment of HIV-infected children. J Pediatr (Rio J) 2006; 82(4): 260-5.[PMID: 16881008] -27Kwobah CM, Mwangi AW, Koech JK, Simiyu GN, Siika AM. Factors associated with first-line antiretroviral therapy failure amongst HIV-infected African patient: A case-control study. World J AIDS 2012; 2: 271-8.[http://dx.doi.org/10.4236/wja.2012.24036] ]. Lack of adherence to HAART results in suboptimal antiretroviral plasma concentration, leading to unsatisfactory viral suppression [16Bunupuradah T, Puthanakit T, Kosalaraksa P, et al. Immunologic and virologic failure after first-line NNRTI-based antiretroviral therapy in Thai HIV-infected children. AIDS Res Ther 2011; 8: 40.[http://dx.doi.org/10.1186/1742-6405-8-40] [PMID: 22026962] ]. In turn, this promotes viral resistance, which eventually leads to treatment failure and regimen modification [16Bunupuradah T, Puthanakit T, Kosalaraksa P, et al. Immunologic and virologic failure after first-line NNRTI-based antiretroviral therapy in Thai HIV-infected children. AIDS Res Ther 2011; 8: 40.[http://dx.doi.org/10.1186/1742-6405-8-40] [PMID: 22026962] , 25Biadgilign S, Deribew A, Amberbir A, Deribe K. Adherence to highly active antiretroviral therapy and its correlates among HIV infected pediatric patients in Ethiopia. BMC Pediatr 2008; 8: 53.[http://dx.doi.org/10.1186/1471-2431-8-53] [PMID: 19061515] ].

Reasons for poor adherence to HAART among HIV infected children is often multifactorial [25Biadgilign S, Deribew A, Amberbir A, Deribe K. Adherence to highly active antiretroviral therapy and its correlates among HIV infected pediatric patients in Ethiopia. BMC Pediatr 2008; 8: 53.[http://dx.doi.org/10.1186/1471-2431-8-53] [PMID: 19061515] , 28Bhattacharya M, Dubey AP. Adherence to antiretroviral therapy and its correlates among HIV-infected children at an HIV clinic in New Delhi. Ann Trop Paediatr 2011; 31(4): 331-7.[http://dx.doi.org/10.1179/1465328111Y.0000000031] [PMID: 22041467] , 29Castro M, González I, Pérez J. Factors related to antiretroviral therapy adherence in children and adolescents with HIV/AIDS in Cuba. MEDICC Rev 2015; 17(1): 35-40.[PMID: 25725767] ]. In general, factors that influence adherence in children can be divided into three main groups, patient or family/carer-related factors, medication-related factors and healthcare delivery system-related factors [30Chesney MA. Factors affecting adherence to antiretroviral therapy. Clin Infect Dis 2000; 30(Suppl. 2): S171-6.[http://dx.doi.org/10.1086/313849] [PMID: 10860902] , 31Shah CA. Adherence to high activity antiretrovial therapy (HAART) in pediatric patients infected with HIV: Issues and interventions. Indian J Pediatr 2007; 74(1): 55-60.[http://dx.doi.org/10.1007/s12098-007-0028-8] [PMID: 17264455] ]. About one third of patients in this study were under the care of a children's home, which may be a potential problem for lack of adherence. The current setting in the local children’s home is such that no specific drug management is available for HIV patients. Children living with a non-parent carer have been demonstrated to worse adherence status in paediatric HIV patients [32Nyogea D, Mtenga S, Henning L, et al. Determinants of antiretroviral adherence among HIV positive children and teenagers in rural Tanzania: A mixed methods study. BMC Infect Dis 2015; 15: 28.[http://dx.doi.org/10.1186/s12879-015-0753-y] [PMID: 25637106] ]. Other reasons for poor adherence in children include psycho-developmental stages [31Shah CA. Adherence to high activity antiretrovial therapy (HAART) in pediatric patients infected with HIV: Issues and interventions. Indian J Pediatr 2007; 74(1): 55-60.[http://dx.doi.org/10.1007/s12098-007-0028-8] [PMID: 17264455] ], increasing age [33], side effect profile, palatability and complexity of the antiretroviral regimen [6Schlatter AF, Deathe AR, Vreeman RC. The need for pediatric formulations to treat children with HIV. AIDS Res Treat 2016.[http://dx.doi.org/10.1155/2016/1654938] , 15Panel on antiretroviral therapy and medical management of HIV-Infected children. Guidelines for the use of antiretroviral agents in pediatric HIV infection 2016. Available from: https://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf, 30Chesney MA. Factors affecting adherence to antiretroviral therapy. Clin Infect Dis 2000; 30(Suppl. 2): S171-6.[http://dx.doi.org/10.1086/313849] [PMID: 10860902] , 31Shah CA. Adherence to high activity antiretrovial therapy (HAART) in pediatric patients infected with HIV: Issues and interventions. Indian J Pediatr 2007; 74(1): 55-60.[http://dx.doi.org/10.1007/s12098-007-0028-8] [PMID: 17264455] ]. A better understanding of factors contributing to poor adherence among HIV-infected children is crucial to prevent frequent regimen modification, which can rapidly lead to antiretroviral treatment option exhaustion among this vulnerable group. Nonetheless, the current study was able to identify factors that affected HAART management in children. Addressing issues regarding poor adherence among children with HIV infection is important as the need for long term HAART could ultimately increase the risk of drug resistance.

As with all studies, there were a few limitations in the current work. Firstly, being a retrospective study, the accuracy of the data could not be confirmed with the patients or clinicians. Furthermore, there were only three participants who fell within the age category of 10-19 years old, and a larger, multi-centred study could reduce these limitations in future work. More importantly, it should be noted that this study intended to serve as a baseline data of paediatric HAART modification in the local setting, looking into general changes of HAART. Thus, the broader term of HAART modification was used in the current work, taking into account major modifications involving two or more agents such as drug toxicity, and minor modifications involving one agent such as product discontinuation. However, findings suggest that drug toxicity and product discontinuation may not be related to differences in adherence. Further work could be performed by separating these two outcomes for a more specific results. In addition to this, other variables such as calendar year effects of drug modification may also affect clinical outcome of HAART. Hence, generalizability of the study should be done with caution.

CONCLUSION

In conclusion, the overall percentage of children infected with HIV that required initial HAART regimen modification was high and the most common reason for initial HAART modification was treatment failure. Poor adherence was found to be an independent predictor of initial HAART regimen modification within the local population. It is important to note that although HIV clinics tend to stress on the importance of adherence to all patients, other factors may also affect medication adherence. Furthermore, findings of the study suggest that more work should be performed to determine factors that may affect HAART modification as adherence of HAART medication may not apply to modifications involving toxicity and product discontinuation.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

The study was conducted by reviewing the patient's medical record from the medical clinics as well as the medication therapy adherence clinic. Ethical approval was obtained from the Malaysian National Research and Ethics Committee (ID: 15-1758-27908).

HUMAN AND ANIMAL RIGHTS

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

CONSENT FOR PUBLICATION

For the study, informed consent was taken from patients.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

The authors would like to acknowledge the Malaysian Paediatric Infectious Disease referral centre for their invaluable help and cooperation throughout the conduct of this study.

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