Selection of the Q148R integrase inhibitor resistance mutation in a failing raltegravir containing regimenписьмо
Аннотация: HIV-2 is naturally resistant to current nonnucleoside reverse transcriptase inhibitors (NNRTIs) and fusion inhibitors [1] and is less sensitive than HIV-1 to several protease inhibitors in vitro[1,2]. Thus, antiretroviral therapeutic options for HIV-2-infected patients are limited compared with HIV-1-infected patients. Despite only 60% sequence identity between the HIV-1 and HIV-2 integrase genes, phenotypic susceptibility to the two available integrase inhibitors (INIs) is similar [3]. We have previously reported good virological and immunological responses to INI-containing highly active antiretroviral regimens (HAART) in two HIV-2-infected patients with multiple treatment failure [4]. Here, we report a case of virological failure associated with the emergence of an INI resistance mutation in an HIV-2-infected patient receiving HAART comprising darunavir/ritonavir (DRV/r) and raltegravir (RAL). A 59-year-old Malian man had been diagnosed with HIV-2 infection in 1994. He had received multiple antiretroviral treatments, including AZT/3TC/NFV between 1999 and 2003, ABC/TDF/LPV/r between 2003 and 2006, ABC/TDF/TPV/LPV/r in 2006, and TDF/ABC/LPV between December 2006 and October 2007. After 1999, his CD4 lymphocyte count never exceeded 175 cells/μl and his plasma HIV-2 viral load never fell below 100 copies/ml. In October 2007, his CD4 cell count was 56 cells/μl (4.9%) and his viral load was 33 820 copies/ml. Plasma RAL and DRV concentrations were adequate at 131 and 2085 ng/ml, respectively. The reverse transcriptase, protease and integrase genes of his plasma viruses were sequenced as previously described [3]. The K65R, N69S and Q151M mutations were found on the reverse transcriptase gene, and the I15V, V33I, I46V, I54M, V71I, I82F, I84V and L90M mutations on the protease gene. These mutations are associated with resistance to NRTIs and protease inhibitors in HIV-1. No mutations associated with RAL resistance in HIV-1 were found in the integrase gene. He was prescribed a combination of DRV/r and RAL. Although the CD4 cell count rose to 244 and 204 cells/μl at month 1 (M1) and at month 4 (M4), respectively, his plasma viral load never became undetectable (18 000 copies/ml at M1 and 71 360 copies/ml at M4). The reverse transcriptase and protease genes were unchanged at M4 relative to M0. Integrase sequencing at M1 and M4, respectively, revealed the Q148K and Q148R mutations, which are associated with INI resistance in HIV-1-infected patients [5,6]. Phenotypic susceptibility to RAL and elvitegravir (EVG) was determined with the ANRS peripheral blood mononuclear cell (PBMC) assay at baseline and at M4 [3]. The median IC50 values of the baseline isolate were 2.65 nmol/l for RAL and 0.8 nmol/l for EVG. Compared with baseline values, the IC50 values of RAL and EVG rose by 55-fold and 99-fold, respectively, at M4. This is the first time that a mutation has been found to emerge during treatment at codon 148 of the HIV-2 integrase gene. Such mutations have previously been linked to virologic failure of RAL-containing HAART regimens in HIV-1-infected patients [7] and with cross-resistance to EVG [8]. Recently, Garrett et al.[9] reported the emergence of the N155H mutation in the HIV-2 integrase gene at M4 of a failing RAL-containing regimen. This is the other HIV-1 mutation known to be associated with RAL failure. Together, these two observations suggest that HIV-1 and HIV-2 share similar INI resistance pathways. They also show that INI resistance can occur rapidly in HIV-2 patients failing raltegravir, as in HIV-1 [7,10]. Acknowledgements Bénédicte Roquebert and Florence Damond oversaw the technical support of HIV-2 viral load analysis. Juliette Leleu and Gilles Collin performed the HIV-2 viral load and the PBMC phenotypic susceptibility tests to raltegravir and elvitegravir. Laurent Blum was in charge of the patient in the Clinical Infectious Department and contributed to the interpretation of findings and comments and co-wrote the first draft. Gilles Peytavin performed raltegravir plasma measurements. Sophie Matheron, Genevieve Chêne and Françoise Brun-Vézinet contributed to the interpretation of findings and comments. Florence Damond and Diane Descamps contributed to the interpretation of findings and comments and wrote the manuscript. There are no conflicts of interest.
Год издания: 2008
Авторы: Bénédicte Roquebert, L. Blum, Gilles Collin, Florence Damond, Gilles Peytavin, Juliette Leleu, Sophie Matheron, Geneviéve Chêne, Françoise Brun‐Vézinet, Diane Descamps
Издательство: Lippincott Williams & Wilkins
Источник: AIDS
Ключевые слова: HIV/AIDS drug development and treatment, HIV Research and Treatment, HIV/AIDS Research and Interventions
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Открытый доступ: bronze
Том: 22
Выпуск: 15
Страницы: 2045–2046