Elsevier

The Lancet

Volume 364, Issue 9428, 3–9 July 2004, Pages 51-62
The Lancet

Articles
Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes

https://doi.org/10.1016/S0140-6736(04)16589-6Get rights and content

Summary

Background

Treatment strategies for patients in whom HIV replication is not suppressed after exposure to several drug classes remain unclear. We aimed to assess the inter-relations between viral load, CD4-cell count, and clinical outcome in patients who had experienced three-class virological failure.

Methods

We undertook collaborative joint analysis of 13 HIV cohorts from Europe, North America, and Australia, involving patients who had had three-class virological failure (viral load >1000 copies per mL for >4 months). Regression analyses were used to quantify the associations between CD4-cell-count slope, HIV-1 RNA concentration, treatment information, and demographic characteristics. Predictors of death were analysed by Cox's proportional-hazards models.

Findings

2488 patients were included. 2118 (85%) had started antiretroviral therapy with single or dual therapy. During 5015 person-years of follow-up, 276 patients died (mortality rate 5·5 per 100 person-years; 3-year mortality risk 15·3% (95% CI 13·5–17·3). Risk of death was strongly influenced by the latest CD4-cell count with a relative hazard of 15·8 (95% CI 9·28–27·0) for counts below 50 cells per μL versus above 200 cells per μL. The latest viral load did not independently predict death. For any given viral load, patients on treatment had more favourable CD4-cell-count slopes than those off treatment. For patients on treatment and with stable viral load, CD4-cell counts tended to be increasing at times when the current viral load was below 10 000 copies per mL or 1·5 log10copies per mL below off-treatment values.

Interpretation

In patients for whom viral-load suppression to below the level of detection is not possible, achievement and maintenance of a CD4-cell count above 200 per μL becomes the primary aim. Treatment regimens that maintain the viral load below 10 000 copies per mL or at least provide 1·5 log10copies per mL suppression below the off-treatment value do not seem to be associated with appreciable CD4-cell-count decline.

Introduction

The aim at the start of antiretroviral treatment is to suppress viral replication so that the viral load is below the level of detection with standard assays in plasma and thereby limit the risk that virus carrying mutations associated with drug resistance can develop and grow.1 The ultimate aim is to improve the overall clinical outcome. However, in some patients plasma viral load does not fall to undetectable levels, and in others the viral load rebounds after becoming undetectable.2, 3 Such cases are normally termed virological failure and are generally (but not exclusively) associated with the presence of drug-resistant viral strains. Virological failure prompts immediate switching of the antiretroviral drug regimen in an attempt to achieve viral suppression to below the level of detection.1 However, an increasing number of patients have virological failure to the three major drug classes—nucleoside reverse-transcriptase inhibitors (NRTI), protease inhibitors (PI), and non-nucleoside reverse-transcriptase inhibitors (NNRTI).

In many of these patients, suppression to viral loads below the limit of detection is impossible to achieve or lasts for only a short time, irrespective of treatment switches.4 Much clinical uncertainty remains about whether and when to change drug regimens in such people. Lack of viral suppression to undetectable loads does not necessarily imply that antiretroviral treatment is no longer having a beneficial effect. As early trials of monotherapy and dual-therapy regimens have shown, any appreciable degree of viral-load suppression by antiretroviral therapy appears to result in some benefit in terms of CD4-positive T-cell count, even if only a reduction in the rate of decline.5, 6, 7 In the presence of virus that carries many resistance mutations and hence perhaps has a reduced replicative capacity, the CD4-cell-count benefit may be even greater.8

The Pursuing Later Treatment Options (PLATO) collaboration was established in 2002, to obtain better understanding of the relation between viral-load suppression and changes in CD4-cell count in patients with three-class failure, and of the factors most closely associated with risk of death.

Section snippets

Patients

We investigated patients with virological failure to all three drug classes. Virological failure of a drug class was defined as a viral load of more than 1000 copies per mL for a total of more than 4 months (not necessarily continuous) after the start of treatment with that drug class while still taking such treatment. Failure of a class could occur when it was given as monotherapy, as part of a double, triple, or more intensive regimen, or a mixture of therapies. The baseline date for the

Results

The characteristics of the 13 participating cohorts are shown in table 1.3, 11, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 Eight cohorts, including the multinational EuroSIDA study, were from European countries, two from Canada, and one each from the USA and Australia. The CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe) collaboration contributed data on 20 seroconverter cohorts from Europe and Australia. The 13 cohorts submitted data on a total of 15 214 patients with

Discussion

These results, based on 2488 people with three-class virological failure, strongly indicate that the current CD4-cell count, but not the current viral load, determines the short-term risk of death in this setting. However, the viral load retains some independent prognostic significance in prediction of risk of new AIDS or death. Viral load appeared to be a major determinant of the CD4-cell-count slope.

The mortality rate in this study of patients with much treatment exposure was 5·5 per 100

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