Definition of loss of virological response in trials of antiretroviral drugs
Staszewski, Schlomoa; Sabin, Carolineb; Dauer, Brendaa; Lepri, Alessandro Cozzib; Phillips, Andrewb
aGoethe Universitat, Frankfurt, Germany; and bRoyal Free Centre for HIV Medicine and Department of Primary Care and Population Sciences, Royal Free and University College Medical School, London, UK.
Received: 20 March 2002; accepted: 8 April 2002.
Definition of the time of loss of virological response is important when designing a viral load endpoint for trials of antiretroviral drugs. We assessed whether, in patients who achieved a viral load below 50 copies/ml, two consecutive values above 50 copies/ml was really indicative of loss of response. It was common for the viral load to return to below 50 copies/ml with no change in regimen, suggesting that a higher threshold for defining the loss of response is required.
The recently published Food and Drug Administration (FDA) guidelines for the analysis of trials of antiretroviral drugs suggest that those who have experienced a virological response (two viral load values below the lower assay quantitation limit; i.e. 50 copies/ml) should be defined as having a ‘loss of virological response’ if two consecutive values above 50 copies/ml are recorded . To now, the more commonly used thresholds to define the loss of virological response are consecutive values above 200 or 500 copies/ml, because of the concern that transient increases in the viral load value above 50 copies/ml, whether caused by assay variability or real fluctuations, are common [2–5]. To evaluate the FDA criterion, we assessed the subsequent viral load values in 376 individuals from the Universitat Clinic in Frankfurt who had experienced consecutive values below 50 copies/ml but then later experienced two values above 50 copies/ml. Those with any change in therapy were excluded. At the time of achieving a viral load below 50 copies/ml all patients were on at least three antiretroviral drugs, including at least two nucleoside analogues. The median (interquartile range; IQR) viral loads for the first and second values above 50 copies/ml were 565 copies/ml (140–9000) and 600 copies/ml (170–7190), respectively (median 35 days between these values). The next viral load value was taken a median of 35 days later. In 86 individuals (23%) this viral load was below 50 copies/ml, despite there being no change in the antiretroviral regimen [median (IQR) viral load 500 copies/ml (70–6950)]. When we further restricted analysis to those 135 individuals for whom the two loss-of-response-defining values above 50 copies/ml were both between 51 and 500 copies/ml, 56 (42%) had the next value below 50 copies/ml. For comparison, we considered other viral load thresholds for defining loss of response. Using 200 copies/ml, 36 out of 296 individuals (12%) who fulfilled the definition of loss of response had the next viral load value below 50 copies/ml, whereas for 500 copies/ml, this was nine out of 228 individuals (4%). These results are consistent with previous findings [4,5], and suggest that many patients who fulfil the FDA definition of loss of virological response may not, in fact, have lost that response and that a higher threshold may be more appropriate.
1. US Department of Health and Human Services, Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Guidance for industry. Antiretroviral drugs using plasma HIV RNA measurements – clinical considerations for accelerated and traditional approval
. October 2002.
2. Havlir DV, Bassett R, Levitan D, Gilbert P, Tegas P, Collier AC, et al. Prevalence and predictive value of intermittent viremia with combination HIV therapy. JAMA 2001, 286:171–179.
3. Greub G, Cozzi-Lepri A, Ledergerber B, Staszewski S, Perrin L, Miller V, et al. Intermittent and sustained low-level HIV viral reboundund in patients receiving potent antiretroviral therapy. AIDS 2002, 16:1967–1969.
4. Moore AL, Youle M, Lipman M, Cozzi-Lepri A, Lampe F, Madge S, et al. Raised viral load in patients with viral suppression on highly active antiretroviral therapy: transient increase or treatment failure? AIDS 2002, 16:615–618.
5. Sklar PA, Ward DJ, Baker RK, Wood KC, Gafoor Z, Alzola CF, et al. Prevalence and clinical correlates of HIV viremia (`blips') in patients with previous suppression below the limits of quantification. AIDS 2002; 16:2035–2041.
© 2003 Lippincott Williams & Wilkins, Inc.