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One Time Viral 'Blips' IN PIs vs NNRTIs- study finds same outcome
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"Intermittent Episodes of Detectable HIV Viremia in Patients Receiving Nonnucleoside Reverse-Transcriptase Inhibitor-Based or Protease Inhibitor-Based Highly Active Antiretroviral Therapy Regimens Are Equivalent in Incidence and Prognosis"
Clinical Infectious Diseases Nov 1, 2005;41:1326-1332
Somnuek Sungkanuparph,1 E. Turner Overton,1 Warren Seyfried,1 Richard K. Groger,1 Victoria J. Fraser,1 and William G. Powderly1,2
1Washington University School of Medicine, St. Louis, Missouri; and 2University College Dublin, Mater Misericordiae University Hospital, Dublin, Ireland
(See the editorial commentary by Hellinger below: ".....Isolated blips seem to be inconsequential, but repeated blips and higher HIV RNA loads may precede virologic failure...."
ABSTRACT
Background. Intermittent episodes of detectable human immunodeficiency virus (HIV) viremia (hereafter referred to as "blips") are generally not predictive of subsequent virologic failure. Limited data are available for patients treated with nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based regimens.
Methods. A retrospective cohort study evaluated patients receiving highly active antiretroviral therapy who were followed for >12 months, achieved an HIV RNA load of <50 copies/mL, and underwent evaluation every 2-3 months. A blip was defined as 1 HIV RNA load measurement of 50-1000 copies/mL that was preceded and followed by another HIV RNA load measurement of <50 copies/mL. The frequency and predictors of blips and virologic failure were studied.
Results. There were 244 patients in the NNRTI group and 136 patients in the protease inhibitor (PI) group. Baseline characteristics between the 2 groups were similar. A total of 34% of patients in the NNRTI group and 33% in the PI group experienced viral blips (P = .855), with corresponding incidences of 19.2 and 19.7 blips, respectively, per 100 person-years. Median time to blips was 50.0 months after initiation of therapy in the NNRTI group (95% confidence interval [CI], 44.8-55.3 months) and 43.6 months in the PI group (95% CI, 33.7-53.6 months; P = .632, by the log-rank test).
By Cox proportional hazards model analysis, only a history of antiretroviral therapy use (hazard ratio [HR], 2.01; P < .001) and a CD4 cell count of <200 cells/mL (HR, 1.70; P = .021) increased the risk for having a blip. During a median follow-up period of 23.5 months, 7.8% of patients in the NNRTI group and 8.1% in the PI group experienced virologic failure (P = .917).
Cox proportional hazards model analysis showed that only a baseline CD4 cell count of <200 cells/mL predicted virologic failure (HR, 2.74; P = .032).
Conclusions. There is no difference in the frequency or prognostic significance of viral blips between patients receiving NNRTI-based therapy and patients receiving PI-based therapy. Our results suggest that viral blips occur at a similar rate among patients receiving NNRTI-based regimens and patients receiving PI-based regimens and that they are not predictive of virologic failure.
DISCUSSION
An HIV blip, defined as a temporary elevation in the HIV load in patients receiving suppressive antiretroviral therapy, is a common phenomenon, occurring in 27%-41% of patients who have achieved viral suppression [5-7, 9-11]. The phenomenon of blips has been studied elsewhere in a small case series [4], in clinical trials [5], and in retrospective cohort studies [6, 7, 9-11]. Although previous studies showed that blips are generally not predictive of subsequent virologic failure [5, 8, 9, 11, 12, 24], in one study, the majority of patients were receiving PI-based regimens because of the randomization process used in clinical trials [5], whereas in other studies, the cohorts were comprised of patients enrolled during 1994-2000, when PI-based regimens were first-line treatment for HIV infection [8, 9, 11]. A recent study of viral blips that involved 10 patients who underwent intensive blood sampling included 8 patients who had received PI-based regimens [24].
The present study shows that the incidences of blips are similar between patients receiving PI-based regimens and patients receiving NNRTI-based regimens. The overall incidence of 19.4 blips/100 person-years is lower than that previously reported from the Swiss HIV Cohort Study and the Frankfurt HIV Clinical Cohort (37.4 blips/100 person-years), which included patients with sustained low-level viremia [10]. A total of 34% of patients in the NNRTI group and 33% in the PI group experienced viral blips, which is consistent with previous studies that mainly involved patients receiving a PI-based regimen [5-7, 9-11]. A subanalysis examining viral blips in subgroups of patients who received different NNRTI-based regimens (i.e., nevirapine vs. efavirenz) and different PI-based regimens (i.e., boosted PIs vs. nonboosted PIs) also showed that there was no difference in the frequency of viral blips (data not shown). Thus, the overall prevalence of this phenomenon appears to be similar across all studied populations. However, Kaplan-Meier estimates from the present study show that the probability of experiencing a viral blip increases over time: the probabilities of having a blip after 36 and 72 months of ART were 33% and 77%, respectively.
Our data also suggest that ART experience and a baseline CD4 cell count of <200 cells/mL are associated with higher risk for having an HIV blip. Patients who were ART experienced had a longer duration of HIV infection, compared with ART-naive patients (data not shown). It has been reported that blip frequency inversely correlates with baseline CD4 cell count [12]. In addition, a recent study of the dynamics of blips also showed that the frequency of viral blips was -2-fold greater among patients with chronic HIV infection than among patients with primary HIV infection [25]. Our findings, as well as those of these 2 previous studies, suggest that the duration of HIV infection may predict the occurrence of viral blips. The occurrence of viral blips might also be explained by host-specific factors.
During a median follow-up period of 2 years, -8% of our patients experienced virologic failure. This failure rate is lower than that reported in other clinical practice settings, because we excluded patients who had primary virologic failure (i.e., those who never achieved an undetectable HIV RNA load) and patients with sustained low-level viremia. Kaplan-Meier survival analysis revealed that the probability of virologic failure was similar between the 2 groups. In addition, the probability of failure for patients who had blips was also similar between the 2 groups. Thus, the prognostic significance of blips for patients who received NNRTI-based regimens is similar to that for patients who received PI-based regimens. Cox proportional hazards models revealed that only a baseline CD4 cell count of <200 cells/mL was associated with a higher risk for virologic failure. This finding is consistent with previous reports that a low baseline CD4 cell count predicts treatment failure [26, 27].
Our finding that HIV blips are not associated with virologic failure support findings from previous studies and suggest that blips should not be an indication for switching the ART regimen. Although NNRTI-based regimens have a lower genetic barrier for viral resistance and virologic failure, such regimens do not seem to be a reason for clinical concern greater than that for PI-based regimens. However, sustained low-level viremia in NNRTI-based regimens may be a greater cause for concern, because previous studies suggest that sustained low-level viremia, in contrast to blips, is associated with viral resistance and virologic failure [8, 10, 28, 29].
There are limitations to our study. First, we studied and analyzed the HIV RNA loads in samples obtained during clinic visits at intervals of 2-3 months. The rate of blips may be lower than that in studies involving more-frequent clinic visits. On the basis of results of the study that involved intensive blood sampling [24], the number of blips detected is likely to be directly related to the frequency of sampling. However, the results from our study may be more applicable to real-life clinical practices in which patients are seen and evaluated every 2-3 months: our definition of "viral blips" is similar to the characteristics of episodes of detectable viremia that we find and face in clinical practice. Second, we did not formally evaluate adherence in our patients, because of the retrospective nature of the study. However, the definition of viral blips used in this study is similar to the definition used in the study by Miller et al. [30], which demonstrated that decreased adherence is not associated with viral blips.
In summary, there is no difference in the incidence or prognostic significance of HIV viral blips between patients receiving NNRTI-based regimens and patients receiving PI-based regimens. ART-experienced patients are more likely to have viral blips. Patients with a baseline CD4 cell count of <200 cells/mL are more likely to have viral blips and virologic failure. Our results suggest that viral blips occur at similar rates among patients receiving NNRTI-based regimens and patients receiving PI-based regimens and that viral blips are not predictive of virologic failure.
EDITORIAL in CID
HIV Blip Synching: Get the Timing Right
James Hellinger
Division of Infectious Diseases, Department of Medicine, Tufts-New England Medical Center, and HIV Program, Community Medical Alliance, Boston, Massachusetts
Sungkanuparph et al. [1] provide useful data addressing a common clinical concern about how to interpret low-level detectable levels and transient levels of plasma HIV RNA (hereafter referred to as "blips") in patients with successful suppression of HIV load during HAART. In light of the findings of Sungkanuparph et al. [1], taken together with findings of recent studies of persons with transient, intermittent HIV viremia, the critical issue is to get the timing right: HIV blip synching. Timing is critical for this classification, because a single, low-level elevation of 50-1000 copies/mL in the HIV RNA load may precede further elevations and virologic failure, or it may represent an innocuous event.
At least 3 assessments of viral load define the waveform of a blip: ⩾1 baseline undetectable load, a low-level "spike," and a subsequent undetectable load. Without confirmation before and after the blip that the detected low-level viremia is transient, the magnitude and duration of unchecked viral replication and, potentially, the risk of developing drug resistance cannot be assessed. (Without the early confirmation that a new spike in the viral load is resolved or sustained, perhaps this finding should be called a "slur.")
The US Department of Health and Human Services (DHHS) treatment guidelines summarize expectations after HAART initiation that link the elements of time and magnitude of the decrease in the viral load. The plasma HIV RNA load is an excellent prognostic indicator of disease progression, and sequential measurements showing a reduction in plasma viremia are linked to improved clinical outcome. Guidelines for monitoring successful treatment initiation in treatment-naive patients anticipate a decrease of at least 1 log copies/mL in the plasma HIV RNA load between weeks 2-8 of HAART, as well as an additional decrease to below the level of detection during weeks 16-24. Quarterly monitoring of viral loads are recommended to confirm ongoing maximal suppression. According to DHHS treatment guidelines, for individuals receiving a new therapy regimen, virologic failure is defined as a confirmed plasma HIV RNA load of >400 copies/mL after week 24 of treatment (or as a plasma HIV RNA load of >50 copies/mL after week 48); for individuals with previous suppression to ⩽400 copies/mL, a sustained level of >400 copies/mL constitutes treatment failure.
Retrospective and prospective studies have clearly documented the emergence of new, clinically significant, drug resistance mutations during sustained, low-level viremia (defined as an HIV RNA load of 20-1000 copies/mL) in patients receiving HAART [2]. Although the estimates of the risk of resistance may vary by patient characteristics and treatment regimen, one prospective study of persons with persisting low-level viremia (defined as an HIV RNA load of 50-400 copies/mL) identified clinically significant drug resistance mutations in 9 of 21 patients receiving a median of 5 antiretroviral drugs who underwent sampling 5 times during an 11-month period [3]. On the basis of past treatment exposure, a minimum of 3 of these 9 mutations were clearly induced by HAART use [3]. Patients with sustained low-level viremia demonstrate evidence of immune activation and emergence of genotypic and phenotypic resistance that may hasten the development of virologic failure and sustained high-level viremia [4]. Although the evolution of drug resistance is well documented by these studies for persons with viral loads <1000 copies/mL, higher detection thresholds for the commercially available resistance assays has limited clinicians' ability to detect this phenomenon in the clinic.
In contrast to persistent low-level viremia, transient viremia (blips) appears to be both common and benign. In clinical trials and cohort studies, 27%-50% of patients who achieve nadir viral loads <50 copies/mL experienced HIV blips [3, 5, 6], which are similar to the 33% and 34% rates among patients who received nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based HAART and protease inhibitor-based HAART in the study by Sungkanuparph et al. [1]. Intensive monitoring of a small cohort of 10 patients who underwent sampling up to 3 times weekly for 3-4 months identified blips with a low magnitude (mean HIV RNA load, 79 copies/mL) and a short duration (median, 2.5 days [range, 2-11 days]). A total of 18 blips were identified in 9 of 10 patients.
The DHHS guidelines warn that viral rebound lasting 2-4 weeks occurs in patients who have reduced antiretroviral drug concentrations, as well as in those who are nonadherent to therapy, those with immune activation due to vaccination, and those with intercurrent illness. In contrast, blips were marginally associated with nonadherence but not with intercurrent illness (upper respiratory and gastrointestinal infection, oral herpes simplex virus infection, or gout flare) or influenza vaccination. In the study by Nettles et al. [7], frequent sampling of patients yielded more blips, but blip sequences (up to 5 clones per time point) did not evolve new mutations in the genes encoding protease or reverse transcriptase. Nettles and colleagues speculate that blip characteristics indicate residual HIV replication and random bursts of drug-susceptible virus from a cellular reservoir that occur regardless of suppressive drug concentrations and generate a mean viral load just below the detection threshold of 50 copies/mL [7].
Whether in vitro or in patients, HIV replication in the presence of nonsuppressive antiretroviral concentrations promotes drug resistance. But how new is the concept of a viral blip? Familiar principles in the treatment of infectious diseases provide reasons to place this concept in a continuum that relates microbial burden and replication over time with the risk of induced drug resistance. In treating Mycobacterium tuberculosis infection, high-grade bacteremia, acute HIV infection, or any condition in which a large number of organisms are actively replicating over sustained periods, clinicians use potent combination therapies to enhance the benefit of antimicrobial treatment and to delay the development of resistance. In contrast, the HIV blip appears to represent a relatively small area under the curve of the graph of the magnitude and duration of viral replication and is, therefore, too inconsequential to induce drug resistance.
It is worth emphasizing that the retrospective nature of most published studies about persistent versus transient viremia have used archived samples and results that allow researchers to categorize events over time and then study diseases predictors and characteristics. Given the greater risk of sustained viral rebound, blips of greater magnitude (particularly those greater than 500-1000 copies/mL) warrant reevaluation, before the next quarterly visit, and consideration for HIV genotype analysis. Clinicians who detect an initial episode of low-level viral rebound need to repeat and confirm this finding. In this context, failure to distinguish a blip from sustained low-level viremia is a missed opportunity to prevent virologic failure and to intervene by addressing patient-specific issues, including treatment intolerance, adherence, pharmacokinetics, and drug-drug interactions.
So when is a blip just a blip (i.e., an innocuous and inconsequential event without future clinical impact), and when does it indicate a significant risk for drug resistance and virologic failure? Results of the intensive sampling study [7], which were similar to results of earlier studies, suggest that blips of higher magnitude (>200 copies/mL) and higher frequency may lead to greater risk of virologic failure [8, 9]. However, as noted in the study by Sungkanuparph et al. [1], blips are more common among patients with ART experience and lower CD4 cell counts, but they do not predict treatment failure. Despite concerns that single-step mutational pathways to drug resistance (i.e., a low genetic barrier) may make the NNRTI more prone to virologic failure, blips that occurred during receipt of NNRTI regimens did not predict virologic failure and occurred at the same rate of 8% over 2 years among patients receiving either NNRTI-based or protease inhibitor-based regimens. Isolated blips seem to be inconsequential, but repeated blips and higher HIV RNA loads may precede virologic failure. Future studies will need to better characterize risks for virologic failure and viral load thresholds for clinically worrisome viral blips, which range from 400 to >1000 copies [8, 9]. We can expect that patients with advanced HIV infection will have more blips, but there seems to be no reason to change current monitoring routines.
BACKGROUND
HAART use in HIV-infected patients has been proven to decrease morbidity and mortality. Laboratory assays to quantify plasma HIV RNA levels are an integral part of standard clinical care for HIV-infected patients. The current goal of antiretroviral therapy (ART) is suppression of the HIV RNA load to an undetectable level of <50 copies/mL, which is the limit of detection of the most sensitive available clinical assay [1, 2]. Achievement of this goal prevents drug resistance and reduces the rate of treatment failure [3].
After the HIV RNA load becomes undetectable, a subset of HIV-infected patients experience intermittent episodes of detectable HIV viremia (hereafter referred to as "blips") [4-12]. These viral blips have been shown by several groups to be associated with increasing levels of replication-competent virus in cellular reservoirs [13, 14], increased rates of evolution within viral envelope sequences [15, 16], and the potential emergence of drug resistance [17].
The clinical importance of blips remains unclear, but several large studies have suggested that isolated blips are not associated with virologic failure [5, 8, 9, 11]. However, the majority of patients in the previous studies of HIV blips were treated with protease inhibitor (PI)-based HAART regimens [4, 5, 8-12].
Nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based ART regimens are increasingly used because of their effectiveness, convenience, and decreased toxicity. The frequency and prognostic significance of viral blips in patients who have received NNRTI-based HAART regimens have not been well evaluated, and results of studies of viral blips in patients receiving PI-based regimens may not be applicable to patients receiving NNRTI-based regimens. NNRTIs have longer half-lives than most PIs [18, 19]. In addition, HIV strains with reduced susceptibility to NNRTIs have been detected that have a single mutation in the gene encoding reverse transcriptase [20, 21]. We therefore wished to study the frequency and clinical significance of HIV blips among HIV-infected patients receiving either NNRTI-based or PI-based regimens.
PATIENTS AND METHODS
Study patients. A retrospective cohort study was performed that involved HIV-infected patients who received HAART between January 1998 and December 2003 at Washington University Hospital (St. Louis). Patients were eligible for the study if they received HAART and were followed up for at least 12 months, achieved an undetectable plasma HIV RNA load (<50 copies/mL) within 6 months after starting HAART, and attended regular visits and underwent measurement of plasma HIV RNA load by means of an ultrasensitive assay every 2-3 months. Patients were excluded if they received both NNRTIs and PIs in the same treatment regimen or if they received triple-nucleoside reverse-transcriptase inhibitor (NRTI) combination therapy, had persistent low-level viremia (defined as detectable plasma HIV RNA levels of 51-1000 copies/mL for >3 months or on >2 consecutive clinic visits), or had early treatment failure with a rebound in the HIV RNA load of >1000 copies/mL within 1 year after initiating HAART. Each eligible patient was followed up until the end of the study (31 December 2004), until HAART was discontinued, or if they were switched to the other treatment group. The study was approved by the Washington University Human Studies Committee (St. Louis, MO).
Data collected included demographic characteristics, history of ART use, previous ART regimens received, baseline CD4 cell count and HIV RNA load before starting previous ART regimens, CD4 cell count and HIV RNA load at every follow-up visit, and HIV genotype. All tests for CD4 cell count, HIV RNA load, and HIV genotype were ordered at the discretion of the attending health care professional in the infectious diseases clinic. Patients were grouped according to their HAART regimen (i.e., NNRTI-based regimens [NNRTI group] or PI-based regimens [PI group]).
Case definitions of viral blip and virologic failure.
Viral blip (i.e., intermittent viremia) was defined on the basis of 3 consecutive HIV RNA load determinations (during 3 clinic visits) during the course of 6-9 months. A viral blip was identified as a plasma HIV RNA load of 50-1000 copies/mL, preceded by 1 and followed by 1 measurement of <50 copies/mL. If patients had >1 viral blip, we considered only the first episode in our analysis. Virologic failure was defined as 2 consecutive plasma HIV RNA levels of >1000 copies/mL.
RESULTS
There were 380 study patients, of whom 258 (67.9%) were men. The mean age (±SD) of the study patients was 38.9 ± 9.8 years. A total of 244 patients (64.2%) were in NNRTI group, and 136 (35.8%) were in the PI group. Characteristics of the 2 groups are shown in table 1. In the NNRTI group, all ART-experienced patients had received 1-2 PIs and 2-4 NRTIs. In the PI group, 68 (94.4%) of 72 patients who were ART experienced had received NNRTIs and 2-5 NRTIs; the other 4 patients had received triple-NRTI combination therapy only.
In the NNRTI group, 106 patients (43.4%) received nevirapine, and 138 patients (56.6%) received efavirenz. The distribution of PIs used in the PI group was as follows: 42 patients (30.9%) received nelfinavir, 42 (30.9%) received lopinavir-ritonavir, 30 (22.1%) received indinavir with or without ritonavir, 11 (8.1%) received saquinavir with or without ritonavir, 10 (7.4%) received atazanavir with or without ritonavir, and 1 (0.7%) received amprenavir. At a median follow-up time of 23.5 months, there was no difference between the 2 groups in terms of the change in the CD4 cell count (P = .052). The median change in the CD4 cell count was 152 cells/mL (interquartile range, 46-268 cells/mL) in the NNRTI group and 204 cells/mL (interquartile range, 70-341 cells/mL) in the PI group.
Presence of and time to HIV blip.
Of 380 patients, 128 had at least 1 viral blip. There were no significant differences in viral blip characteristics between the NNRTI group and the PI group. Patients in the NNRTI group who experienced a viral blip had a greater chance of having a second viral blip than did patients in the PI group who experienced a viral blip (P = .013). Figure 1 shows the Kaplan-Meier estimates of the probability of having a viral blip. The median time to the first viral blip was 50.0 months in NNRTI group (95% CI, 44.8-55.3 months) and 43.6 months in the PI group (95% CI, 33.7-53.6 months). The difference between the 2 groups was not significant (P = .632, by the log-rank test). A Cox proportional hazards model to determine predictors for viral blips showed that patients with a higher risk for HIV blips were ART experienced (hazard ratio, 2.01; P < .001) or had a CD4 cell count of <200 cells/mL (hazard ratio, 1.70; P = .021).
Presence of and time to virologic failure.
During a median time follow-up time of 23.5 months (range, 15.0-42.3 months), 30 (7.9%) of the 380 patients experienced virologic failure. The proportions of patients with virologic failure were similar between the NNRTI group and the PI group. Figure 2 shows the Kaplan-Meier estimates for the probability of virologic failure between the 2 groups, stratified according to patients with and patients without viral blips. The median time to virologic failure was >72 months in all 4 subgroups. The difference among the 4 subgroups were not significant (P = .271, by the log-rank test). A Cox proportional hazards model to determine predictors for virologic failure showed that only patients with a baseline CD4 cell count of <200 cells/mL had a higher risk for virologic failure (hazard ratio, 2.74; P = .032) (table 5). Among patients with viral blips, neither the number of viral blips (P = .480) nor the size of the blips (P = .430) affected the probability of virologic failure, according to Kaplan-Meier survival analysis.
HIV genotyping.
Of the 30 patients with virologic failure, 28 had HIV isolates that underwent genotyping at the time of failure. Eighteen (64.3%) of these 28 patients had HIV isolates with new, confirmed primary mutations in the genes encoding reverse transcriptase or protease that contributed to antiretroviral resistance.
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