Immunological and clinical response to antiretroviral therapy according to baseline CD4+ T-cell count in Karamara General Hospital, Jigjiga, Ethiopia

In resource limited countries, there is scarcity of information regarding the degree of immunological and clinical recovery in remote communities with ART service. This study retrospectively assessed the degree of immune recovery by CD4 count after initiation of ART. A retrospective cohort study was conducted on adult HIV patients who have been on ART for more than one year at Karamara Hospital. All analyses were performed using SPSS software version 19.0 and findings were compared using the appropriate statistical tests. The median change from baseline to the most recent CD4 cell count was 141 cells/μl. By 5 years, the overall median CD4 cell count was 472 cells/μl while the median CD4 cell count was 401 cells/μl among patients with baseline CD4 cell counts ≤100 cells/μl, 467 cells/μl among those with baseline CD4 cell counts of 100 to 199 cells/μl, and 586 cells/μl among those with baseline CD4 cell counts equal to greater 200 cells/μl. At the end of the study, patients with higher baseline CD4 cell stratum returned to normal CD4 cell counts compared to those with the least baseline CD4 cell stratum. The findings suggest that consideration be given to initiation of ART at a CD4 cell count >350 cells/μl to achieve better immune recovery.


INTRODUCTION
Human immunodeficiency Virus (HIV), the agent that causes acquired immune deficiency syndrome (AIDS), is classified as members of the lentivirus subfamily of retroviruses. The virus principally infects cells with a CD4 receptor, including T helper lymphocytes, macrophages, and other cell types. Viral replication results in progressive T-cell depletion and diminished cell-mediated immunity. The gp120 virus surface antigen binds with high affinity to the cell surface CD4, promoting fusion between virus and cell membranes. Co-receptor chemokine receptors CXCR4 and CCR5 may also play a role in internalization as well as immunoglobulin that assist in antibody dependent uptake. The natural history of HIV depicts the outcome of HIV infection, which leads to destruction of lymphocytes and development of AIDS (Actor et al., 2007).
Since its recognition, HIV has created an enormous challenge worldwide, it has infected close to 70 million people, and more than 30 million have died due to acquired immunodeficiency syndrome (AIDS). More than 66% of the 40 million people living with HIV/AIDS are in sub-Saharan Africa, where AIDS is the leading cause of death. Ethiopia is the second most populous and one of the seriously affected countries in sub Saharan Africa. With more than 1.3 million people living with HIV and an estimated 277,800 people requiring treatment, the Government of Ethiopia has taken measures to reduce the risk of HIV transmission and mitigate the impact of the epidemic on society. In 2003, the Government of Ethiopia introduced its ART program with the goal of reducing HIV-related morbidity and mortality, improving the quality of life of people living with HIV and mitigating some of the impact of the epidemic (Seoane et al., 2008).
According to the 2012 UNAIDS Report on the HIV epidemic, there were 333,434 people (249,174 adults and 16,000 children) on antiretroviral treatment at the end of 2011. This represents 86% coverage of adults in need of treatment and 20% in children. In Ethiopia, after the beginning of free ART, though the adult prevalence of HIV showed reduction its epidemic continued and estimated to be 1.5% (1.9% among women and 1.0% among men) with marked regional variations which ranges from 0.9% in Southern Ethiopia (SNNPR) to 6.5% in Gambella region in the Western part of the country. There is also wide urban rural variation in HIV prevalence with urban areas estimated to have a prevalence of 4.2% compared to 0.6% in rural areas (UNAIDS, 2012;WHO, 2005;ORC Macro, 2012).
Much is not known about immune recovery of patients taking ART in Somali region. Hence, aims of this study are to explore immune recovery by CD4+ T-cell count according to baseline CD4+ T-cell and to investigate clinical outcome in a retrospective cohort of HIV-infected patients over the 60 months of treatment.

Study site and design
A retrospective cohort study was employed from January 2015 to January 2016 in Jigjiga to assess the immunological response mainly of their CD+4 count after ART initiation. Jigjiga is the capital city of Ethio-Somali regional state that located about 620 km East of Addis Ababa. It is one of the cities where wide ART services are given in the region. Karamara hospital provides general outpatient and inpatient services, including surgical and obstetric emergency care. The adult HIV prevalence rate of the region is 1.1% based on EDHS (2011).

Study population
The study population were all HIV positive patients at Karamara hospital who have been on ART for more than or equal to 12 months.

Sample size
Eligible adults who started ART treatment during the period of September 2007 to September 2014 were included. The study included all cases with complete baseline information from Karamara hospital ART clinic during the period of September 2007 to September 2014. Therefore, this was a census type study and didn't involve any sampling. Clinical documents of all patients who started HAART and who had a minimum of two follow up period at study period were recruited for this study.

Sampling technique
General information about patients in the hospital enrolled during the study period was evaluated. Using ART unique identification number from ART register in Karamara Hospital documents of all patients enrolled for ART care between September 2007 and September 2014 were evaluated.

Inclusion criteria
The inclusion criteria for the recruitment of the study participants included those HIV positive adult patients above 15 years of age and who started HAART between September 2007 and September 2014; and all HIV positive patients on HAART, who have at least been treated for 1 year and have a baseline CD4 determination for at least two follow-up or above.

Exclusion criteria
All transferred HIV patients on HAART and those who have incomplete baseline, CD4 determination or clinical and sociodemographic information were excluded.

Outcome variables
Change in immune recovery (that is, CD4+ T cell number) between initiation of HAART and the most recent available follow-up times.

Independent variables
Socio-demographic characteristics (Age, sex, marital status, educational status, employment, religion), behavioral factors (adherence to treatment/loss to follow-up), clinical information (Weight, WHO stage, past history of TB treatment, baseline regimens, substitution of regimen from baseline, OI at baseline) and laboratory result information (CD4 + T cell counts category at the time of initiation of ART) were included.

Ethical consideration
This study was conducted after formal approval of the protocol was made by Research, Publication and Technology Transfer Committee

Immune recovery by CD4 count
Overall, median CD4 increased from a baseline value of 141 cells/mm3 (IQR, 78 to 213 cells/mm 3 ) to 249 cells/mm 3 (IQR, 180 to 341 cells/mm 3 ) at 6 months and to 446 cells/mm3 (IQR, 298 to 584 cells/mm 3 ) by year 5 (Figure 1). Although CD4 continued to increase throughout the 5 years, the first 2 years after ART initiation showed a steeper increase compared to the latter 3 years.

Gender response to HAART
Among the adherent patients in the study, there were a higher proportion of women (64.6%) than men (35.4%). Women exhibited higher median CD4 count values (148 cells/μl) than men (127 cells/ μl) before the start of therapy. The respective CD4 increases for men and women were 232 and 258 cells/ μl at 6 months, and 243 and 304 cells/μl at 12 months, respectively (Figure 2). At five years follow up of treatment, CD4 count had increased from baseline of 127cells/μl to 409.5 cells/μl in men, and from baseline of 148 cells/μl to 511 cells/μl in women.

DISCUSSION
This retrospective cohort study was carried out to assess the trends in CD4 cell recovery and clinical response among HIV patients on ART utilization and the effect of baseline characteristics on CD4 cell count response. CD4+ cell responses was evaluated whether patients  failed to attain mean CD4+ cell count increase from baseline of at different interval months (defined as immunological non-response) and whether patients achieved an absolute CD4+ count of 200 cells/μl at the 12th months visit (Kelley et al., 2009) At baseline, the mean CD4 cell count of ART-naïve HIV infected patients was 141 cells/μl, this is comparable with other reports from Tigray (Asfaw et al., 2015) and Burkina faso (Tiba et al., 2012) but higher than the reports from Zewditu hospital Addis Ababa, 81 cells/ul (Moges et al., 2013) and Lao, 41 cells/ul (Bastard et al., 2013). This could be due to the delay in presentation or ART initiation. As like other studies so far conducted on this area, better improvements in overall CD4 cell count among the patients was seen over time mainly for the first two years generally up to year 3 after these it showed slight increment until five years. These findings are consistent with the study conducted in northern and eastern Ethiopia where the median CD4 lymphocyte count had improved over the five year period in the similar fashion to our study (Asfaw et al., 2015;Reda et al., 2013) and elsewhere clearly investigated that CD4 cell counts were increased significantly until year 4 though varied among different CD4 cell strata thereafter (Moore et al., 2009).
On the other hand, the present work reported that patients with lower baseline CD4 cell counts had lower peaks of CD4 cell counts. While patients with a high baseline CD4 cell count (>200 cells/μl) had CD4 cell counts that returned to almost normal levels. These results are consistent with reports from other studies which shows only patients with high baseline CD4 cell count had CD4 cell counts that returned to nearly normal levels though CD4 cell count (WHO, 2005;MacLennan et al., 2007).
In this study, female HIV patients showed a better CD4 cell count after HAART initiation was pointed out than male. This is consistent with other report by Asfaw et al. (2015), Zhou et al. (2010), Kumar et al. (2017), and Malaza et al. (2013). In contrast, a study of immunological recovery in patients indicated that gender was not associated with the increase in CD4 counts (Smith et al., 2004;Lawn et al., 2006).
This study attempted to determine the loss to follow up from ART treatment program among adult population. The loss to follow up rate was 11.6% in this study. This finding is comparable with studies which were conducted in Northwest Ethiopia but lower than studies from Bahrdar Felege Hiwot Hospital and Gonder Referral Hospital which showed that the lost to follow up rate were 8.4, 18 and 19% respectively (Gezie et al., 2017;Molla et al., 2018).

Conclusion
The findings of this study depicted that there are an improvement in CD4 recovery and the highest CD4 cell counts were achieved when HAART was started at a high baseline CD4 cell count. The CD4 cell count is less likely to return to normal when HAART is started at lower CD4 cell counts, this could be a reason to consider initiating HAART before high CD4 cell count decreases. The present findings confirm the previous studies that the degree of CD4 depletion prior to ART initiation is the most consistent determinant of subsequent immune reconstitution. Therefore, initiation of HAART before the CD4 cell count decreases to <200 cells/μl is recommended to achieve and maintain normal CD4 cell Negussie et al. 7 count. Females HIV patients achieved better immune recovery as compared with male.