Curr opin hiv blips 2006

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Curr opin hiv blips 2006

  1. 1. Update on HIV-1 viral load blipsRichard E. Nettles and Tara L. Kieffer Purpose of review Abbreviations Many patients on highly active antiretroviral therapy with EDTA ethylenediamine tetraacetic acid undetectable levels of HIV-1 RNA experience viral load HAART highly active antiretroviral therapy PPT plasma preparation tube blips. True periods of detectable viremia raise concerns that regimen potency is inadequate to suppress viral replication ß 2006 Lippincott Williams & Wilkins completely, which could lead to the development of 1746-630X resistance. Because blips are not associated with long-term clinical or virological failure in most studies, there is Introduction uncertainty over their clinical significance. Highly active antiretroviral therapy (HAART) is the Recent findings current standard treatment for patients infected with Recent data help explain the lack of association between HIV-1. Although this treatment significantly decreases blips and clinical or virological failure. Many blips are not an viral loads and allows a considerable degree of immune actual rise in viral load, but instead represent normal reconstitution, it is unable to eradicate the virus com- biological fluctuations around a mean viral load below pletely because of the existence of long-lived reservoirs, 50 copies/ml as well as statistical variations around the such as within CD4 resting memory T cells. The optimal detection limit of the viral load assay. Some blips may also response a patient can achieve on HAART is a rapid and result from laboratory processing artefacts. Therefore, most sustained drop in plasma virus to levels that are below our blips are not reproducible on duplicate viral load ability to measure with current ultrasensitive assays measurements. With frequent viral load measurements, (< 50 copies/ml). The goal of therapy is to reach and there is less correlation between blips and demographic, maintain viral loads below this level to avoid the emer- treatment, or HIV-associated clinical factors than previously gence of drug resistance. Unfortunately, many patients reported. Likewise, many blips are often unrelated to experience ‘blips’, intermittent episodes of detectable intercurrent illnesses, vaccination, non-adherence, or low-level HIV-1 viremia, which resolve spontaneously by decreases in antiretroviral drug concentrations. Most returning to less than 50 copies/ml without a change in importantly, new genotypic resistance mutations do not therapy [1–5]. Although there is no consensus on the develop before, during, or immediately after most blips. maximum duration or magnitude of a blip, episodes of Summary persistently detectable viremia or episodes of detectable Despite recent findings suggesting that many blips are viremia of marked magnitude are typically considered laboratory or statistical aberrations, it remains important to distinct from blips. Mathematical modeling proposes a differentiate blips from early virological failure or persistent typical blip magnitude of approximately 158 copies/ml detectable low-level viremia. Once the episode of and a total duration of 20–30 days [6–8]. Blips have detectable viremia is clearly defined as a blip, however, previously been attributed to periods of poor antiretro- there should be no cause for clinical concern. viral adherence or bioavailability, vaccination, or sickness [9,10]. There has been concern that blips could be Keywords associated with increased viral replication, leading to AIDS, blips, drug resistance, highly active antiretroviral the development of new drug resistance mutations therapy, HIV [11,12]. Likewise, there was a fear that blips could allow for the replenishment of physical or cellular viral reser-Curr Opin HIV AIDS 1:157–161. ß 2006 Lippincott Williams & Wilkins. voirs, thereby complicating efforts at eradication and allowing for the cataloging of new resistant variantsDepartments of Medicine, Johns Hopkins University School of Medicine, BaltimoreMaryland, USA [13]. Despite the apparent loss of suppression of viralCorrespondence and requests for reprints to Richard E. Nettles, Bristol Myers load, most studies have shown that blips are not associ-Squibb, MS E12-16 PO Box 4000, Princeton, NJ 08543, USA ated with long-term clinical failure [1–4]. Recent litera-Tel: +1 609 252 3719; fax: +1 609 252 7034; e-mail richard.nettles@bms.com ture concerning blips helps explain why most blips do notSponsorship: This study received financial support from NIAID grants K08 compromise long-term clinical or virological outcomes.AI060367 (to R.E.N.).Current Opinion in HIV and AIDS 2006, 1:157–161 Blips are often not real clinical increases in viral load$ Current affiliations: R.E.N. is currently employed by Bristol Myers Squibb; T.L.K. is Viral load assay variation and laboratory processing arte-currently employer by Vertex Pharmaceutic. facts can be responsible for many blips without actual 157Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
  2. 2. 158 Reservoirs: basic science significant increases in viral replication. Blips associated three patients (69.6 versus 5.4%, P < 0.0001), respect- with these phenomena are of limited clinical significance. ively. Low-level viremia was measured in 34 patients These findings may explain why blips do not compromise (60.7%), which subsequently resolved with the resump- long-term outcomes in most studies. tion of the use of EDTA tubes, whereas only three (5.4%) experienced low-level viremia with PPT use that per- Random biological fluctuation and statistical sisted after EDTA tube use resumed. The authors con- assay variation cluded that for patients with viral suppression, viral load Our laboratory recently published results from a prospec- measurements performed on specimens collected and tive analysis of blips using frequent viral load sampling stored in PPTs result in factitious low-level viremia, (every 2–3 days) for 3–4 months in a group of 10 HIV-1- and they therefore cautioned against the use of PPTs infected individuals [14]. Viral loads were measured in for viral load testing. The conclusion of the study by duplicate in two independent laboratories, both using the Stosor et al. [16] was validated by the producer of PPTs, same ultrasensitive Roche Amplicor system assay, version who also found discordant results when comparing viral 1.5 (Roche Diagnostic Systems, Inc., Branchburg, New loads from blood collected in PPTs versus EDTA tubes Jersey, USA). Blips were detected in nine out of 10 [17]. Rainen and colleagues [17] concluded that patients. Of 713 viral load measurements, 26 (3.6%) were samples collected in PPTs should be centrifuged within greater than 50 copies/ml, constituting 18 total blips. 6 h of phlebotomy and stored at 48C for no longer than Nine blips were detected by one laboratory, eight by 72 h, and that PPT plasma should not be frozen in situ in the other laboratory, and only one was detected by both. order to obtain consistent, concordant viral load results. Although there was no difference in the sensitivity of assays used by the two laboratories, concordance was poor Blip genesis (kappa 4.4%). Using the coefficient of variation of the Many authors continue to consider all blips as actual viral load assay, it was shown that the proportion of periods of increased HIV viremia. As such, there con- positive assays was consistent with random variation tinues to be a search for clinical factors that may act as the around a mean viral load level of 10–20 copies/ml. There- trigger for increased viral replication resulting in blips. fore, in this study it appeared that many blips resulted from random assay variations around a mean viral load Demographics, vaccination, and concurrent illness below 50 copies/ml, rather than clinically significant Previous studies have linked blips to multiple clinical elevations in viremia. The finding that many blips are factors, such as poor antiretroviral adherence, vaccination, statistical aberrations probably explains the lack of associ- or sickness. Many of these earlier studies were based on ation between blips and an increased risk of clinical or infrequent viral load sampling, retrospective chart virological failure seen in several clinical trials. The major review, and patient self-reported adherence. Therefore, limitation of the study by Nettles et al. [14] is that the the findings of many of these studies, although important, sample size was very small (10 patients) and relatively may not be sufficiently precise to define the true relation- homogenous (most started HAART after reaching low ship of blips to clinical events. In an effort to overcome CD4 cell nadirs with high viral loads). this limitation, Nettles and colleagues [14] prospec- tively collected clinical data in addition to the viral load Blips as a laboratory processing artefact data described previously. They found that when viral The lack of congruity between blips and the increased load was sampled up to three times a week, blips did not risk of failure may also be explained if many blips are occur more frequently in any demographic group defined actually factitiously elevated viral loads. There has been by sex, race, or age. There was no correlation between concern that viral loads are falsely elevated by the ultra- the frequency of blips and clinical parameters such as sensitive Roche Amplicor test versions 1.0 or 1.5 (Roche CD4 cell nadir, pretreatment viral load, duration of HIV Diagnostics, Inc.) from blood collected in plasma prep- infection, duration of virological suppression, or number aration tubes (PPTs) compared with blood collected in of previous blips. Temporally, blips were not observed ethylenediamine tetraacetic acid (EDTA) tubes [15]. in relation with intercurrent illnesses or influenza vacci- Stosor and colleagues [16] recently confirmed that viral nation. loads may be misleadingly elevated when using PPTs for the collection of plasma to be used for viral load measure- Blip frequency in relation to timing of initiation of highly ments. In their study, 56 HAART recipients with three or active antiretroviral therapy more consecutive undetectable viral loads from plasma Di Mascio and colleagues [18] compared blip frequency collected in EDTA tubes were identified. There was among patients starting HAART during acute/early subsequently an 8-month period of PPT use and a infection versus during chronic infection. They found successive period of 6-month EDTA tube use. Substan- that blip frequency was nearly twofold higher in the tially more patients experienced viremia with PPTs than chronically infected group compared with the acute/early during the following period of EDTA tube use; 39 versus infected group (P ¼ 0.001). They concluded that theCopyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  3. 3. Update on HIV-1 viral load blips Nettles and Kieffer 159duration of infection before the initiation of HAART is not temporally associated with blips. In addition, proteasepossibly related to the tendency to experience blips. If inhibitor and non-nucleoside reverse transcriptase inhibi-these findings are confirmed by additional studies, and it tor concentrations in plasma at each timepoint in eachis shown that blips predict an adverse outcome in some patient were measured to determine whether blips werepatients, this could be an argument for the initiation of temporally associated with decreased drug concen-HAART early in the course of infection. trations. There was no correlation between blips and insufficient drug concentrations.Plasmid vaccinationThe authors of one study report that the receipt of an HIV Mathematical modelingplasmid vaccine decreased blip frequency in patients on Jones and Perelson [22] developed a mathematicalHAART [19]. The vaccine was a combination of two HIV- model of intercurrent infection on patients with low viralDNA constructs, which drive the expression of env/rev and loads on HAART. On the basis of their model, theygag/pol genes. In that study, three out of five placebo concluded that viral blips with a duration and amplituderecipients had a blip (10/49 assays) versus one out of 13 similar to those seen by their previous models can bevaccinees (1/130 assays; P 0.04). Mainly on the basis of generated by opportunistic infections.this finding, the authors concluded that DNA immuniz-ation in HAART-treated patients may have therapeutic Blip dynamicspotential. Importantly, it appears that all of the placebo Although there remain some discrepancies between bliprecipients experienced detectable viremia of a marked dynamics, as defined by frequent viral load sampling andmagnitude or duration that many clinicians would con- mathematical modeling, the frequency, amplitude andsider viral failure rather than a blip, and so the applica- duration of typical blips has been clarified.bility of that study to this current review is marginal. Frequent viral load sampling3-Hydroxy-3-methylglutaryl coenzyme A To define an extremely precise profile of blip frequency,reductase inhibitors amplitude, and duration, Nettles and colleagues [14]Based on a report that patients receiving 3-hydroxy-3- used frequent viral load sampling as defined above. Mostmethylglutaryl coenzyme A reductase inhibitor therapy blips (15 out of 18) represented isolated measurements(or ‘statins’) for hyperlipidemia, but not receiving above 50 copies/ml, with the subsequent measurementHAART, were found coincidentally to have lowered being undetectable. The typical blip was brief (medianHIV-RNA levels, Waters and colleagues [20] looked duration 2.5 days; range 2–11.5 days) and low in magni-to see if statins lowered the frequency of blips. Using tude (median 79 copies/ml; range 51–201 copies/ml),a prospective database of 1521 patients on first-line with a clustering of values towards the 50 copies/ml limitHAART (78 of which were also prescribed a statin) for and only one value greater than 200 copies/ml.at least 3 months, they found no significant decrease inblip frequency in those patients prescribed a statin. Mathematical modeling Mathematical modeling predicts an entirely differentNon-adherence blip profile. Previously, mathematical models proposedIt has long been assumed that many blips result from a mean blip amplitude of 158 Æ 132 copies/ml and a blipperiods of poor adherence to HAART. This assumption duration of 20–30 days [6–8]. Di Mascio and colleagueswas not supported by a careful assessment of adherence [23] have recently refined their mathematical model andin 128 patients, using pill count, self-report and the applied it to the same population of patients as theirMedication Event Monitoring System (MEMS; AAR- previous publication to conclude that blips extend for aDEX Ltd., Switzerland), an electronic pill bottle cap period of approximately 3 weeks.that records each time a patient opens a pill bottle[21]. Twenty-five per cent of the patients experienced Immune response to blipsa blip. Among those patients who experienced a blip, In one study, the effect of blips on the immune systemthere was no significant decrease in adherence before the was compared with patients with persistent undetectableblip. Patients who experienced a blip had higher rates of viral loads. Karlsson and colleagues [24] categorizedoverall adherence (P ¼ 0.046). There were no significant patients on HAART as having sustained undetectabledifferences in the dose-timing error between those who levels of viremia or intermittent detectable viremiaexperienced a blip and those who did not. The authors of 50–1000 copies/ml (blips). The viral load wasconcluded that blips do not appear to be associated with measured every 4 months in that study. Patients withnon-adherence. intermittent viremia had an HIV-specific CD8 T-cell response statistically significantly greater in magnitudeSimilar results were found by Nettles and colleagues and breadth compared with those with sustained suppres-[14], in which patient-reported non-adherence was sion of viremia (P 0.001 for magnitude and breadth). InCopyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  4. 4. 160 Reservoirs: basic science particular, patients with blips had greater immune loads that are below 50 copies/ml, rather than clinically responses to gag, pol, env, and nef. In addition, HIV- significant elevations in the level of viral replication. specific cellular immune response to the HIV proteins Most blips are not surrogate markers for periods of were generally higher at those timepoints when blips non-adherence, immune system activation, inadequate were detected (P ¼ 0.057). The study is intriguing; how- drug concentrations, or HAART impotency, and there- ever, it was somewhat limited by the infrequent viral fore should not serve as such. Care should be exercised in load measurements. the interpretation of data generated from studies of blips with infrequent viral load measurements or viral loads Blips and antiretroviral drug resistance measured from blood collected by PPTs. Despite these The authors of two studies have previously reported recent findings, it remains clinically important to differ- finding new resistance mutations in association with blips entiate blips from early virological failure or persistent [11,12]. Those studies were compromised by having a detectable low-level viremia. Studies defining the mag- limited assessment of preexisting mutations and limited nitude and duration of viremia necessary for the per- sensitivity of genotyping assays. In a large prospective mission of viral replication, leading to the development study incorporating an ultrasensitive genotyping method of new drug resistance mutations and for the replenish- before, during, and after blips and performing extensive ment of physical or cellular viral reservoirs, are urgently baseline genotyping of the virus residing in the plasma needed. However, once an episode of detectable viremia and the resting CD4 T-cell reservoir [14], no such link is clearly defined as a blip, a low level measurement was found. During the course of that study, nearly 1000 (50–200 copies/ml) with a subsequent and immediate viral clones were genotyped, including approximately return to an undetectable measurement, it should not 150 clones obtained during blip timepoints. New be a cause of clinical concern. mutations were not seen before, during or immediately after blips. Patients with more resistance mutations did not experience a greater number of blips. In addition, References and recommended reading Papers of particular interest, published within the annual period of review, have viruses present during blips were not phylogenetically been highlighted as: distinct from non-blip samples, indicating that viral evol- of special interest of outstanding interest ution was probably not greater during blip timepoints. Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 180). Blips effect on clinical and 1 Havlir DV, Bassett R, Levitan D, et al. Prevalence and predictive value of virological outcome intermittent viremia with combination hiv therapy. JAMA 2001; 286:171– 179. Most studies have shown that blips are not associated 2 Raboud JM, Rae S, Woods R, et al. Consecutive rebounds in plasma viral load with long-term clinical failure or virological failure. Havlir are associated with virological failure at 52 weeks among HIV-infected and colleagues [1] first made this observation on the basis patients. AIDS 2002; 16:1627–1632. of data from two clinical trials in which patients received 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 indinavir plus two nucleosides. The study showed that or immunological failure. Antiviral Ther 2002; 7:251–256. blips were associated with higher steady-state levels of 4 Sklar PA, Ward DJ, Baker RK, et al. Prevalence and clinical correlates of HIV viremia, but were not associated with virological failure viremia (‘blips’) in patients with previous suppression below the limits of quantification. AIDS 2002; 16:2035–2041. for up to 4.5 years (P ¼ 0.53). 5 Greub G, Cozzi-Lepri A, Ledergerber B, et al. Intermittent and sustained low- level HIV viral rebound in patients receiving potent antiretroviral therapy. AIDS Martinez and colleagues [25 ] essentially reproduced the 2002; 16:1967–1969. findings of Havlir and colleagues [1] recently in patients 6 Di Mascio M, Markowitz M, Louie M, et al. Viral blip dynamics during highly active antiretroviral therapy. J Virol 2003; 77:12165–12172. treated with non-nucleoside reverse transcriptase inhibi- 7 Percus JK, Percus OE, Markowitz M, et al. The distribution of viral blips tor-based HAART. They found that eight out of 43 observed in HIV-1 infected patients treated with combination antiretroviral patients (18%) experienced a blip during 18 months of therapy. Bull Math Biol 2003; 65:263–277. follow-up. Patients with blips had a significantly lower 8 Di Mascio M, Ribeiro RM, Markowitz M, et al. Modeling the long-term control of viremia in HIV-1 infected patients treated with antiretroviral therapy. Math CD4 cell count after 12 and 18 months than did those who Biosci 2004; 188:47–62. had not experience a blip. As in previous studies, blip 9 Gunthard HF, Wong JK, Spina CA, et al. Effect of influenza vaccination on viral occurrence was not associated with virological failure. replication and immune response in persons infected with human immuno- deficiency virus receiving potent antiretroviral therapy. J Infect Dis 2000; This is reassuring, given the low genetic barrier of resist- 181:522–531. ance for non-nucleoside reverse transcriptase inhibitors 10 Kolber MA, Gabr AH, De La RA, et al. Genotypic analysis of plasma HIV-1 compared with protease inhibitors. RNA after influenza vaccination of patients with previously undetectable viral loads. AIDS 2002; 16:537–542. 11 Cohen Stuart JW, Wensing AM, Kovacs C, et al. Transient relapses (‘blips’) of Conclusion plasma HIV RNA levels during HAART are associated with drug resistance. J Acquir Immune Defic Syndr 2001; 28:105–113. Among patients on HAART with suppression of HIV-1 12 Easterbrook PJ, Ives N, Waters A, et al. The natural history and clinical viremia, most blips represent laboratory artefacts or nor- significance of intermittent viraemia in patients with initial viral suppression mal biological and statistical variations around mean viral to 400 copies/ml. AIDS 2002; 16:1521–1527.Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  5. 5. Update on HIV-1 viral load blips Nettles and Kieffer 16113 Ramratnam B, Mittler JE, Zhang L, et al. The decay of the latent reservoir of 20 Waters L, Stebbing J, Jones R, et al. The effect of statins on hiv rebound and replication-competent HIV-1 is inversely correlated with the extent of residual blips. J Acquir Immune Defic Syndr 2005; 39:637–638. viral replication during prolonged anti-retroviral therapy. Nat Med 2000; 6: There was no significant decrease in blip frequency in those patients prescribed a 82–85. statin in this study.14 Nettles RE, Kieffer TL, Kwon P, et al. Intermittent HIV-1 viremia (blips) and drug resistance in patients receiving HAART. JAMA 2005; 293:817–829. 21 Miller LG, Golin CE, Liu H, et al. No evidence of an association betweenThis study defines blip dynamics, clinical associations, and genotypic resistance transient HIV viremia (‘blips’) and lower adherence to the antiretroviralconsequences with frequent viral load sampling of 10 patients. Most importantly, medication regimen. J Infect Dis 2004; 189:1487–1496.no new resistance mutations before, during, or immediately after blips were The authors conclude that blips do not appear to be associated with non-detected. adherence. This finding is consistent with the conclusion of others that many15 Squires K, Lazzarin A, Gatell JM, et al. Comparison of once-daily atazanavir blips are related to laboratory or statistical aberrations rather than clinical events with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, generating increased viral replication. as initial therapy for patients infected with HIV. J Acquir Immune Defic Syndr 2004; 36:1011–1019. 22 Jones LE, Perelson AS. Opportunistic infection as a cause of transient viremia16 Stosor V, Palella FJ, Berzins B, et al. Transient viremia in HIV-infected patients in chronically infected HIV patients under treatment with HAART. Bull Math and vacutainer plasma preparation tubes. Clin Infect Dis 2005; 41:1671– Biol 2005; 67:1227–1251. 1674. A mathematical model demonstrates that blips can be generated by opportunisticThis study demonstrates that viral load measurements performed on specimens infections.collected and stored in PPTs result in factitious low-level viremia. The interpretationof viral loads originating from PPTs should be done with caution in both clinical and 23 Di Mascio M, Percus JK, Percus OE, et al. Duration of an intermittent episoderesearch settings. of viremia. Bull Math Biol 2005; 67:885–900.17 Rainen L, Salimnia H, Fairfax M, et al. Sample handling parameters affecting A mathematical model demonstrates that blips may extend for a period of performance of BD vacutainer1 PPTTM and plus K2EDTA tubes with the approximately 3 weeks. Roche AMPLICORTM and COBAS AMPLICORTM HIV-1 MONITOR1 test, v1.5 UltraSensitive and Standard specimen processing procedures. BD 24 Karlsson AC, Younger SR, Martin JN, et al. Immunologic and virologic Diagnostics, Franklin Lakes, NJ, USA. www.bd.com. Released 3 March 2005. evolution during periods of intermittent and persistent low-level viremia. AIDSThis report defines the PPT handling conditions necessary to obtain consistent, 2004; 18:981–989.concordant viral load results. Patients with intermittent viremia had an HIV-specific CD8 T-cell response18 Di Mascio M, Markowitz M, Louie M, et al. Dynamics of intermittent viremia statistically significantly greater in magnitude and breadth compared with those during highly active antiretroviral therapy in patients who initiate therapy during with sustained suppression of viremia. chronic versus acute and early human immunodeficiency virus type 1 infec- tion. J Virol 2004; 78:10566–10573. 25 Martinez V, Marcelin AG, Morini JP, et al. HIV-1 intermittent viraemia in patientsBlip frequency was nearly twofold higher in a chronically HIV-infected group treated by non-nucleoside reverse transcriptase inhibitor-based regimen.compared with an acute/early HIV-infected group. This study may be seen by AIDS 2005; 19:1065–1069.some as another reason to initiate HAART early in the course of infection. This study shows that the occurrence of blips was not associated with virological19 MacGregor RR, Boyer JD, Ugen KE, et al. Plasmid vaccination of stable HIV- failure for patients on non-nucleoside reverse transcriptase inhibitor-based positive subjects on antiviral treatment results in enhanced CD8 T-cell immunity HAART. This is another confirmation that blips do not predict future failure, and increased control of viral ‘blips’. Vaccine 2005; 23:2066–2073. regardless of the HAART regimen.Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

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