Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study

doi:10.1016/S0140-6736(07)60948-9

The Lancet

Volume 370, Issue 9585, 4–10 August 2007, Pages 407-413

https://doi.org/10.1016/S0140-6736(07)60948-9 Get rights and content

Summary

Background

Combination antiretroviral therapy (cART) has been shown to reduce mortality and morbidity in patients with HIV. As viral replication falls, the CD4 count increases, but whether the CD4 count returns to the level seen in HIV-negative people is unknown. We aimed to assess whether the CD4 count for patients with maximum virological suppression (viral load <50 copies per mL) continues to increase with long-term cART to reach levels seen in HIV-negative populations.

Methods

We compared increases in CD4 counts in 1835 antiretroviral-naive patients who started cART from EuroSIDA, a pan-European observational cohort study. Rate of increase in CD4 count (per year) occurring between pairs of consecutive viral loads below 50 copies per mL was estimated using generalised linear models, accounting for multiple measurements for individual patients.

Findings

The median CD4 count at starting cART was 204 cells per μL (IQR 85–330). The greatest mean yearly increase in CD4 count of 100 cells per μL was seen in the year after starting cART. Significant, but lower, yearly increases in CD4 count, around 50 cells per μL, were seen even at 5 years after starting cART in patients whose current CD4 count was less than 500 cells per μL. The only groups without significant increases in CD4 count were those where cART had been taken for more than 5 years with a current CD4 count of more than 500 cells per μL, (current mean CD4 count 774 cells per μL; 95% CI 764–783). Patients starting cART with low CD4 counts (<200 cells per μL) had significant rises in CD4 counts even after 5 years of cART.

Interpretation

Normalisation of CD4 counts in HIV-infected patients for all infected individuals might be achievable if viral suppression with cART can be maintained for a sufficiently long period of time.

Introduction

Combination antiretroviral therapy (cART) has been shown to reduce mortality and morbidity in patients with HIV.¹ The goal of cART, according to current treatment guidelines, is to reduce HIV viral replication to below the limit of detection.² As viral replication falls, the CD4 count increases.3, 4 The initial increase is rapid and usually lasts 3–6 months, followed by a phase of slower CD4 count increases.⁵ The factors that determine CD4 count responses are only partly known and are thought to depend on both the host and the virus, and there is substantial variation in CD4 count recovery.⁶ In patients with virological suppression (HIV-RNA viral load <1000 copies per mL), older age, a longer duration of HIV infection, and lower CD4 counts at starting cART were predictors for maintaining lower CD4 counts.7, 8 In the Swiss HIV Cohort Study,⁷ a third of patients were incomplete responders, and only half continued to have CD4 count increases. The remainder were described as reaching a CD4 plateau, with no further increases in CD4 count. This finding led to the conclusion that not all patients might eventually respond to cART by achieving a CD4 count in the normal range.

Several factors have been investigated to establish the relation with CD4 count recovery, including viral pathogenicity, host factors, or co-infection with hepatitis B or C.6, 9, 10 The most consistent finding, however, is that patients who start cART with lower CD4 counts need longer treatment to achieve CD4 counts in the normal range.3, 7 There has been little research to date on CD4 count increases in analyses restricted to patients with maximum virological suppression (viral load <50 copies per mL). Previous work from the EuroSIDA study¹¹ assessed the increases in CD4 count in patients with maximum virological suppression, and found some differences according to cART regimen in use, but this previous study did not specifically address long term CD4 count increases and when or at what level CD4 counts were no longer increasing. The objectives of our study were therefore to describe the relation between duration of treatment, CD4 count at the start of cART, current CD4 count, and CD4 count increases in antiretroviral-naive patients starting cART who achieve maximum virological suppression.

Section snippets

Patients

EuroSIDA is a prospective, European study of 14 262 patients with HIV-1 infection in 92 centres across Europe (including Israel and Argentina as non-European representatives). Details of the study have been published previously.¹² Seven cohorts have been recruited to date, the first in May, 1994, of 3116 patients, and the latest, of 2337 patients, was recruited from November, 2005. At recruitment, in addition to demographic and clinical information, a complete antiretroviral history was

Results

There were 3365 antiretroviral-naive patients who started cART in the EuroSIDA study; of these, 2598 had at least one viral load measured with a lower limit of detection of 50 copies per mL, and 2000 had a pair of consecutive viral loads of less than 50 copies per mL. Of these 2000 patients, 1835 had a CD4 count measured before starting cART and were therefore included in analyses (table 1). The median CD4 at the arbitrarily defined baseline was 404 cells per μL (IQR 251–580); 742 patients

Discussion

This study of CD4 count increases in antiretroviral-naive HIV-infected patients starting cART and who subsequently achieve maximum viral suppression has found little evidence of a plateau effect. Most patients continued to have significant rises in CD4 count, even at more than 5 years after cART initiation, whereas significant, but smaller, increases were seen in patients who started cART with low CD4 counts. Normalisation of CD4 counts in HIV-infected patients for all infected individuals was

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^‡: For a list of study group members see webappendix

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ArticlesNormalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients

Results

Discussion

Lancet

Lancet Infect Dis

Lancet

Lancet

Blood

Lancet

Lancet

Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents

CD4 T-lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for 4 years

Arch Intern Med

Determinants of sustainable CD4 lymphocyte count increases in response to antiretroviral therapy

AIDS

Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation

Nat Med

Characteristics, determinants, and clinical relevance of CD4 T cell recovery to <500 cells/ul in HIV type-1 infected individuals receiving potent antiretroviral therapy

Clin Infect Dis

Influence of age on CD4 cell recovery in human immunodeficiency virus infected patients rewcieving highly active antiretroviral therapy: evidence from the EuroSIDA study

J Infect Dis

Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy

J Infect Dis

Relationship between antiretrovirals used as part of a cART regimen and CD4 cell count increases in patients with suppressed viremia

AIDS

Reference ranges and sources of variability of CD4 counts in HIV-seronegative women and men

Genitourin Med

Nadir CD4+ T-cell count and numbers of CD28+CD4+ T-cells predict functional responses to immunizations in chronic HIV-1 infection

AIDS

A clinically prognostic scoring system for patients receiving highly active antiretroviral therapy: Results from the EuroSIDA study

J Infect Dis

The values of quantitive serum HIV-1 RNA levels and CD4 cell counts for predicting survival time among HIV-positive individuals with CD4 counts of <=50×106 cells/l

AIDS

Articles
Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study