Elsevier

The Lancet

Volume 353, Issue 9171, 26 June 1999, Pages 2195-2199
The Lancet

Articles
Drug-resistance genotyping in HIV-1 therapy: the VIRAD APT randomi sed controlled trial

https://doi.org/10.1016/S0140-6736(98)12291-2Get rights and content

Summary

Background

Growing evidence has linked HIV-1 resistance mutations and drug failure. The use of genotypic-resistance analysis to assist therapeutic decision-making in patients failing therapy has not been investigated. We assessed the virological and immunological impact of genotypic-resistance testing.

Methods

We did a prospective, open, randomised, controlled study of HIV-1-infected patients in whom combination therapy was not successful. We randomly assigned patients standard care (control, n=43) or treatment according to the resistance mutations in protease and reverse-transcriptase genes (genotypic group, n=65). The major endpoint was the change in HIV-1 RNA viral load. Analysis was by intention to treat.

Findings

108 patients were enrolled. All patients were similar for risk factors, age, sex, previous treatment, CD4-cell count (214/fxL [SD14]) and log HIV-1 RNA viral load at baseline (4–7 copies/ml [0–1]). At month 3, the mean change in HIV-1 RNA was -1-04 log (0–14) in the study group compared with −0–46 log (0–17) in the control group (mean difference 0–58 log [95% Cl 0-14-1-02], p=0–01). At month 6, changes were −1–15 (0–15) log copies/mL, and −0-67 (0–19) log copies/mL in the genotypic group and the control group, respectively (mean difference 0–48 log [0-01-0-97], p=0-05). Difference in the drop in viral load combined at 3 months and 6 months was significant (p=0-015). At month 3, HIV-1 RNA was lower than detection level (200 copies/mL) in 29% (19/65) of patients in the genotypic group versus 14% (6/43) in the control group (p=0-017). At month 6, the values were 32% (21/65) and 14% (6/43) (p=0-067) for the genotypic group and the control group, respectively. Therapy was generally well tolerated, with ten patients (six in the genotypic group, four in the control group) requiring toxic-effect-related drug modification.

Interpretation

We found genotypic-resistance testing to have a significant benefit on the virological response when choosing a therapeutic alternative. Further study of the use of genotypic-resistance testing in assisting clinical decision-making is warranted.

Introduction

Drug resistance is the inevitable consequence of incomplete suppression of HIV-1 replication. The rapid turnover of HIV-1 RNA and its genetic variability have led to the production of many HIV-1 variants with decreased drug susceptibility.1, 2 There are currently ten drugs available to treat HIV-1-infected patients in France, including four protease inhibitors, and an additional three drugs available through the expanded access programme. Despite this selection, many patients do not achieve or maintain complete viral suppression. Virological response rates to initial therapy with a protease inhibitor and two nucleoside reverse-transcriptase inhibitors range from 60% to 90% and success is less likely in advanced stages of the disease.3, 4 Many factors (drug, host, viral) contribute to drug failure. However, drug-resistance mutations in the HIV-1 reverse-transcriptase and protease genes lead to lower sensitivity to antiretroviral agents and are an important cause of drug failure. An increasing number of retrospective studies link the appearance of such mutations with a rebound in the viral load.5, 6, 7 Information on patterns of resistance to and cross-resistance between antiretroviral agents is increasingly available and may be important for decisions on how to combine drugs to achieve an optimum antiviral effect.8

Improved genotypic assays to assess resistance mutations are becoming available, but the clinical use of these results has not yet been investigated.2 We assessed the clinical benefit of HIV-1 resistance testing in a drug-experienced population in a prospective, randomised, open, controlled pilot study.

Section snippets

Patients

We did the study in three hospitals in southern France. The study protocol was approved by the institutional ethics committee of our hospital. Written informed consent was obtained from all study participants.

Entry criteria were a plasma HIV-1 RNA of more than 10 000 copies/mL despite at least 6 months' treatment with nucleoside analogues and at least 3 months' treatment with a protease inhibitor. Eligibility criteria also included age older than 18 years and a Karnofsky score higher than 50.

Results

From March, 1997, until March, 1998, 114 patients were screened, of whom 108 were randomised (figure 1). 41 patients in the control group completed 3-month follow-up after treatment adaptation, and 40 completed 6-month follow-up. In the genotypic group, 62 patients completed 3 months of follow-up after treatment adaptation, and 59 completed 6 months of follow-up. 103 (95-4%) of 108 patients could be assessed at month 3, and 99 (91-6%) of 108 at month 6 (four patients were lost to follow-up,

Discussion

Genotypic-resistance testing was beneficial for decisions about changes to treatment. The decrease in HIV-1 RNA, and the percentage of patients with HIV-1 RNA lower than the detection level was better in the genotypic group than in the control group.

Several retrospective studies have shown that the presence of drug-resistance mutations at baseline was predictive of the virological responses. The probability of virological response to the combination of saquinavir and ritonavir in patients

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