JAC Advance Access originally published online on March 13, 2006
Journal of Antimicrobial Chemotherapy 2006 57(5):803-805; doi:10.1093/jac/dkl092
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Leading article |
HIV-1 viral load blips are of limited clinical significance
1 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2 Howard Hughes Medical Institute, Baltimore, MD, USA
* Correspondence address. Bristol-Myers Squibb, MS E12-16 PO Box 4000, Princeton, NJ 08543, USA. Tel: +1-609-252-3719; Fax: +1-609-252-7034; E-mail: Richard.Nettles{at}BMS.com
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Abstract |
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 Top Abstract IntroductionBlips are random variations...Blips are laboratory assay...Blips and development of...ConclusionsTransparency declarationsReferences |
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Many patients on highly active antiretroviral therapy (HAART) who achieve undetectable HIV-1 RNA levels experience transient episodes of detectable viraemia or blips, suggesting there is incomplete suppression of viral replication. This raises concern that drug resistance mutations could develop and cause eventual treatment failure. However, data from recent studies indicate that most blips are actually random biological and statistical variations around a mean viral load below detectable levels (<50 copies/mL) or due to false elevations of viral load from laboratory processing artefacts. Blips are not typically associated with the development of resistance mutations and most importantly are not associated with virological or clinical failure of previously adequate HAART.
Keywords: HIV , genotypes , HAART , drug resistance
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Introduction |
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TopAbstractIntroductionBlips are random variations...Blips are laboratory assay...Blips and development of...ConclusionsTransparency declarationsReferences |
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The current standard treatment for patients with HIV infection is highly active antiretroviral therapy (HAART). While this therapy can significantly decrease HIV RNA levels and permit immune reconstitution, complete viral eradication remains elusive due to the existence of long-lived reservoirs such as latently infected CD4+ resting memory T-cells. Therefore, the goal of HAART is to minimize active viral replication to avoid emergence of drug resistance by maintaining plasma virus levels below the limit of detection of current ultrasensitive assays (<50 copies/mL). However, many patients on HAART with full suppression of viraemia to <50 viral copies/mL experience ‘blips’, defined as intermittent episodes of detectable low-level viraemia which return spontaneously to an undetectable range without any change in therapy1–5 (Figure 1). These occurrences are distinct from episodes of persistently detectable or episodic high-level viraemia observed in some patients. Serious concerns have been raised regarding the clinical significance of blips; specifically it is unclear whether they represent inadequate viral suppression and bursts of active viral replication with consequential development of drug resistance. Blips have generated much anxiety and uncertainty among clinicians and patients alike about the adequacy of individual HAART regimens, sometimes leading to alterations of therapy.
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Blips are random variations around an undetectable mean viral load |
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TopAbstractIntroductionBlips are random variations...Blips are laboratory assay...Blips and development of...ConclusionsTransparency declarationsReferences |
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Blips are not associated with long-term clinical failure in most studies.1–4,6,7 Havlir et al.1 conducted the first detailed examination of blip data from two clinical trials in which patients received indinavir (a protease inhibitor) and two nucleoside analogue RT inhibitors. In this study, blips were associated with higher steady-state levels of viraemia but were not associated with virological failure for up to 4.5 years (P = 0.53). Similarly, there was no correlation between blips and subsequent clinical failure in two studies of patients taking NNRTI-based HAART.6,7 Nettles et al.8 recently published data from a prospective analysis of blips using frequent viral load sampling (every 2–3 days) for 3–4 months in a group of 10 HIV-infected individuals. This study revealed that blips represent random variations around a mean viral load level <50 copies/mL. Plasma viral loads were measured in two independent laboratories using the same ultrasensitive assay. Blips were detected in 9 of 10 patients and of the 713 total viral load measurements, 26 (3.6%) were >50 copies/mL, constituting 18 total blips. Nine of these were detected solely by one laboratory, eight only by the other and one by both. Despite the use of the same assay with comparable sensitivities, the concordance between the two labs was poor. Moreover, the proportion of viral load measurements >50 copies/mL was consistent with random biological and statistical variations around a mean viral load level of 10–20 copies/mL. The apparent random nature of blips may explain their lack of association with increased risk for virological failure observed in prior studies.1–4,6,7
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Blips are laboratory assay artefacts |
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TopAbstractIntroductionBlips are random variations...Blips are laboratory assay...Blips and development of...ConclusionsTransparency declarationsReferences |
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Blips may also be attributed to laboratory processing artefacts as evidenced by studies of Stosor et al.9 who confirmed artefactual elevations of viral loads with the use of Plasma Preparation TubesTM (PPTTM) during collection of blood samples as compared with use of EDTA tubes. Fifty-six patients receiving HAART with
3 consecutive undetectable viral loads from plasma collected in EDTA tubes subsequently underwent an 8 month period of plasma collection with PPTTM. Significantly more patients (69.6% versus 5.4%, P < 0.0001) experienced viraemia with PPTTM use than with EDTA tubes and in 60.7% of these patients, the low-level viraemia resolved when use of EDTA tubes was resumed. The manufacturers of PPTTM found similar results when comparing the two plasma collection methods and issued guidelines for proper specimen processing when using PPTTM for the collection of blood for viral loads.10 While blips generated by laboratory assay artefacts are of no direct clinical significance, they can significantly increase patient anxiety, complicate clinical decision making and confound interpretation of research data. Given this, we recommend caution when using PPTTM for the collection of blood for viral load measurement, and we urge thorough validation of new viral load assays and blood collection procedures as they become available. |
Blips and development of antiretroviral drug resistance |
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TopAbstractIntroductionBlips are random variations...Blips are laboratory assay...Blips and development of...ConclusionsTransparency declarationsReferences |
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Previous studies have reported the emergence of new drug resistance mutations in association with blips.11–13 However, these observations have been complicated by limited assessment of pre-existing mutations as well as poor sensitivity of the genotyping assay employed. Nettles et al.8 utilized an ultrasensitive genotyping method to characterize nearly 1000 viral clones obtained before, during and after blip occurrences. No new resistance mutations were identified. Importantly, viruses obtained during blips were not genetically distinct from non-blip samples suggesting no significant viral evolution during blip episodes (Figure 2). Also of note, no correlation was found between patients with greater number of pre-existing resistance mutations and frequency of blips.
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Conclusions |
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TopAbstractIntroductionBlips are random variations...Blips are laboratory assay...Blips and development of...ConclusionsTransparency declarationsReferences |
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Existing data suggest that most blips represent normal biological and statistical variations around a mean viral load <50 copies/mL. Laboratory artefacts related to the method of blood collection and processing are probably responsible for some blips. Most blips do not represent a period of significant viral replication as to permit generation of new resistance mutations. Most importantly, blips have not been correlated with worse clinical prognosis. While it remains important to differentiate blips from early virological failure or persistently detectable low-level viraemia, once an episode of detectable viraemia is clearly identified as a blip, it should not warrant significant clinical response.
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Transparency declarations |
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TopAbstractIntroductionBlips are random variations...Blips are laboratory assay...Blips and development of...ConclusionsTransparency declarationsReferences |
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Financial disclosures/potential conflicts of interest are as follows: P. K. L. has no conflict; T. L. K. has no conflict; R. F. S. was a consultant for Schering-Plough on an unrelated project and received research reagents from Merck for an unrelated project; R. E. N. received honoraria from Abbott.
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Footnotes |
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Present address. Stanford University Medical Center 
Present address. Vertex Pharmaceuticals
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Acknowledgements |
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Financial support was from NIAID grant K08 AI060367 (to R. E. N.), NIH grants AI43222 and AI51178 and a grant from the Doris Duke Charitable Foundation (to R. F. S.).
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References |
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TopAbstractIntroductionBlips are random variations...Blips are laboratory assay...Blips and development of...ConclusionsTransparency declarationsReferences |
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1. Havlir DV, Bassett R, Levitan D et al. Prevalence and predictive value of intermittent viremia with combination HIV therapy. JAMA 2001; 286: 171–9.
2. Rabound JM, Rae S, Woods R et al. Consecutive rebounds in plasma viral load are associated with virological failure at 52 weeks among HIV-infected patients. AIDS 2002; 16: 1627–32.[CrossRef][Web of Science][Medline]
3. Mira JA, Macias J, Nogales C et al. Transient rebounds of low-level viraemia among HIV-infected patients under HAART are not associated with virological or immunological failure. Antivir Ther 2002; 7: 251–6.[Web of Science][Medline]
4. Sklar PA, Ward DJ, Baker RK et al. Prevalence and clinical correlates of HIV viremia (‘blips’) in patients with previous suppression below the limits of quantification. AIDS 2002; 16: 2035–41.[CrossRef][Web of Science][Medline]
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Nettles RE, Kieffer TL, Kwon P et al. Intermittent HIV-1 viremia (Blips) and drug resistance in patients receiving HAART. JAMA 2005; 293: 817–29.
9. Stosor V, Palella FJ, Berzins B et al. Transient viremia in HIV-infected patients and use of plasma preparation tubes. Clin Infect Dis 2005; 41: 1671–4.[Medline]
10. Rainen L, Salimnia H, Fairfax M et al. Sample handling parameters affecting performance of BD vacutainer PPTTM and plus K2EDTA tubes with the Roche AMPLICORTM and COBAS AMPLICORTM HIV-1 MONITOR TEST, v1.5 UltraSensitive and Standard specimen processing procedures. Released 3 March 2005 by BD Diagnostics, Franklin Lakes, NJ, USA. Available at www.bd.com.
11. Cohen Stuart JW, Wensing AM, Kovacs C et al. Transient relapses (‘blips’) of plasma HIV RNA levels during HAART are associated with drug resistance. J Acquir Immune Defic Syndr 2001; 28: 105–13.[CrossRef][Web of Science][Medline]
12. Easterbrook PJ, Ives N, Waters A et al. The natural history and clinical significance of intermittent viraemia in patients with initial viral suppression to <400 copies/ml. AIDS 2002; 16: 1521–7.[CrossRef][Web of Science][Medline]
13. Macias J, Palomares JC, Mira JA et al. Transient rebounds of HIV plasma viremia are associated with the emergence of drug resistance mutations in patients on highly active antiretroviral therapy. J Infect 2005; 51: 195–200.[CrossRef][Web of Science][Medline]
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