Immunologic and virologic responses to antiretroviral therapy in treatment-naïve,HIV-infected elderly patients

Abstract

Currently available data on immunologic and virologic responses to antiretroviral therapy (ART) in elderly patients are conflicting. The primary objective of this study was to assess immunologic and virologic responses to ART in treatment-naïve, HIV-infected elderly patients compared to younger patients. This was a single center, retrospective, descriptive study including treatment-naïve, HIV-infected adults initiated on ART between 1 January 2005 and 30 April 2015. Immunologic and virologic responses were compared between the ages ≥50 and < 50 years old. A total of 158 patients were included. By 14 months of ART, 85.9% (n = 67/78) of the patients ≥50 years old and 92.5% (n = 74/80) of those < 50 years old achieved immunologic response (p = 0.02). By 24 weeks of ART, 64.1% (n = 50/78) of the patients ≥50 years old and 65% (n = 52/80) of those < 50 years old achieved virologic response (p = 1). The amount of time it took the elderly patients to achieve virologic suppression was not significantly different compared to the younger patients (p = 0.459). Treatment-naïve, HIV-infected elderly patients achieved virologic response to ART that was comparable to younger patients although their immunologic response to ART was significantly lower.

Keywords

Human immunodeficiency virus antiretroviral therapy treatment

Introduction

The effectiveness of antiretroviral therapy (ART) has lengthened the life expectancy of older people living with human immunodeficiency virus (HIV) infection (PLWH). The U.S. Department of Health and Human Services (DHHS) defines elderly PLWH as 50 years of age and older. According to the Center for Disease Control and Prevention (CDC), nearly half of the people estimated in the U.S. living with a diagnosis of HIV are aged 50 years of age and older. In 2016, the people newly diagnosed with HIV aged 50 and older accounted for 17% (6812) of the 39,782 total newly diagnosed individuals. Among older adults newly diagnosed with HIV infection, the largest percentage was aged 50 to 54 years (43%). The total number of older PLWH is increasing, and there are limited clinical trial or pharmacokinetic studies on antiretroviral medications including this aging population.¹

Given the growing newly diagnosed elderly PLWH population, the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents has devoted a specific section addressing key issues in this specific population. According to their guidelines, initiation of ART is recommended in all patients irrespective of baseline CD4 cell count. ART initiation is important in the elderly as they are at an increased risk for developing acquired immunodeficiency syndrome (AIDS) complications and have a decreased immune recovery. There are no data supporting a specific ART regimen in the elderly population; however, drug–drug interactions and other comorbidities must be taken into consideration when deciding on an ART regimen.²

An important laboratory marker to monitor in the management of HIV is the CD4 cell count, which serves as an indicator of immune function. The U.S. DHHS recommendation is to obtain a CD4 cell count every three to six months during the first year of initiating ART. An adequate response is defined as an increase in CD4 cell count by 50 to 150 cells/μL during the first year of ART initiation. The plasma HIV-1 RNA, viral load (VL), is measured for PLWH at entry into care and subsequently thereafter, and it is utilized as an indicator of an individual patient’s response to ART. In individuals being initiated on ART, it is recommended to obtain a VL within two to eight weeks of starting ART by the U.S. DHHS. If VL is detectable, it is recommended to repeat the VL every four to eight weeks until it is below 200 copies/mL and every three to six months thereafter. Individuals that are adherent to their ART and do not harbor resistance mutations are expected to achieve viral suppression within 8 to 24 weeks after the initiation of ART.²

There have been a small number of studies conducted to compare the elderly to younger treatment-naïve, PLWH based on immunologic response to ART. Some studies indicated that patients aged 50 years and over have a reduced immunologic response to ART compared to those less than 50 years of age.^3–8 However, other studies demonstrated no difference in immunologic response to ART based on age.^9–11 Conversely, several studies were able to identify older patients progressing more rapidly to undetectable VL as defined by the investigators.^4,5,7,10 There are limited data correlating virologic and immunologic responses with regards to a patient’s age and specific ART regimen initiated. Of note, only one of the studies included a small percentage of patients on an integrase strand transfer inhibitor (INSTI)-based regimen. Given the increase in INSTI prescribing as well as the recommendations by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents for the use of INSTI-based regimens, it is anticipated that the majority of the patients within our study population to be on an INSTI-based regimen.

The purpose of this study is to assess virologic and immunologic responses in older treatment-naïve, HIV-infected individuals initiated on ART compared to the younger treatment-naïve, PLWH initiated on ART.

Methods

Patient population

The study included treatment-naïve, PLWH 18 years and older who were initiated on ART at the HIV ambulatory clinic affiliated with an urban academic medical center in Brooklyn, New York from 1 January 2005 to 30 April 2015. Patients were included if they had the following documented: CD4 cell count and HIV-1 RNA VL at baseline prior to initiating ART, a repeat CD4 cell count within 3 to 14 months following ART initiation, and a HIV-1 RNA VL within 8 to 24 weeks following ART initiation. Patients were excluded if they were not initiated on an ART regimen or discontinued the ART regimen prior to completing at least eight weeks of therapy.

Study design

This was a single center, retrospective, cohort study. The study protocol was approved by the institutional review board of the State University of New York (SUNY) Downstate Medical Center, Brooklyn, NY. Patients were identified through a computer-generated report from the electronic health record system in the HIV ambulatory clinic, Office Practicum™ version 14, based on initial clinic visits from 1 January 2005 to 30 April 2015. Patients were divided into those 50 years of age and older (elderly patient group) and those younger than 50 years of age (younger patient group). Once the number of elderly patient meeting inclusion criteria were identified, then an approximately equal random sample size of younger patients meeting inclusion criteria was identified.

Data collection

Electronic health records were reviewed to obtain patient demographics including age, gender, ethnicity, other comorbidities (i.e. asthma, chronic heart failure [CHF], chronic obstructive pulmonary disease [COPD], coronary artery disease [CAD], hyperlipidemia hypertension, renal dysfunction), mode of HIV exposure, opportunistic infection at the time of diagnosis, ART regimen classified based on the classes, and documented hepatitis C virus (HCV) co-infection. The following laboratory values were collected: CD4 cell count and HIV-1 RNA VL at baseline, subsequent CD4 cell count within a 14-month follow-up period following the initiation of ART, lowest HIV-1 RNA VL within 8 to 24 weeks after initiating ART, and time required to achieve viral suppression after ART initiation. Viral suppression was defined as achieving a HIV-1 RNA VL below the quantitative amount detected by the COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 Test v2.0, which has a lower limit quantification of 20 copies/mL.

Outcome measures

The primary outcomes were immunologic and virologic responses in the elderly PLWH to the initiation of ART compared to younger PLWH. Immunologic response was defined as achieving an increase in the CD4 cell count within a 14-month follow-up period after ART initiation by 50 to 150 cells/μL. If patients could achieve an undetectable VL within 24 weeks of following ART initiation, then they were determined to have had a virologic response. The secondary outcomes included the results of the primary outcome stratified by baseline CD4 cell count (≤200 vs. >200 cells/µL) and ART regimen in PLWH greater than 50 years of age. The time until achieving an undetectable HIV-1 RNA VL in relation to the age at the time of ART initiation was assessed, as well as the median change in CD4 cell count and percentage, CD8 cell count, and CD4 to CD8 ratio from baseline to the 14-month follow-up study period once ART was initiated.

Statistical analysis

Data were analyzed utilizing descriptive statistics and expressed as mean with standard deviation (SD) and percentages. The Fisher’s exact test was used for comparison of the two age groups with respect to attainment of the immunologic and virologic responses. The Mann–Whitney test was used to compare the difference between the two groups with respect to the changes observed in the CD4 cell count and percentage, CD8 cell count, and CD4 to CD8 ratio. The Log-rank test was used to determine the time until an undetectable VL. Significance level was set at p-value of 0.05.

Results

Enrollment

There were a total of 126 patients who were ≥50 years of age and 48 of the 126 patients were excluded. The most common reason for exclusion was never initiating ART (n = 28), lost to follow-up or non-adherent to regimen (n = 8), and ART changed during the study period (n = 6). These exclusions resulted in 78 patients to be included for those ≥50 years of age. There were a total of 266 patients who were <50 years of age, and they were randomly reviewed until 80 patients were identified to have met inclusion criteria in order to have a similar number of patients in each study arm (Figure 1).

Figure 1.

Enrollment.

Patient characteristics

At the time of ART initiation, the mean age was 46.4 ± 14 years of which 62% were male and majority were African American (96.2%) between both groups at the time of inclusion. The elderly group was found to have more comorbidities overall; however, more of the younger patients had asthma and COPD. The most common ART regimen was nucleoside reverse transcriptase inhibitor (NRTI) based and a non-nucleoside reverse transcriptase inhibitor (NNRTI), followed by a protease inhibitor (PI). The regimen including NRTIs and an INSTI was the least prevalent amongst our study population. The elderly group had a mean baseline CD4 cell count of 251 ± 230 cells/μL and a mean baseline VL of 204,534 ± 618,794 copies/mL. At baseline, the younger patient group was found to have a greater CD4 cell count of 278 ± 230 cells/μL and a lower VL of 140,756 ± 334,481 copies/mL when compared to the elderly (Table 1). The CD4 cell count (p = 0.77) and VL (p = 0.79) were not found to be statistically significant amongst the two groups at baseline.

Table 1.

Baseline characteristics.

Demographics
Characteristics	<50 years of age (n=80)	≥50 years of age (n=78)
Mean age (years ± SD)	35.5 ± 8.7	57.6 ± 6.8
Male, n (%)	49 (61.3)	49 (62.8)
Ethnicity, n (%)
Caucasian	3 (3.8)	3 (3.8)
African American	77 (96.3)	75 (96.2)
Comorbidities, n (%)
Hypertension	12 (15)	46 (59)
Hyperlipidemia	1 (1.3)	9 (11.5)
Diabetes	5 (6.3)	20 (25.6)
Asthma/COPD	9 (11.3)	5 (6.4)
CKD	1 (1.3)	3 (3.8)
ESRD/HD	1 (1.3)	2 (2.6)
HCV co-infected	2 (2.5)	7 (9)
ART regimen, n (%)
NRTI + NNRTI	44 (55)	47 (60.3)
NRTI + PI	25 (31.3)	21 (26.9)
NRTI + INSTI	11 (13.8)	8 (10.3)
Other	0	2 (2.6)
Opportunistic infection history, n (%)	13 (16.3)	13 (16.7)
Oral candidiasis	11 (13.8)	7 (9)
Esophageal candidiasis	0	1 (1.3)
Pneumocystis jirovecii pneumonia	3 (3.8)	8 (10.3)
Cryptococcal meningitis	1 (1.3)	0
Mode of transmission, n (%)
Sexual	47 (58.8)	47 (60.3)
Intravenous drug use (IVDU)	3 (3.8)	3 (3.8)
Transfusion	1 (1.3)	4 (5.1)
Unknown	31 (38.8)	28 (35.9)
Mean baseline CD4 (cells/μL ± SD)	278 ± 230	251 ± 230
Mean baseline VL (copies/mL ± SD)	140,756 ± 334,481	204,534 ± 618,794

SD: standard deviation; COPD: chronic obstructive pulmonary disease; CKD: chronic kidney disease; ESRD: end stage renal disease; HD: hemodialysis; HCV: hepatitis C virus; NRTI: nucleoside reverse transcriptase inhibitor; NNRTI: non-nucleoside reverse transcriptase inhibitor; PI: protease inhibitor; INSTI: integrase strand transfer inhibitor.

Outcomes

Overall, immunologic response was achieved in 89.2% (n = 141/158) of patients. The CD4 cell count was significantly increased by 50 to 150 cells/μL within 14 months of study initiation in 92.5% (n = 74/80) of young and 85.9% (n = 67/78) of elderly patients. (p = 0.0207). Out of 158 patients including the young and elderly, 102 patients obtained an undetectable VL by 24 weeks overall. There was no significant difference between the two groups in regards to virologic response (elderly, 64.1% (n = 80/78) vs. young, 65% (n = 52/80), p = 1) (Figure 2).

Figure 2.

Percent of patients achieving the primary outcome.

The median change of CD4 cell percentage was significantly different between the young at 10% (IQR: 6% to 14.5%) and elderly at 7% (IQR: 7% to 11%) (p = 0.004). Also, there was a significant difference in the median change of CD4 to CD8 ratio over the 14-month follow-up period in the young at 0.27 (IQR: 0.13 to 0.48) and elderly at 0.18 (IQR: 0.09 to 0.39) (p = 0.018) (Table 2). In patients ≥50 years of age, baseline CD4 cell count was not significantly associated with either immunologic (≤ 200 cells/µL, 85.3% [n = 29/34] vs. > 200 cells/µL, 86.4% [n = 38/44], p = 1) or virologic (≤ 200 cells/µL, 64.7% [n = 22/34] vs. > 200 cells/µL, 63.6% [n = 28/44], p = 1) response (Table 3). Also, immunologic (p = 0.179) and virologic (p = 0.13) responses were not significantly different among ART regimens in the elderly patients (Table 4). The amount of time it took the elderly patients to achieve virologic suppression was not significantly different compared to the younger patients (p = 0.459) (Figure 3).

Table 2.

Median change in T-lymphocyte cell panel.

	Age (years)	Median change (IQR)	p-value
CD4 cell count (cells/µL)	<50	192.8 (81.2–320)	0.076
CD4 cell count (cells/µL)	≥50	149 (81.5–226)	0.076
CD4 cell percent (%)	<50	10 (6–14.5)	0.004
CD4 cell percent (%)	≥50	7 (4–11)	0.004
CD8 cell count (cells/µL)	<50	0	1
CD8 cell count (cells/µL)	≥50	0	1
CD4/CD8 ratio	<50	0.27 (0.13–0.48)	0.018
CD4/CD8 ratio	≥50	0.18 (0.09–0.39)	0.018

Table 3.

Patients ≥50 years of age stratified based on baseline CD4 cell count.

Outcomes, n (%)	CD4 cell count ≤200 cells/µL (n=34)	CD4 cell count >200 cells/µL (n=44)	p-value
Immunologic response	29 (85.3)	38 (86.4)	1
Virologic response	22 (64.7)	28 (63.6)	1

Table 4.

Patients ≥ 50 years of age stratified based on ART regimen.

Outcomes, n (%)	NRTI + NNRTI (n=41)	NRTI + PI (n=21)	NRTI + INSTI (n=8)	p-value
Immunologic response	41 (87.2)	19 (90.5)	5 (62.5)	0.179
Virologic response	34 (72.3)	10 (47.6)	5 (62.5)	0.13

NRTI: nucleoside reverse transcriptase inhibitor; NNRTI: non-nucleoside reverse transcriptase inhibitor; PI: protease inhibitor; INSTI: integrase strand transfer inhibitor.

Figure 3.

Time until virologic suppression.

Discussion

In this study that reviewed a 124-month period of data, 78 HIV-infected, treatment-naïve, elderly patients were identified and compared to a younger patient population of 80 treatment-naïve PLWH over the same study period. There was a statistically significant difference between the two groups for immunologic response. The median change in the CD4 cell percentage as well as the CD4 to CD8 ratio was found to be statistically significant in HIV-infected, treatment-naïve patients initiated on ART based on their ages. These findings are suggestive that elderly patients have a reduced immunologic response compared to the younger patient population when initiated on ART.

Althoff et al. compared the time until an increase in the CD4 cell count by at least 100 cells/μL and the time until undetectable VL amongst several age categories. Patients were divided into five groups based on their ages (18 to 29, 30 to 39, 40 to 49, 50 to 59, and > 59 years) and compared immunologic and virologic responses. The authors concluded that while immunologic response was greater in the younger patients, there was no significant difference between the age and virologic response.⁶ A study including patients from a HIV program in South Africa by Mutevedzi et al. compared immunologic response of a CD4 increase by 50 cells/μL or greater following a six-month period after ART initiation and virologic suppression. The authors observed that patients 50 years of age and greater demonstrated a reduced immunologic response; however, the greatest response in virologic suppression was observed in the older patients.⁷ Greig et al. compared the median gain in CD4 cell count from patients treated in sub-Saharan Africa. The study revealed a significantly greater increase in the CD4 cell count in patients less than 50 years of age following ART initiation.⁸ Grabar et al. compared the mean increase in CD4 cell count over time and the time needed for undetectable VL between patients 18 to 48 years and ≥50 years of age. The study identified that the patients who were ≥50 years of age had a reduced immunologic response but a greater virologic response when compared to younger patients.⁵ Another study by Greenbaum et al. conducted a retrospective cohort study assessing the time until patients obtained an increase of ≥50 cells/μL in their CD4 cell count and the time until an undetectable VL. The authors concluded that the ≥50 years of age group had an improved virologic response compared to the 18 to 40 years of age group; however, no significant difference was observed in respect to immunologic response.¹⁰ Navarro et al. demonstrated no significant difference between the elderly (≥50 years of age) and those between 18 and 49 years of age with respect to median change in CD4 cell count over time. However, an improved virologic response was demonstrated in the older patient group.⁹ Ssebutinde et al. observed an overall increased risk of decline in the CD4 cell count in the older age group following treatment’ however, this was not identified as statistically significant.¹¹ A study by Sabin et al. included pediatric and adult patients as part of an observational multicohort study. They compared numerous age groups (<2, 2 to 5, 6 to 12, 13 to 17, 18 to 29, 30 to 39, 40 to 49, 50 to 54, 55 to 59, and > 59 years of age) for the evaluation of immunologic and virologic responses. Immunologic response was defined as an increase in the CD4 cell count by at least 100 cells/μL, and virologic response was defined as an undetectable VL, all within a 12-month follow-up period. The researchers concluded that the elderly patients have a reduced immunologic response but improved virologic response when compared to the younger patient populations.⁴ A more recent study by Blanco et al. conducted a pooled analysis of a prospective cohort in which they compared the immunologic (mean CD4 cell count increase at 48 and 96 weeks) and virologic responses (achievement of an undetectable VL at 48 and 96 weeks) between two age groups (18 to 49 years of age vs.≥50 years of age). This was the first study to include patients on an INSTI-based regimen, although it was a small percentage. The authors observed a reduced immunologic response in the older patients.³

Our study identified a reduced immunologic response in the older patient population similar to the other studies that indicated that patients aged 50 years and greater have a reduced response to ART compared to those less than 50 years of age.^3–8 However, other studies demonstrated no difference in response to ART based on age.^9–10 Conversely, several studies were able to identify older patients progressing more rapidly to undetectable VL as defined by the investigators while our studies identified no difference in virologic response amongst the two groups.^4,5,7,10 This difference observed maybe due to differences in the patients' baseline immune system given variability among different ethnicities. To our knowledge this is the first study assessing the baseline median change of CD4 cell count, CD4 cell percentage, CD8 cell count, and CD4 to CD8 ratio in comparison to the follow-up after ART initiation amongst patients in different age categories. However, our study had some limitations. It was a retrospective, single-center study with a small sample size. Most of the patient population included in the study was African American, potentially limiting the generalizability to other ethnicities. The predetermined timeframe to meet the endpoints are based on the recommendations from the U.S. DHHS guidelines; however, immunologic and virologic suppression are time dependent for individual patients requiring the potential of a longer observational period. Also, the distribution of patients into the various ART regimens varied with only a small number of patients on an INSTI-based regimen. Further research to understand the mechanism driving the reduced immunologic response in our elderly patient population is warranted, as well as the implications of the reduced immunologic response on patient outcomes.

Conclusion

In conclusion, treatment-naïve, elderly PLWH achieved virologic responses to ART that were comparable to younger patients although their immunologic responses to ART were significantly lower.

Footnotes

Acknowledgements

All authors contributed equally in the writing and revising of this manuscript.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

References

CDC. HIV among people aged 50 and older, www.cdc.gov/hiv/group/age/olderamericans/index.html (accessed 12 July 2019).

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services, www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf (accessed 27 December 2018).

Blanco

Jarrin

Perez-Elias

, et al.

Combined effect of sex and age in response to antiretroviral therapy in HIV-infected patients.

Antivir Ther 2017; 22:21–29.

The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study group. Response to combination antiretroviral therapy: variation by age. AIDS 2008; 22: 1463–1473.

Grabar

Kousignian

Sobel

, et al. Immunologic and clinical responses to highly active antiretroviral therapy over 50 years of age. Results from the French Hospital Database on HIV. AIDS 2004; 18: 2029–2038.

Althoff

Justice

Gange

, et al. Virologic and immunologic response to HAART, by age and regimen class. AIDS 2010; 24: 2469–2479.

Mutevedzi

Lessels

Rodger

, et al. Association of age with mortality and virological and immunological response to antiretroviral therapy in rural South African adults. PLoS ONE 2011; 6: e21795.

Greig

Casas

O’Brien

, et al. Association between older age and adverse outcomes on antiretroviral therapy: a cohort analysis of programme data from nine countries. AIDS 2012; 26: S31–S37.

Navarro

Nogueras

Segura

, et al. HIV-1 infected patients older than 50 years. PISCIS cohort study. J Infect 2008; 57: 64–71.

10.

Greenbaum

Wilson

Keruly

, et al. Effect of age and HAART regimen on clinical response in an urban cohort of HIV-infected individuals. AIDS 2008; 22: 2331–2339.

11.

Ssebutinde

Kyamwanga

Turyakira

, et al. Effect of age at initiation of antiretroviral therapy on treatment outcomes: a retrospective cohort study at a large HIV clinic in southwestern Uganda. PLoS ONE 2018; 13: e0201898.