Immunological outcomes of neverapin (NVP) versus efafrenz (EFV) based antiretroviral therapy (ART) regimen among children on ART: A study from Black Lion Hospital, Addis Ababa, Ethiopia

Antiretroviral therapy has reduced HIV-related morbidity and mortality substantially. WHO recommends the use of Nevirapine or Efavirenz as first line combined with two from nucleoside reverse transcriptase inhibitors. In this study the immunological outcomes of Neverapin versus Efafrenz based ART was assessed. Medical records of patients were retrieved and important variables were captured to standard questionnaire. Medical records of 120 patients from NVP-based regimen and 60 patients from EFV groups were revised. The CD4 cell count at the start of HAART ranged from 3-2003 cell/ml with an inter quartile range (IQR) of 231-317 cell/ml among NVP group. And among patients taking EFV based ART regimen, baseline CD4 count ranged 13-2095 cell/ml with an IQR range of 250-345 cell/ml. After six months of HAART, the CD4 cell count of NVP based regimen range from 71-2300 c/ml with IQR of 458612 c/ml, and mean CD4 cell count difference of 215, 95% CI (175.414-245.613). From EFV based group, CD4 count ranged from 65-2100 c/ml with IQR of 435-605 c/ml, and the mean CD4 cell count difference of 205, 95% CI (155.404-235.623). The immunological recovery was found to be comparable among the two groups. Advanced clinical stage of the disease, severe immune suppression, presence of anemia, presence of chronic diarrhea , poor weight gain during first six months of ART were adversely affected the trends of CD4 recovery. This research report demonstrated that immunological outcomes were comparable among patient taking NVP vs EFV based ART regimen.


INTRODUCTION
Antiretroviral therapy (ART) reduces HIV-related mortality and morbidity substantially among HIV infected patients.If HAART is not started timely, a third of children infected prenatally will not survive to their first birthday, and more than half will succumb to death by their second birthday (Abebe, 2017).The advent of highly active antiretroviral therapy (ART) has brought a paradigm shift in the survival of HIV infected patient.The standard therapy consists of two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase *Corresponding author.E-mail: nathanabebe08@gmail.com.
Author(s) agree that this article remain permanently open access under the terms of the Creative Commons Attribution License 4.0 International License inhibitor (NNRTI).In resource-limited countries, World Health Organization (WHO) recommends the use of either nevirapine (NVP) or efavirenz (EFV) as first line NNRTI (Tadesse et al., 2017).The controversy over which of the two drug dNNRTI should be started in combination with NRTI for the treatment of HIV infection has been growing recently (Tadesse et al., 2017;Kate et al., 2014).Previous studies comparing NVP-based and EFV-based regimens in adult patients have shown comparable effectiveness.However, some studies have shown the superiority of EFV.There are limited data comparing NVP to EFV in HIV-infected children (Lapphra et al., 2008).A study from the United States also found an increased risk of virologic failure for patients on NVP as compared to EFV based regimen (Tadesse et al., 2017;Brian et al., 2012).However, study from Nepal showed that patient taking NVP based regimen had superior clinical outcomes than EFV based regimen (Theophilus et al., 2015).
Children's immune response to ART differs based on age at ART initiation and degree of viral level.As shown in recent adult studies, there are likely other baseline factors contributing to differential immunologic responses (Ojha et al., 2016).Studies are, however, scarce in assessing the potential difference based on type of ART regimen.
This study focuses on assessing immunologic outcomes of the two first lines (NVP versus EFV) NNRTI which could contribute some inputs for the scarce and conflicting data so far reported.

Objective
The objective of this study was to compare immunological outcomes of NVP versus EFV based regimen among HIV infected children.

METHODOLOGY
A comparative cross sectional study was conducted by evaluating ART documents of children infected with HIV who were taking ART at Pediatric Infectious Disease clinic (PIDC), Black Lion Hospital (BLH).The hospital is a teaching specialized and national tertiary hospital.Pediatric and child health department is one of the major departments delivering patient caring service, teaching and research activities under different unit categories.Pediatric infectious clinic (PIDC) is one of the well-organized subspecialty unit of the hospital giving care for patients with infectious disease with major focus of delivering pediatric HIV/AIDS care and treatment.

Sample
At the time of data collection, about 1145 children with HIV infection were on follow up at pediatric infectious disease clinic.A total of 503 patients have already been on HAART and 405 patients have been on ART for at least six months duration at the time of the study.The sampling procedure was determined by patients' ART regimen and patients and to minimize sampling error and to have proportional representation from each groups; the number of patients taking 30 patients were taking d4T/3TC/EFV regimen which represent the least proportion of patients' ART regimen and the base for requirement of other patient from other regimen.Patients from the other regimens were selected based on the aforementioned figure to make the NVP to EFV group ratio 2:1.Accordingly, systematic cross matching was made among the four group of patients based on the ART regimen, and they were taken so as to recruit total of 180 study participants, with 120 patients from NVP arm and 60 from EFV arm (Figure 1).A simple random sampling technique was used to select patient charts from each regimens using computer generated random number.For one patient from EFV based regimen selected; two patients from NVP based regimen were selected, yielding a total of EFV group (n1=60) and NVP group (n2 = 120).

Data collection and analysis
Data were collected from the patients' ART documents (medical records, ART log books, HMIS books) using standardized format.Data entry was made to EPI info software for cleanup and analysis; exported to SPSS version 17 for further analysis.The factors considered to affect the immunologic recovery in both groups include: baseline CD4%/count, WHO clinical staging, presence of chronic diarrhea, anemia, and baseline weight.The patients were grouped into two based on the age of the patients: under 5 years and 5 to 14 years old.Independent t-test was used to assess the difference in CD4 cell count recovery among the two groups' patients.Binary and multiple logistic regressions were used to assess factors affecting CD4 cell recovery in both groups of patient.95% CI with p value of less than 0.05 was considered statistically significant.

RESULTS
ART documents of 120 patients from NVP based groups and 60 patients from EFV based regimen were reviewed.Important clinical and laboratory data were captured to standardized questionnaires.
The youngest age at the initiation of ART was 4 months from NVP-based regimen and 37 months from EFVbased groups with the highest being 144 and 168 months (IQR age 74-104 and 95-130 months), respectively.
Baseline anthropometry showed that 20.4 and 1.5% from NVP-based regimen and 22 and 2.5% from EFV based regimen were having moderate and severe wasting, respectively.Anemia was observed in 15% (18/120) of patients from NVP-arm regimen and 20% (12/60) of EFV-arm at the initiation of ART with the majority of the cases were having mild anemia.
Similarly, the mean weight gain at three and six months of EFV-based ART were 0.75 and 1.70 kg with CI (0.588 -0.954) and 1.70 kg, 95% CI (1.50 -1.95).Still there is no significant difference in weight gain among the two groups (Table 1).Advanced WHO clinical staging and severe immune suppression at start of ART negatively affected the degree of CD4 recovery among the two groups of patients (Table 3).Similarly, low baseline weight, presence of, presence of chronic diarrhea, and poor weight gain at three and six months of ART was found to have detrimental impact to CD4 cell recovery (Table 3).

DISCUSSION
In this study, after six months of NVP based ART regimen, the CD4 cell count increased to the level of 75 to 2400 c/ml with IQR of 468 to 632 c/ml with the mean CD4 cell count difference of 215, 95% CI (175.414-245.613)from baseline value.From EFV based group, CD4 count ranged from 65 to 2100 c/ml with IQR of 435 to 605 c/ml, and the mean CD4 cell count difference is 205, 95% CI (155.404-235.623)with comparable finding between two wings of treatment, P-0.34.Similar reports from central China disclosed that ART ( AZT/3TC/NVP) comparably effective in achieving an adequate response in HIV-infected children (Junwen, 2014), which is also This is in accordance with the study from Thailand children which showed comparable CD4 cell count gains between the NVP and EFV groups (Hai-Yin et al., 2014).Likewise, a Cochrane review of seven randomized clinical trials demonstrated that the two drugs provided comparable levels of viral suppression in non-TB patients infected with HIV when combined with two nucleoside reverse transcriptase inhibitors (Hai-Yin et al., 2014).However, in a meta-analysis, patients in the EFV treatment group achieved statistically higher rates of virological response, likely due to the effects of rifampin on drug metabolism (Hai-Yin et al., 2014).Another cohort study in ARV Thai adult patients with advanced HIV infection showed that NVP-and EFV-based HAART regimens were equally effective in terms of virological and immunological responses (Lapphra et al., 2008).The positive association between younger age groups and better immune recovery demonstrated comparably among the two groups in this study which is in congruence with other previous pediatric and adult reports (de Castilla et al., 2008;Reda et al., 2013;Gezie, 2016;Asfaw et al., 2015;Eshun-Wilson et al., 2012).This might be justified by high reserve of lymphocytes cell and early initiation of ART among younger age groups.On the other hand, in the present study, there is no relationship between gender of the patient and immunologic recovery from both NVP and EFV based regimen though other studies were with discordant results; some reported female gender is associated with better immune recovery others showed no gender difference (Crum-Cianflone et al., 2011;Mihiretu et al.,  ).Presence of chronic diarrhea during ART treatment is associated with poor CD4 cell recovery independent of nutritional status of the patient which is in agreement with most previous studies.The reason is not clearly identified so far but could be because of associated mal-absorption and poor adherence during the illness.Our study also showed that the presence of anemia at baseline (Hgb<10 g/dl) is related with poor immune system regeneration which is in concordant with similar studies from other sites (Puthanakit et al., 2009;Ethiopia Ministry of Health, 2012;Bacha et al., 2012).For instance, the report from South Africa demonstrated that children living with HIV who started on ART with lower hemoglobin level at the start of ART had significant risk of adverse CD4 cell recovery (OR = 0.87 for each 1 g/dl decrease in hemoglobin; 95% CI: 0.75-0.99)(Doris et al., 2015;Brian et al., 2012).Such relationship is apparently reasonable as there are evidences from other literature supporting the contribution elemental irons in immune restoration system.This research findings of lower baseline CD4 cell value predicting poor six month CD4 cell recovery in both groups of patients is supported with a large cohort study involving 861 adult patients living with HIV in Spain which showed that patients with baseline CD4 count of 200 and of 201 to 350 cells/mm 3 had a significantly lower chance of achieving CD4 count of 500 cells/mm 3 when compared with patients with baseline CD4 350 cells/mm 3 and above (Mihiretu et al., 2014;Third International Work Shop on HIV in Pediatrics, 2011;Zanoni et al., 2012).
This research finding also disclosed comparable weight recovery between the two wings of treatment category at three and six months of ART which is also in compatible with other research findings (Abebe, 2017).Weight gain of greater than 10% at six months of ART was demonstrated in 44% of the patients in our study which was in consistence with the study from Brazil which showed mean weight-for-age z scores increment from -1.62 (±1.32) at baseline to -1.14 (±1.12) weight-for-age z scores at week 24 (Diniz, 2011).
The suboptimal weight recovery after initiation of ART could imply poor adherence, an advancing disease stage or associated opportunistic infection signaling that the patient should undergo extensive clinical and blood test assessment.Likewise study in South Africa and elaborated lower percentiles of weight gain after six months of ART were associated with poor subsequent treatment outcomes and higher risk of mortality independent of other baseline characteristics (Kaufmann et al., 2005;Chiappini et al., 2009;Ahoua et al., 2009;Madec et al., 2009;Yotebieng et al., 2010).Likewise, underweight at start of ART was an independent prognosticator of poor CD4 outcome in both wings of the study, which is in line with other observational studies where patients who were underweight had a two-fold increased risk of dying (Madec et al., 2009).

Conclusion
This research finding demonstrated that there is no difference in immunological outcomes among patients taking NVP versus EFV.Higher WHO clinical stage of the disease, severe degree of immunosuppression, lower hemoglobin level at start of ART and presence of chronic diarrhea, and suboptimal weight increment at first six months of ART were factors that negatively affected the patterns of CD4 recovery.

Table 2 .
Proportion of weight increment and CD4 cell recovery at three and six month of ART, BLH, Addis Ababa Ethiopia, 2014.

Table 3 .
Displaying predictors CD4 cell recovery of >20% baseline increment among patient at six months of ART, Pediatric infectious clinic; BLH, Addis Ababa Ethiopia, 2014.