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Intermittent Viremia Increases Risk 3 Times for Viral Failure and Impairs CD4 Response
  The authors suggest found resistance develops; and nonadherence, therapy interruption, vaccination, and intercurrent illness may contribute to viral rebound.
The authors suggest considering therapy intensification when there is intermittent viremia (one or more episode >400 viral load) and caution against therapy interruptions.
The natural history and clinical significance of intermittent viraemia in patients with initial viral suppression to < 400 copies/ml
AIDS 2002;16:1521-1527
An English research group studied the prevalence and significance of intermittent viraemia (IV) in patients who attained an undetectable viral load (VL) < 400 copies/ml within 6 months on highly active antiretroviral therapy (HAART).
The authors did a retrospective analysis (look back) of 765 patients who had viral load rebound > 400 copies/ml and they looked to see if this affected their rise in CD4 cell counts. The patients were followed for 12 months following initial VL undetectability, comparing the 226 (29.5%) who maintained an undetectable VL for > 1 year from initiation of HAART and 122 (15.9%) who had one or more episodes of intermittent viremia (IV). Genotypic resistance was evaluated at the time of the first episode of IV > 2000 copies/ml.
Patients with IV had a threefold higher rate of sustained virological rebound [hazards ratio (HR), 3.15; P < 0.001). For patients with and without IV, the Kaplan-Meier estimates for sustained viral rebound at 24 and 36 months after initiation of HAART were 19.3% versus 7.7% and 31.6% versus 12.9%, respectively (P < 0.001). The median CD4 cell count rise at 18 and 24 months was significantly lower in those with IV than in those without: 138 versus 224 and 200 versus 260 (P = 0.003), respectively. In a subgroup of 16 patients, genotypic resistance mutations were found in the reverse transcriptase gene for five (31%) and in the protease gene in one. A probable contributing factor/event was identified for most patients with IV, such as poor adherence (42.6%), intercurrent infection (26.2%) or drug interaction (6.8%).
The authors concluded that patients with IV > 400 copies/ml are three times more likely to experience sustained viral rebound and to have an impaired CD4 cell rise relative to those who maintain undetectable VL. This supports the adoption of a more pro-active approach to treatment intensification and the need for caution with structured treatment interruptions.
Eligible patients were those who (i) attained an undetectable VL (defined as < 400 copies/ml) within 6 months of initiating HAART; (ii) had at least 12 months of follow-up following initial VL undetectability; and (iii) had at least four documented serial VL measurements following initial VL undetectability, at approximately 3 month intervals. Patients were grouped according to their subsequent virological response following initial VL undetectability: the first group were those with a sustained undetectable VL [i.e., patients in whom the VL remained undetectable (< 400 copies/ml) for at least 1 year from initiation of HAART] and the second group were those with intermittent viraemia (i.e., patients who had one or more episodes of a VL 400 copies/ml followed by a VL < 400 copies/ml).
Pattern of intermittent viraemia
The median time from initial VL undetectability to the first episode of intermittent viraemia was 6.1 months. The median VL at first episode was 1153 copies/ml. Initial VL was < 1000 copies/ml in 45%, 1001-5000 copies/ml in 26%, 5001-100 000 copies/ml in 17% and > 100 000 copies/ml in 12%. The majority of patients had a single episode of virological breakthrough, but 22 (18%) patients had two or more episodes (20 patients had two episodes and two patients had three episodes). The median VL at the second episode was 799 copies/ml (IQR, 651-4316) and this followed the initial episode after a median of 9 months (IQR, 5.8-11.8). In those patients with two or more episodes, the magnitude of the VL at the first and second episodes was 1591 (IQR, 662-5300) and 799 copies/ml (IQR, 651-4316), respectively.
Characteristics of patients with sustained undetectable viral load and those with intermittent viraemia
In a univariate analysis, younger age (P = 0.003), female gender (P = 0.05) and more than 6 months prior nucleoside reverse transcriptase inhibitor exposure (P = 0.05) were significantly associated with the development of intermittent viraemia. There was also an inverse relationship between baseline VL and development of intermittent viraemia. Compared with patients with a VL < 20 000 copies/ml, there was a significantly reduced risk of intermittent viraemia in those with a VL 20 000-100 000 copies/ml and > 100 000 copies/ml. However, in the multivariate analysis, only age and gender remained significant predictors of intermittent viraemia (P = 0.002 and 0.02, respectively).
Reasons for episodes of intermittent viraemia
There were 103 episodes of intermittent viraemia in 96 patient from the three hospital sites. In the majority of these, there was a documented event in the medical records: most commonly a period of non-adherence, an intercurrent illness or vaccination in the month prior to the episode of intermittent viraemia. The most common reasons identified were a documented period of poor adherence, drug interruption or change in 44 (42.6%), intercurrent infection or vaccination in 27 (26.2%) and drug interaction in four (6.8%). In 25 (24.3%) patients, there was no clear documented reason to account for the episode of intermittent viraemia.
Author Discussion
Intermittent viraemia, as defined by a VL > 400 copies/ml, occurred in 16% of all our patients initiating HAART, and in 27% of patients who initially attained an undetectable VL. This is consistent with the reported prevalence of 20% of 241 patients initiating HAART based on a more conservative definition of intermittent viraemia as > 200 copies/ml (or 40%, when a threshold of > 50 copies/ml was used). In the majority of our patients, there were documented events that may have contributed to the episodes of viraemia. A period of poor adherence or an intercurrent infection or vaccination, which are well-established causes of transient viraemia, were recorded in approximately three-quarters of all episodes of viraemia. However, levels of adherence and drug levels were not documented longitudinally in this study, and it is, therefore, difficult to quantify the level of poor adherence or low drug concentration that may have contributed to these episodes of viraemia. In addition, primary genotypic resistance mutations to reverse transcriptase and protease genes were found in almost a third of a subgroup of patients at their first episode of viraemia, although this may represent an underestimate as only those patients with viraemia > 2000 copies/ml were examined. It also remains unclear as to whether this resistance was the cause or consequence of the viraemic episodes. However, several of these patients had prior experience of nucleoside reverse transcriptase inhibitor drugs, suggesting that resistance to these drugs may have been already present at baseline and contributed to subsequent viraemia. In another recent study of 15 patients with intermittent viraemia > 50 copies/ml, resistance mutations in the reverse transcriptase and protease gene to one or more drugs were present at the time of relapse in 8 of 11 patients. Several of these patients had prior nucleoside reverse transcriptase inhibitor experience, and the authors concluded that half of the cases of viral breakthrough were the result of selection of resistant viruses, and the remainder were caused by the presence of wild-type virus produced from activation of memory cells infected before therapy.
In four separate studies of patients with episodes of much lower-level viral breakthrough, between 50 and 400 copies/ml, no association was found with an increased rate of viral rebound.
Importantly, the development of one or even two episodes of viraemia does not imply the inevitable development of virological failure. At 2 and 3 years after the initiation of HAART, 80 and 70%, respectively, of patients who had experienced at least one episode of intermittent viraemia showed no evidence of sustained virological breakthrough. We were unable to identify any demographic, clinical or laboratory characteristics among patients with intermittent viraemia, that would predict the development of sustained VL rebound.
Overall, our findings suggest a clear clinical benefit from consistently maintaining viral suppression below a threshold of 400 copies/ml, although based on other studies not necessarily < 50 copies/ml. From these other studies, there appears to be no significant short- or medium-term adverse effects from episodes of much lower level viraemia: 50-200 copies/ml, although these observations remain in conflict with a body of work showing that achieving a VL < 50 copies/ml results in a more durable virological response compared with those whose nadir is between 50 and 400 copies/ml. It remains possible, given the higher rates of drug resistance observed in the four studies cited that, with longer follow-up and either repeated episodes or increasing levels of viraemia, virological failure would eventually result.
The clinical management implications of our findings include the need to optimize adherence, assess drug levels and avoid treatment interruptions, particularly where these have been identified as contributing factors to episodes of intermittent viraemia > 400 copies/ml.
For the same reason, structured treatment interruption studies designed to test the hypothesis that the immunological set-point can be increased and plasma viraemia be reduced for prolonged periods by stimulation of HIV-specific CD4 T cells and broadly directed cytotoxic T lymphocyte responses, should proceed with great caution.
Recent data have highlighted the adverse consequences of interrupting treatment, including the emergence of drug-resistant virus, substantial declines in CD4 T cells and new or recurrent opportunistic infections. Treatment intensification (rather than a complete treatment change) is a further therapeutic approach to the management of frequent and higher-level intermittent viraemia. Recent data based on a study of only five patients suggest that the frequency of viraemic episodes can be reduced and the decay rate of the latent reservoir accelerated by increasing the potency of the antiretroviral regimen, and this provides support for treatment intensification. However, this approach needs to be guided by resistance testing and confirmed in a larger study. Future studies are also needed to address the possible contribution of latently infected cells and sanctuary sites to the episodes of intermittent viraemia.
Authors: Philippa J. Easterbrooka; Natalie Ivesa; Anele Watersa; Jane Mullenb; Siobhan O'Sheab,c; Barry Petersc; Brian G. Gazzardd
From the Department of HIV/GUM, Guy's, King's and St Thomas' School of Medicine, King's College Hospital, the bDepartment of Infection, Virology Section, Guy's and St Thomas's Hospital Trust, the cDepartment of HIV/GUM, Guy's and St Thomas's Hospital Trust and the dDepartment of HIV/GUM, Chelsea and Westminster Hospital, London, UK.
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