|Year : 2020 | Volume
| Issue : 1 | Page : 22-28
Determinants of discordant immune response in a cohort of human immunodeficiency virus-infected patients initiating antiretroviral therapy
Abdullahi Umar1, Mufutau Muphy Oripelaye2, Fatai Olatunde Olanrewaju2, Olaniyi Onayemi2, Olayinka Abimbola Olasode2, Olumayowa Abimbola Oninla2
1 Department of Medicine, Dermatology/Infectious Disease Unit, Ahmadu Bello University Zaria, Kaduna State, Nigeria
2 Department of Dermatology and Venereology, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
|Date of Submission||08-Jan-2019|
|Date of Decision||20-Mar-2019|
|Date of Acceptance||01-Sep-2019|
|Date of Web Publication||18-Mar-2020|
Dr. Mufutau Muphy Oripelaye
Department of Dermatology and Venereology, Obafemi Awolowo University, Ile-Ife, Osun State
Background: The introduction and wide use of highly active antiretroviral therapy (HAART) have significantly resulted in decline in morbidity and mortality from human immunodeficiency virus (HIV) infection and its related complications. These drugs can effectively induce virological suppression of the HIV-RNA replication to below the level of quantification, with eventual rise in the CD4+ cells counts. This is the therapeutic goal of using HAART in HIV-infected patients. However, some HIV-infected patients commencing HAART might have adequate virological suppression without a corresponding rise in CD4+ cells count-a phenomenon referred to as discordant immune response (DIR) or immunological nonresponse. Objective: The objective is to determine the factors associated with DIR among HIV-infected patients with adequate virological suppression, after initiating HAART. Materials and Methods: This study was a descriptive, retrospective, cross-sectional study that analyzed data from 200 HIV-infected adults that have been on HAART for 12 months descriptive statistics were used to describe the demographic profile of the participants, and binary logistic regression was used to assess the factors predicting DIR among the studied population. Results: One hundred and thirty-six (68%) were female with a mean age of 40.5 ± 10.9 years. The mean baseline CD4+ cells count was 162 ± 95.9 cells/mm3. Twelve months after HAART initiation, 64 (32%) of patients were immunological nonresponders. On multivariate analysis (logistics regression), patients initiating treatment at a higher CD4+ cells count >200 cells/mm3 (adjusted odds ratio [AOR] 3.89; confidence interval [CI]: 1.64–9.22; P = 0.002), the presence of anemia (hemoglobin <11.0 g/dl) (AOR 2.58; CI: 1.11–5.98; P = 0.027), and hepatitis C virus (HCV) positivity (AOR 9.84; CI: 3.10–18.12; P = 0.003) were independently associated with the development of DIR among the studied population. Conclusion: DIR among the studied population was common and associated with high baseline CD4+ cells count, baseline anemia, and HCV positivity from our HIV-infected patients. Thus, there is a need for adequate evaluation and monitoring of at-risk individuals to improve clinical outcomes.
Keywords: Antiretroviral therapy, discordant, highly active antiretroviral therapy, human immunodeficiency virus
|How to cite this article:|
Umar A, Oripelaye MM, Olanrewaju FO, Onayemi O, Olasode OA, Oninla OA. Determinants of discordant immune response in a cohort of human immunodeficiency virus-infected patients initiating antiretroviral therapy. Sahel Med J 2020;23:22-8
|How to cite this URL:|
Umar A, Oripelaye MM, Olanrewaju FO, Onayemi O, Olasode OA, Oninla OA. Determinants of discordant immune response in a cohort of human immunodeficiency virus-infected patients initiating antiretroviral therapy. Sahel Med J [serial online] 2020 [cited 2020 May 26];23:22-8. Available from: http://www.smjonline.org/text.asp?2020/23/1/22/280935
| Introduction|| |
There has been a dramatic reduction in mortality and morbidity from human immunodeficiency virus (HIV) and its related complications since the advent of highly active antiretroviral therapy (HAART) in the mid to late 1990s. The antiretroviral drugs work by effectively suppressing HIV-RNA replication to below the level of quantification, which typically results in a significant rise in CD4+ cells counts. This rise sometimes referred to as immunologic response to HAART, is central to restoration of the integrity of the immune system with eventual reduction in HIV-related morbidity and mortality. Adherence to HAART for at least 6 months should lead to rapid and sustained HIV-RNA virological suppression to undetectable levels (≤400 copies/ml) and subsequently to ≤50 copies/ml after 12 months. The “Complete” responses (bot virological and immunological) in patient on HAART, are associated with improved clinical outcomes when compared with patients with discordant responses or patients who experience neither a virologic nor immunologic response. Even though there is no agreed definition of discordant immune response (DIR), it is a situation whereby there is a failure to satisfactorily increase CD4+ cells count on HAART despite successful virological control. This paradoxical response is referred to by various terms in the literature including DIR, poor or suboptimal immune reconstitution, incomplete immune recovery (IR) or restoration and immunological nonresponse. DIR is seen in up to 20%–40% of patients on HAART. This condition has been linked with significant increases in the risk of AIDS-related and non-AIDS-related mortality and morbidity, including cardiovascular, hepatic, renal diseases, and malignancies.,, The exact pathogenesis of DIR is still not fully understood; however, it may arise either as a result of failed immune reconstitution or the excessive destruction of CD4+ cells. Several risk factors have been put forward to explain this paradoxical phenomenon which includes older age, male sex, poor virologic response, injection drug use as an HIV acquisition risk factor, hepatitis C virus (HCV) coinfection, and lower baseline CD4+ cell count and HIV-RNA viral load.
Some suggested etiopathogenic mechanisms of DIR include depletion thymic progenitor cells caused by untreated HIV infection, lymphoid tissues fibrosis, especially the gastric associated lymphoid tissues caused by the virus and chronic immune system activation.,, Other factors play an important role in the occurrence of DIR especially in causing T-cell activation include microbial translocation, low-level persistent HIV viral replication within the fibrosed lymph nodes and latent co-infection such as cytomegalovirus and latent tuberculosis.,
Despite the relative high frequency of DIR among HIV patients on HAART, not much has been published in the literature regarding the prevalence and associated risk factors, especially in our setting (sub-Saharan Africa), where the high burden of HIV infection is characterized by late presentation with advanced disease, delay in HAART initiation, multiple opportunistic infections, and comorbidities such as viral hepatitis. Adequate knowledge about this phenomenon may contribute to their clinical management. This descriptive, retrospective cross-sectional study describes this phenomenon, and factors associated with DIR in a cohort of HIV-infected patients initiating HAART in Nigeria.
| Materials and Methods|| |
The study was carried out at the Virology research clinic of Obafemi Awolowo University Teaching hospitals Complex (OAUTHC) Ile Ife. A significant number of patients seek medical treatment in this center as a first point of contact. The HIV clinic also receives patients referred to as HIV-positive following screening tests with rapid kits within and outside the hospital and also offers voluntary counseling and testing.
This was a hospital-based retrospective cross-sectional study.
The study was conducted over 3 months.
The study participants comprise of HIV-positive patients aged 18 years and older, receiving treatment and care at the virology clinic of OAUTHC.
Ethical approval was obtained before the commencement of this research (Protocol no: ERC/2019/09/06. Date: 11/09/2019. Ethics and Research Committee (ERC), Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife). We adhered to 2013 Helsinki's declaration and guidelines. The data collected were de-identified, and unique research identification numbers were used instead of patient's names, and patient's records were handled with strict confidentiality.
Study procedure and data collection
We retrospectively reviewed the case folders of 200 HIV-infected patients, who had nadir presuppression CD4+ cells count of <350 cells/mm3, have been on HAART for 12 months with evidence of good adherence and has achieved plasma HIV-RNA <20 copies/ml. Data were extracted from the case folders of each participant. Information on socio-demographic characteristics (age, gender, education level, occupation status, and alcohol/cigarette use), medical history including HIV disease stage, history of tuberculosis and HAART information were extracted. Physical examination findings such as body mass index (BMI) and blood pressure were recorded. Laboratory parameters such as hepatitis B and C serology results, hemoglobin (Hb) values, and CD4+ cells count were recorded at HAART initiation (i.e., baseline) and at 12 months' post-HAART initiation as the case may be. In addition, viral load results at 12 months after ART initiation were recorded.
For this study, the following outcomes definitions were adopted; virologic suppression was defined as a viral load value of <20 copies/ml at 12 months after HAART initiation. Immune reconstitution was defined as an absolute increase in the CD4+ cells count value of at least 100 cells/mm3 at 12 months after ART initiation. This is because the expected rate of CD4+ cells count increase following HAART initiation is 20–30 cells per month in the first 6 months and then 5–10 cells per month between 6 months and 24 months. DIR was defined as a rise of CD4+ cells count of <100 cells/mm3 at 12 months' following commencement HAART, in patients who have achieved virological suppression. This definition of DIR applies to those commencing HAART with CD4+ cells count <350 cells/mm3 so as to avoid overdiagnosis of DIR in a population starting with higher CD4 counts. Viral load results obtained at 12 months after HAART initiation was used, in accordance with the 6 and 12 months' follow-up recommendation of the national HIV treatment guidelines, for CD4 cells count and viral load check after HAART initiation.
Data management and data analysis
Study group characteristics were described using descriptive statistics, means and standard deviations for continuous variables when normally distributed, median for skewed data, and frequencies for categorical variables. Means were compared using the student t-test for normally distributed data and Chi-square test was used for categorical variables. Associations between the occurrence of DIR and possible risk factors were assessed using logistic regression, adjusted odds ratios (AORs) at 95% confidence intervals (CIs) to express the measure of association. Factors that were significant at P ≤ 0.25 in the bivariate analysis were considered for inclusion in the logistic regression model.
| Results|| |
The socio-demographic characteristics of the study population are shown in [Table 1]. Among the studied population, 68% (n = 136) were female with a mean age of 40.5 ± 10.9 years. The mean baseline CD4+ cells count of the studied population was 162 ± 95.9 cells/mm3, median baseline weight was 53.3 kg, 65.5% (n = 131) of the patients were anemic with a mean baseline Hb level of 10.3 ± 1.7 g/dl and 55% (n = 110) of the studied population were commenced on tenofovir-lamivudine-efavirenz/nevirapine based HAART regimen. Twelve months after HAART initiation, 32% (n = 64) of patients are immunological nonresponders, compared to 68% (n = 136) who had an optimal immune response. The mean CD4+ cells count of the immunological nonresponders group at HAART initiation was significantly higher at 187 ± 95.8 cells/mm3 compared to that of the optimal immune responders group with 150 ± 93.9 cells/mm3 (P = 0.009), and the mean increment in the CD4+ cells count at 12 months for the immunological nonresponders group was significantly lower at 46 ± 28.5 cells/mm3 compare to the optimal immune responders group which was 251 ± 134.4 cells/mm3 (P = 0.0001).
Predictors of discordant immune response in the studied population
The baseline characteristics of the immunological nonresponders and that of the immunological responders were compared using multivariate analysis and binary logistic regression, as shown in [Table 2]. Patients initiating treatment at a higher CD4+ cells count >200 cells/mm3 (AOR 3.89, CI; 1.64–9.22, P = 0.002), and the presence of anemia (Hb <11.0 g/dl), (AOR 2.58, CI; 1.11–5.98, P = 0.027), were significantly associated with immunological nonresponse after adjusting for baseline education level, the WHO clinical stage, and HAART regimen. HCV positivity (AOR 9.84, CI; 3.10–18.12, P = 0.003) was also independently associated with the development of immunological nonresponse among the studied population. Other factors such as gender, HBV positivity, HAART type, and BMI were not significant predictors of immunological nonresponse in this study.
|Table 2: Factors associated with immunological nonresponse with logistic regressions|
Click here to view
| Discussion|| |
DIR in HIV-positive patients still remains a common phenomenon affecting up to 20%–40% of patients on HAART, which has been linked to increase morbidity and mortality in the affected patients. The observed proportion of HIV-infected patients from this study having DIR following HAART falls within the above range. Factors that were found to predict DIR from this study include initiating HAART at a higher CD4+ cells count >200 cells/mm3, initiating HAART with mild anemia and HCV coinfection. However, this study did not observe any significant associations between DIR and age, gender, BMI, or HAART regimen, even though these were previously reported as risk factors by other studies.,
The findings of an association between commencing HAART at a higher baseline CD4+ cells count >200 cells/mm3 and DIR from this study was similar to reports from South Africa, Uganda, and some other western countries.,,,,, This can be explained by the nonlinear nature of CD4+ cells count increase following HAART initiation across the different baseline CD4+ cells count strata, in that commencing HAART at higher CD4 cell counts limits the scope for further rise in the CD4+ cells.,, Furthermore, patients with baseline CD4+ cells counts <50 cells/mm3 tend to have a steeper gradient of CD4+ cells count increase compare to patients with baseline CD4+ cells counts between 50 and 199 cells/mm3 as was reported by large HIV treatment programs in South Africa. Nakanjako et al. in a study that described patterns of suboptimal (SO-IR) and associated HIV-related-illnesses during the first 5 years' following first-line antiretroviral therapy (HAART) initiation across seven HIV treatment sites in East Africa, reported SO-IR in 40% of adults initiated on HARART with CD4+ cells counts <350 cells/ml after 5 years. Factors that were reported to predict SO-IR in that study were older age, male sex, and anemia. They also found that patients with an advanced stage of HIV disease (WHO stage three and four, and baseline CD4+ cells counts <100 cells/mm3) were less likely to have SO-IR.
However, it is contrary to several studies conducted in resource-rich settings that have reported low baseline CD4+ cells count at initiation of HAART to be associated with DIR.,,,
This study also found that anemia at the initiation of HAART is associated with DIR, a finding that was reported by similar studies.,, HIV-related anemia is often anemia of chronic illness which can be caused by many factors. The mechanisms of cytokine-induced bone marrow stem cell suppression caused by continuous immune system activation, and membrane changes in both erythrocytes and CD4+ T-lymphocytes could explain the association between anemia when starting HAART and a subsequent DIR. Some studies have also shown that anemia in HIV-infected patients is associated with CD4+ cells depletion and progression to AIDS, and is one of the strongest predictors of HIV mortality and poor response to HAART.,
Finally, DIR was also found to be associated with HCV co-infection in HIV patients from our study. This is similar to the findings in studies conducted in developed countries to determine the effects of CD4+ cells recovery in patients with HIV/HCV coinfection following initiation of HAART, where it was found that presence of HCV coinfection significantly affects CD4+ cells recovery without any effect on the viral load., HCV/HIV coinfection is known to result in a higher level of immune activation. This persistent immune activation makes the CD4+ cells to be trapped in secondary lymphoid organs, as well as die by apoptosis. This has been linked with incomplete CD4+ cells regeneration in HIV/HCV coinfection following initiation of HAART.
Limitations of the study
It is possible that some of the observed risk factors may be absent, as well as reduced percentage of the immune discordant subjects, if the outcomes were assessed after a longer period on HAART like 2–5 years. The multicenter study would have given a better picture of the factors associated with DIR in Nigeria.
| Conclusion|| |
The findings from this study suggest that 32% of patients initiating HAART in Nigeria have a DIR after 12 months on HAART, despite adequate virological suppression. Factors that were found to be significantly associated with DIR in these patients were baseline CD4+ cells count >200 cells/mm3, anemia, and HCV coinfection. While further multicenter studies are required, to involve a large cohort of HIV-infected patients from different parts of the country to examine these associations, these data may assist in the early identification of patients that are likely to have DIRs on HAART.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, et al
. Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA study group. Lancet 1998;352:1725-30.
Grabar S, Le Moing V, Goujard C, Leport C, Kazatchkine MD, Costagliola D, et al
. Clinical outcome of patients with HIV-1 infection according to immunologic and virologic response after 6 months of highly active antiretroviral therapy. Ann Intern Med 2000;133:401-10.
Piketty C, Weiss L, Thomas F, Mohamed AS, Belec L, Kazatchkine MD. Long-term clinical outcome of human immunodeficiency virus-infected patients with discordant immunologic and virologic responses to a protease inhibitor-containing regimen. J Infect Dis 2001;183:1328-35.
Kelly C, Gaskell KM, Richardson M, Klein N, Garner P, MacPherson P. Discordant immune response with antiretroviral therapy in HIV-1: A systematic review of clinical outcomes. PLoS One 2016;11:e0156099.
Zoufaly A, an der Heiden M, Kollan C, Bogner JR, Fätkenheuer G, Wasmuth JC, et al
. Clinical outcome of HIV-infected patients with discordant virological and immunological response to antiretroviral therapy. J Infect Dis 2011;203:364-71.
Moore DM, Hogg RS, Chan K, Tyndall M, Yip B, Montaner JS, et al
. Disease progression in patients with virological suppression in response to HAART is associated with the degree of immunological response. AIDS 2006;20:371-7.
Muzah BP, Takuva S, Maskew M, Delany-Moretlwe S. Risk factors for discordant immune response among HIV-infected patients initiating antiretroviral therapy: A retrospective cohort study. S Afr J HIV Med 2012;13:168-72.
Vaamonde CM, Hoover DR, Anastos K, Tan T, Shi Q, Gao W, et al
. Factors associated with poor immunologic response to virologic suppression by highly active antiretroviral therapy in HIV-infected women. AIDS Res Hum Retroviruses 2006;22:222-31.
Bandera A, Ferrario G, Saresella M, Marventano I, Soria A, Zanini F, et al
. CD4+T cell depletion, immune activation and increased production of regulatory T cells in the thymus of HIV-infected individuals. PLoS One 2010;5:e10788.
Zeng M, Southern PJ, Reilly CS, Beilman GJ, Chipman JG, Schacker TW, et al
. Lymphoid tissue damage in HIV-1 infection depletes naïve T cells and limits T cell reconstitution after antiretroviral therapy. PLoS Pathog 2012;8:e1002437.
Serrano-Villar S, Sainz T, Lee SA, Hunt PW, Sinclair E, Shacklett BL, et al
. HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+T cell activation, and increased risk of non-AIDS morbidity and mortality. PLoS Pathog 2014;10:e1004078.
Funderburg NT. Markers of coagulation and inflammation often remain elevated in ART-treated HIV-infected patients. Curr Opin HIV AIDS 2014;9:80-6.
Nakanjako D, Kiragga A, Ibrahim F, Castelnuovo B, Kamya MR, Easterbrook PJ. Sub-optimal CD4 reconstitution despite viral suppression in an urban cohort on antiretroviral therapy (ART) in sub-Saharan Africa: Frequency and clinical significance. AIDS Res Ther 2008;5:23.
Lawn SD, Myer L, Bekker LG, Wood R. CD4 cell count recovery among HIV-infected patients with very advanced immunodeficiency commencing antiretroviral treatment in sub-Saharan Africa. BMC Infect Dis 2006;6:59.
Tuboi SH, Brinkhof MW, Egger M, Stone RA, Braitstein P, Nash D, et al
. Discordant responses to potent antiretroviral treatment in previously naive HIV-1-infected adults initiating treatment in resource-constrained countries: The antiretroviral therapy in low-income countries (ART-LINC) collaboration. J Acquir Immune Defic Syndr 2007;45:52-9.
Gilson RJ, Man SL, Copas A, Rider A, Forsyth S, Hill T, et al
. Discordant responses on starting highly active antiretroviral therapy: Suboptimal CD4 increases despite early viral suppression in the UK collaborative HIV cohort (UK CHIC) study. HIV Med 2010;11:152-60.
Schomaker M, Egger M, Maskew M, Garone D, Prozesky H, Hoffmann CJ, et al
. Immune recovery after starting ART in HIV-infected patients presenting and not presenting with tuberculosis in South Africa. J Acquir Immune Defic Syndr 2013;63:142-5.
Zhang F, Sun M, Sun J, Guan L, Wang J, Lu H. The risk factors for suboptimal CD4 recovery in HIV infected population: An observational and retrospective study in Shanghai, China. Biosci Trends 2015;9:335-41.
Kroeze S, Ondoa P, Kityo CM, Siwale M, Akanmu S, Wellington M, et al
. Suboptimal immune recovery during antiretroviral therapy with sustained HIV suppression in Sub-Saharan Africa. AIDS 2018;32:1043-51.
Sorsa A. Predictors of sub-optimal CD4 recovery during the first six months of anti-retroviral treatment (ART) in HIV infected children: A retrospective cross sectional study from Tikur Anbessa tertiary hospital, Addis Ababa, Ethiopia. J Blood Lymph 2017;7:178.
Al-Majid F, Shakoor Z, Barry M. Suboptimal immune reconstitution among HIV-infected Saudi patients following successful antiretroviral treatment. Can J Infect Dis Med Microbiol 2019;2019:1842106.
Moore RD, Forney D. Anemia in HIV-infected patients receiving highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2002;29:54-7.
Mata-Marín JA, Gaytán-Martínez JE, Martínez-Martínez RE, Arroyo-Anduiza CI, Fuentes-Allen JL, Casarrubias-Ramirez M, et al
. Risk factors and correlates for anemia in HIV treatment-naïve infected patients: A cross-sectional analytical study. BMC Res Notes 2010;3:230.
Siegfried N, Uthman OA, Rutherford GW. Optimal time for initiation of antiretroviral therapy in asymptomatic, HIV-infected, treatment-naive adults. Cochrane Database Syst Rev. 2010;(3):CD008272.
Greub G, Ledergerber B, Battegay M, Grob P, Perrin L, Furrer H. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: The Swiss HIV cohort study. Lancet 2000;356:1800-5.
Lincoln D, Petoumenos K, Dore GJ; Australian HIV Observational Database. HIV/HBV and HIV/HCV coinfection, and outcomes following highly active antiretroviral therapy. HIV Med 2003;4:241-9.
Gonzalez VD, Falconer K, Blom KG, Reichard O, Mørn B, Laursen AL, et al
. High levels of chronic immune activation in the T-cell compartments of patients coinfected with hepatitis C virus and human immunodeficiency virus type 1 and on highly active antiretroviral therapy are reverted by alpha interferon and ribavirin treatment. J Virol 2009;83:11407-11.
Corbeau P, Reynes J. Immune reconstitution under antiretroviral therapy: The new challenge in HIV-1 infection. Blood 2011;117:5582-90.
[Table 1], [Table 2]