The Efficacy and Safety of Maraviroc Addition to a Stable Antiretroviral Regimen in Subjects with Suppressed Plasma HIV-RNA Is Not Influenced by Age

Abstract

There are few data about the immunovirological efficacy, safety/tolerability, and durability of maraviroc (MVC) addition to aging patients on suppressive antiretroviral therapy (cART) and undetectable viral load (<50 copies/ml). The aging population is underrepresented in most HIV clinical trials. This study included 80 patients aged ≥50 years and 161 aged <50 years and showed that after 48 weeks of treatment, there was no between-group differences in the median increase of CD4⁺ T cells or the virological suppression rate. Safety and tolerability were also comparable. In multivariable analysis, the effect of age was not modified and was independent of the response to MVC. An immunological recovery of ≥100 CD4⁺ T cells was significantly less common in those with a longer HIV history (≥15 years) (OR 0.43; p=0.016) or having <200/mm³ CD4⁺ T cells at MVC initiation (OR 0.27; p=0.004). Meanwhile, achieving a CD4/CD8 ratio ≥0.5 at week 48 was less likely in those with CD4⁺ T cell counts <200 at MVC initiation (OR 0.09; p<0.0001) or with a previous AIDS event (OR 0.43; p=0.028). In summary, the immunovirological efficacy, safety/tolerability, and durability of MVC addition in patients virologically suppressed were independent of the patient's age at treatment onset.

Introduction

The prevalence of HIV-infected patients older than 50 years is increasing steadily. Although these patients achieve an equal or better virological suppression than younger patients, they usually have a poorer immunological recovery.¹ In addition, older HIV-infected patients have a faster HIV disease progression and a higher risk of related complications.¹

The clinical benefits obtained by combined antiretroviral therapy (cART) are strongly correlated with CD4⁺ T cell recovery.^2,3 However, successful cART and effective control of HIV-1 replication do not always correlate with achieving an optimal CD4⁺ T cell count.^4
–6 This inadequate immunological restoration increases AIDS and non-AIDS-related morbidity and mortality.^2,3,6,7 For this reason, several therapeutic strategies have aimed to improve the immunological status of these individuals with a discordant immune response and persistent immune activation and markers of inflammation.^8,9

One of the drugs used to enhance CD4⁺ T cell recovery has been maraviroc (MVC), a CCR5 antagonist that has demonstrated an intrinsic antiinflammatory activity. In previous clinical trials, treatment with MVC was associated with significant increases in CD4⁺ T cell counts both in treatment-naive and pretreated patients with virological failure.^10
–12 In addition, adding MVC to suppressive cART reduces markers of immune activation through an incompletely understood mechanism.^13

–16 Nevertheless, other studies have observed that adding MVC to patients on stable cART and sustained virological suppression was not beneficial in terms of CD4⁺ T cell count increase.^8,14

Our a priori hypothesis was that the addition of MVC to suppressive cART could improve the immunological response in patients with insufficient immunological restoration, regardless of the patient's age.

Materials and Methods

This was an observational, retrospective, multicenter study of adult HIV-infected patients on stable cART and undetectable viral load (VL <50 copies/ml) in which MVC was added to their existing cART regimen and they had at least one follow-up visit. The entire Spanish National Cohort Database on Maraviroc has been reported elsewhere.¹⁷

Patients with acute infectious diseases (i.e., leishmaniasis), transplant recipients, and pregnant or breastfeeding women were excluded. MVC treatment groups were divided into patients <50 years of age (“younger”) and patients ≥50 years of age (“older”) based on previous studies in which this age cut-off was used to define medically advanced age in HIV-infected people.¹⁸

Tropism determination was performed before MVC addition in most subjects. The MVC dose was adjusted depending on pharmacokinetic interactions with the accompanying drugs.^19,20

The primary objective of the study was to assess the impact of age on CD4⁺ T cell count change from baseline to week 48. Immune discordance was defined as a CD4⁺ cell count <350 cells despite having an undetectable plasma HIV-1 RNA for more than 3 years.

Efficacy was assessed by the proportion of patients with a CD4⁺ T cell count increase ≥100 cells/mm³ at week 48 of MVC addition. Secondary objectives included the increase in CD4/CD8 ratio ≥0.5, the virological efficacy (plasma HIV-RNA <50 copies/ml), and the proportion of patients discontinuing therapy due to toxicity or intolerance by age at week 48.

Descriptive and exploratory analyses were done by Chi-squared test for categorical variables and the Mann–Whitney test for continuous variables. Fisher's exact test was used if any individual cell in cross-tabulations had less than five observations. The level of significance was set at p<0.05. The probability of increasing >100 CD4⁺ cells or a CD4/CD8 ratio >0.5 at weeks 48 and 96 was modeled using a binary logistic multivariable regression, testing age, sex, HIV risk factors, HCV coinfection, CD4 cell count, and AIDS events. An intention-to-treat (ITT) analysis was performed, including all subjects receiving a first MVC dose. For the lost data from CD4 and CD8 during the follow-up monitoring a “Last Observation Carried Forward” was performed.

Results

In all, 241 patients were included in the final analysis; of these, 80 were ≥50 years of age (33.2%). Their characteristics at the beginning of treatment with MVC are showed in Table 1. Information about antiretroviral backbones and/or third agents is shown in Table 2. Genotypic tropism was available for 58 patients ≥50 years (96.6% CCR5) and 134 patients <50 years (94% CCR5) (p=0.73).

Table 1.

Baseline Patient Demographic, Virological, and Immunological Characteristics

	≥50 years N=80	<50 years N=161	p-value
Age [years, median (IQR)]	53 [7.75]	43 [7]
Male, n (%)	67 (83.8)	119 (73.9)	0.087^*
HIV transmission category, n (%)
Men who have sex with men	21 (28.4)	51 (33.3)	0.183^**
Heterosexual	24 (32.4)	30 (19.6)
Injection drug use	28 (37.8)	66 (43.1)
Other	1 (1.4)	6 (4)
CDC stage C, n (%)	21 (41.2)	54 (49.5)	0.323^*
Immunodiscordant, n (%)	22 (42.3)	36 (22.5)	0.005^*
Median CD4⁺ (cells, IQR)	401 (197–590)	383 (165–626)	0.994^***
CD4 ≥350 at the beginning of MVC addition, n (%)	48 (60)	86 (55.1)	0.475^*
CD4 ≥200 at the beginning of MVC addition, n (%)	60 (75)	111 (71.2)	0.53^*
CD4/CD8 ratio ≥0.5 at the beginning of MVC addition, n (%)	29 (38.7)	72 (49.3)	0.13^*
Duration of current cART, months median (IQR)	15.3 (10.8–23.4)	14.6 (11.0–21.9)	0.90^***
Hepatitis B coinfection, n (%)	4 (5.2)	7 (4.5)	0.75^**
Hepatitis C coinfection, n (%)	38 (48.7)	73 (47.1)	0.815^*

Chi-square test.

Fisher's exact test.

***

Mann–Whitney U test.

Immune discordance was defined as a CD4⁺ T cell count <350 cells despite having undetectable plasma HIV-1 RNA for more than 3 years.

p values based on the comparison between patients ≥50 years and <50 years; the percentage mentioned is the percentage of each subset.

Statistical significance (p<0.05) is marked in bold letters.

MVC, maraviroc; cART, combined antiretroviral therapy.

Table 2.

Antiretroviral Regimens Prescribed at Baseline

	≥50 years N=80	<50 years N=161	Total
Maraviroc+2 NRTIs, n (%)	10 (12.5)	25 (15.5)	35
Maraviroc+PIs±NRTIs, n (%)	34 (42.5)	81 (50.3)	115
Maraviroc+ITNN±NRTIs, n (%)	7 (8.7)	10 (6.2)	17
Maraviroc+IIs±NRTIs, n (%)	7 (8.7)	11 (6.8)	18
Maraviroc+PIs+NNRTIs, n (%)	9 (11.2)	5 (3.1)	14
Maraviroc+PIs+INIs, n (%)	12 (15)	26 (16.1)	38
Maraviroc+IIs+NNRTIs, n (%)	1 (1.2)	2 (1.2)	3
Maraviroc salvaje therapy, n (%)	0	1 (0.6)	1

IIs, integrase inhibitors; NNRTIs, nonnucleoside reverse transcriptase inhibitors; NRTIs, nucleos/tide reverse transcriptase inhibitors; PIs, boosted protease inhibitors.

After 48 weeks of treatment, the median increase from baseline was +116.6 cells/mm³ [median CD4⁺ T cell count of 517.6 (272.5–643.25) cells/mm³ at 48 weeks] in patients ≥50 years and +114 cells/mm³ in those aged <50 years [497 (245.5–758.35) cells/mm³ at 48 weeks] (p=0.511). At this time, a plasma VL <50 copies/ml was achieved by 84.1% and 85.1% of patients, respectively (p=0.84). Similarly, an increase of CD4⁺ T cell count ≥100 cells/mm³ at week 48 was observed in 30% and 33.3% of patients, respectively (p=0.68). Meanwhile, the percentage of patients with ≥200/mm³ CD4⁺ T cells/mm³ was 80.9% and 79.1%, respectively (p=0.76). When we analyzed the CD4/CD8 ratio, it was >0.5 in 46.2% and 51.8%, respectively (p=0.45). However, the increase in the proportion of patients achieving this ratio was higher in patients ≥50 years, although the difference was not significant (+7.5% vs. +2.5%; p=0.49).

MVC was stopped in 15 subjects ≥50 years (28.7%) and 35 subjects <50 years (32.9%) (p=0.62); the main reasons were a medical decision (20%) followed by virological failure (confirmed VL >50 copies/ml) (18%) (only three cases in those ≥50 years and six cases in those <50 years). No switch in viral tropism could be detected. Lack of adherence was the most likely reason underlying virological failure, at least in some of these patients.

In a multivariable analysis adjusted for age, sex, HIV risk factors, HCV coinfection, CD4 cell count, and AIDS events, age was not associated with CD4⁺ T cell recovery. On the other hand, an increase of >100 CD4⁺ T cells/mm³ was seen less frequently in those with prolonged HIV infection (≥15 years) (OR 0.43; p=0.016) or those having <200 CD4⁺ T cells at the commencement of MVC (OR 0.27; p=0.004). Meanwhile, achieving a CD4/CD8 ratio ≥0.5 at week 48 was less likely in those with a CD4⁺ count <200 cells/mm³ at MVC initiation (OR 0.09; p<0.0001) or with a previous AIDS-defining event (OR 0.43; p=0.028) (Table 3).

Table 3.

Comparative Analysis Between Baseline and Follow-up CD4 ⁺ and CD8 ⁺ Cell Counts and CD4/CD8 Ratio

	≥50 years N=80	<50 years N=161
VL at 48 weeks
≥50 copies/ml	9	18
<50 copies/ml	71	143
	0.004^a	0.000^a
VL at 96 weeks
≥50 copies/ml	5	5
<50 copies/ml	75	156
CD4 at 48 weeks
≥200 cells/ml	53	99
<200 cells/ml	2	13
		0.007^a
CD4 at 96 weeks
≥200 cells/ml	30	49
<200 cells/ml	2	8
		0.008^a
CD4/CD8 ratio at 48 weeks
≥0.5	24	61
<0.5	6	9
CD4/CD8 ratio at 96 weeks
≥0.5	13	29
<0.5	4	7

McNemmar test.

VL, viral load.

Discussion

In this study, we have observed that patient's age did not have a negative impact on the immunological or virological efficacy, durability, and safety of adding MVC to a current suppressive cART. This information is relevant because older patients, either by age itself or by age-associated comorbidities, are often excluded from participating in HIV clinical trials that evaluate the impact of cART. Therefore, data on these subjects are urgently needed, as the median age of HIV-infected individuals in all cohorts is increasing steadily. Actually, clinical trials usually exclude both older patients and their comorbidities, and do not compare their outcomes in this scenario.^1,21 In this cohort, we did not find differences in responses to MVC addition between older patients and younger ones, both immunologically and virologically.

Treatment with MVC may impact CD4⁺ T cell counts in subjects with suppressed HIV viremia by different mechanisms such as modulating the role played by CCR5-attached chemokines in immune activation or by blocking the cellular pathways leading to apoptosis.²² The effects of MVC intensification on CD4⁺ T cell restoration have been favorable in some studies,^12,23 but neutral in others.^14,16,24,25 Although it has not been evaluated in previous studies, we observed a poorer immune recovery (≥100 CD4⁺ T cells) in those patients with a long HIV history (≥15 years) and in those with CD4⁺ counts <200 cells/mm³ at the beginning of MVC addition.

Due to the increasing clinical relevance of the CD4/CD8 ratio, we considered evaluating it of interest. Among treated adults, the CD4/CD8 ratio appears to correlate with markers of T cell activation and senescence^26,27 and with the risk of non-AIDS morbidity and mortality as well.^28,29 In our cohort, achieving a CD4/CD8 ratio ≥0.5 at week 48 was less likely in those with CD4⁺ counts <200 cells/mm³ at MVC initiation and those with a history of previous AIDS events, but not in those aged ≥50 years.

MVC has been well tolerated in large clinical trials both in treatment-naive and treatment-experienced patients.^11,30 Although older subjects are more likely to change therapy due to adverse events,¹ in our study the proportion of patients who discontinued therapy motivated by intolerance or side effects was similar in both age groups.

There are several limitations to this study. This was a retrospective study of previously treated subjects, with different cART regimens. Also, no power and/or sample size calculations were performed due to its retrospective design, and several medical conditions accounted for the addition of MVC. However, this cohort reflects the “real world” situation in clinical practice, as patient care and treatment decisions were completely entrusted to the treating physician. The inclusion of 27 centers across Spain reduces the impact of local guidelines or practices on MVC use on the overall cohort. Furthermore, we performed a restrictive ITT analysis, including a multivariable analysis of different parameters of CD4⁺ T cell restoration, with concordant and robust results.

In summary, the inmunovirological efficacy, the safety/tolerability, and the durability of MVC addition in virologically suppressed subjects were independent of the age of patients at treatment onset. On the basis of these data, age should not be seen as a counterindication for MVC use in this scenario. Further studies on this population would be necessary to fully assess the clinical relevance of our findings.

Footnotes

Acknowledgments

All study monitoring was done by Cristina Herrero at FLS Research Support. David Arroyo and Javier Zamora undertook the statistical analyses. José R. Blanco and Josep M. Llibre wrote the first draft of this article. Josep M. Llibre, Santiago Moreno, and Antonio Rivero designed the study. All authors critically reviewed and subsequently approved the final version.

This work was supported by the “Lluita contra la SIDA” Foundation (Badalona, Spain).

We thank the study participants, study investigators, and study site staff.

Members of the MVC Cohort Spanish Group : John Fredy Rojas, Iñaki Pérez, Josep M^a Gatell (Hospital Clinic IDIBAPS, Barcelona); Isabel Bravo, Jordi Puig, Cristina Herrero, Silvia Gel, Josep M. Llibre (Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona); Loreto Martínez-Dueñas López-Marín, Antonio Rivero (Hospital Universitario Reina Sofía, Córdoba); María Jesús Perez-Elías, Alberto Díaz, David Arroyo, Javier Zamora, Santiago Moreno (Hospital Universitario Ramón y Cajal, Madrid); Miguel García del Toro, Puri Rubio (Consorcio Hospital General Universitario, Valencia); Juan A. Pineda; Eva Recio (Hospital Universitario Ntra Sra de Valme, Sevilla); Juan Pasquau, Coral García-Valdecillos (Hospital Universitario Virgen de las Nieves); Mar Masià, Catalina Robledano, Félix Gutiérrez (Hospital General Universitario, Elche, Alicante); Manel Crespo, Jordi Navarro, Ariadna Torrella (Hospital Universitari Vall d'Hebrón, Barcelona); José Hernández-Quero, Valme Sánchez-Cabrera (Hospital Universitario San Cecilio, Granada); Jesús Sanz (Hospital Universitario La Princesa, Madrid); Manuel Márquez (Hospital Clínico Universitario Virgen de la Victoria, Málaga); Antonio Ocampo, Fernando Warncke (Complejo Hospitalario Universitario de Vigo, Vigo); Josean Iribarren, Miriam Aguado-Atorrasagasti (Hospital Universitario Donostia, San Sebastián); María José Galindo, Ramón Ferrando (Hospital Clínico Universitario, Valencia); Carlos Minguez (Hospital General de Castellón); Daniel Podzamczer, Maria Saumoy (Hospital de Bellvitge, L'Hospitalet de Llobregat, Barcelona); Alberto Terrón, Patricia Bancalero Herrera (Hospital del SAS de Jerez de la Frontera, Cádiz); José Ramón Arribas, María Yllescas (Hospital Universitario La Paz, Madrid); Hernando Knobel, Judith Villar (Hospital del Mar, Barcelona); Manuel Fernández-Guerrero (Fundación Jiménez Díaz, Madrid); Pere Domingo, Jessica Muñoz (Hospital Sant Pau, Barcelona); Teodoro Martín (Hospital Universitario Puerta de Hierro, Majadahonda, Madrid); Juan Miguel Santamaría, Oscar Luis Ferrero (Hospital de Basurto, Bilbao); M^a Rosario Pérez-Simón (Complejo Asistencial Universitario, León); Rafael Torres (Hospital Universitario Severo Ochoa, Leganés, Madrid); Rafael Rubio, Angel Portillo (Hospital Universitario 12 de Octubre, Madrid).

Author Disclosure Statement

JR Blanco, JM Llibre, S Moreno, and A Rivero have served as an advisor or speaker or have been awarded with grants for clinical research from Gilead Sciences, Merck Sharp & Dohme, ViiV Healthcare, Bristol-Myers Squibb, and Janssen-Cilag. The remaining authors do not have an association that might pose a conflict of interest.

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