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• W2056521704 abstract "For HIV patients, structured treatment interruption is considered a treatment option to allow the reversion of a highly resistant virus population to wild type [1]. Structured treatment interruption is an attractive alternative strategy to continuous treatment, particularly in resource-constrained settings, because it reduces both side-effects and costs [2]. One major concern, however, is the development of resistance to antiretroviral drugs that can occur during multiple cycles of starting and stopping therapy. Furthermore, treatment-associated costs (particularly in resource-poor areas), difficulty in maintaining long-term optimal adherence, and the emergence of viral resistance have all limited the feasibility of life-long antiretroviral therapy (ART)-mediated viral suppression, increasing the need for alternative treatment strategies [3]. Intermittent therapy strategies, consisting of alternating cycles on and off ART, have increasingly emerged to address the limitations of continuous ART [4]. It was reported that 2 years after structured treatment interruption, only a low proportion of patients who had a good immunological profile at the end of the structured treatment interruption period still had a good virological response [5]. HIV drug resistance mutations (HDR) can accumulate, persist in the proviral genome, and re-emerge, thereby promoting the further failure of rescue regimens [6]. We and others have demonstrated that in a structured treatment interruption strategy, the mutant HIV populations completely or partly reverted to wild type by 4 months in the majority of patients [1]. No persisting HDR have been evidenced in patients after a long structured treatment interruption of nearly 2 years, without any therapeutic pressure. In the present study, we report on the persistence of HDR in the reverse transcriptase and protease gene after 2 years of treatment interruption. The patient was a 30-year-old woman nurse, Centers for Disease Control and Prevention disease stage A, who was contaminated in 1990 by intravenous drug abuse treated by an antiretroviral treatment combining videx, viramune and ziagen until May 2003, when the treatment was stopped because of marked lipodystrophy in the face and a low viral load, lower than 5000 copies/ml, and a CD4 cell count greater than 500 cells/mm3. In December 2002, the CD4 cell count was 424 cells/mm3, the HIV viral load was 1660 copies/ml, and HIV-1 drug resistance assessed by sequence analysis (Trugene; Visible Genetics, Bayer, Puteaux, France) showed the following pattern of mutations: L10I, I13V, I15V, K20M, M36I, R41K, L63P, A71T, L90M, M41L, L74V, L210W, T215D, T215Y, V108I, and Y181C. The patient was monitored using the viral load and CD4 cell count in January 2003, October 2004, December 2004, and February 2005. The corresponding HIV viral loads were, respectively: 2200, 10 300, 31 200, and 78 200 copies/ml, and the CD4 cell counts were 485, 516, 373, and 289 cells/mm3. All mutations found in the HIV protease and reverse transcriptase genes were present before the interruption of treatment, and 18 months and 21 months after. Plasma levels of the protease inhibitor and nucleoside reverse transcriptase inhibitor drugs were assessed at the same dates and no drugs were detected. The latter result rules out that the patient covertly administered herself an antiretroviral treatment. Figure 1 shows the CD4 cell count, viral load, and resistance mutation pattern at this time.Fig. 1: Viro-immunological and therapeutic course. Resistance tests were performed at three dates: December 2002, December 2004 and January 2005. The respective pattern of mutations are indicated at these three dates. —▪— Viral load; —♦— CD4 cell count.The panel of HDR found in this patient is compatible with the well-established resistance mutations pattern associated with these drugs. During the 24 months after the interruption of treatment, as attempted, the viral load increased to 78 200 copies/ml, whereas the CD4 cell count decreased to a nadir of 289 cells/ml. Surprisingly, after 24 months interruption of treatment, no reverse transcriptase gene and protease gene mutations decreased. Moreover, the three patterns of mutations were the same in December 2002, December 2004 and January 2005. These results show the persistence of mutations and suggest that it is very difficult to return to a wild-type viral population, sensitive to antiretroviral treatment. However, the stability of these mutants in the absence of drug selection pressure is not known. This case cannot be attributed to the role of immune pressure in the development of a drug-resistant virus because the CD4 cell count was never lower than 400 cells/mm, as described [7]. One hypothesis for the absence of reversion after a long structured treatment interruption in this patient is that plasma and intracellular HIV compartments found a balance under conditions of active viral replication, which could hamper the detection of resistance mutations [6]. It could also be suggested that the fitness of this particular strain should be considered as a parameter influencing the outcome of therapeutic intervention in chronic infection. This case highlights the stability of these mutants in the absence of drug selection pressure, which can evolve to increased replication capacity and significant pathogenicity [8]." @default.
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• W2056521704 date "2005-10-14" @default.
• W2056521704 modified "2023-10-12" @default.
• W2056521704 title "Long-term persistence of HIV with drug resistance after CD4 cell count-guided structured treatment interruption" @default.
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• W2056521704 doi "https://doi.org/10.1097/01.aids.0000184404.37282.8f" @default.
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