Genotypic Resistance Analysis of the Virological Response to Fosamprenavir-Ritonavir in Protease Inhibitor-Experienced Patients in CONTEXT and TRIAD Clinical Trials

Marcelin, Anne–Geneviève; Flandre, Philippe; Molina, Jean‐Michel; Katlama, Christine; Yéni, Patrick; Raffi, François; Antoun, Zeina; Ait‐Khaled, Mounir; Cálvez, Vincent

doi:10.1128/aac.00514-08

Cited by 8 publications

(5 citation statements)

References 19 publications

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“…This mutation is associated with low‐level resistance to most PIs except darunavir. Several studies have associated this mutation with the loss of virological response to nelfinavir [27], saquinavir [28], fosamprenavir [29], lopinavir [30], indinavir [31], atazanavir [32] and tipranavir [33]. Moreover, the L10I/V mutation was observed at a higher frequency in Mali (18.81%) than in Burkina Faso (11.7%) [34], which borders Mali.…”

Section: Discussionmentioning

confidence: 99%

High level of primary drug resistance in Mali

et al. 2010

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Background As access to antiretroviral drugs increases in developing countries, it will become increasingly important to monitor the emergence of resistance and to define the molecular pathways involved to identify optimal therapeutic regimens. Methods We performed genotypic resistance testing on plasma obtained from 101 HIV-infected treatment-naı¨venaı¨ve individuals from Mali. Genotyping was carried out using the Virco protocols and HXB2 was used as the reference strain. Results CRF02_AG was the most common subtype, present in 71.3% of our patient population. Other subtypes included B, C, G, CRF06_CPX, CRF09_CPX, CRF01_AE, A2/CRF16_A2D, A1 and CRF13_CPX. A total of 9.9% [95% confidence interval (CI) 6.9-12.9%] of patients had at least one resistance mutation. The prevalences of mutations conferring resistance to nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were 5% (95% CI 0.7-9.2%), 6% (95% CI 1.3-10.6%) and 0%, respectively. The most frequent mutations were T215A/Y for NRTIs and K103N/T for NNRTIs. One patient harboured three NRTI resistance mutations and one NNRTI mutation. This is the first reported case of multi-drug-resistant viral transmission in Mali. Polymorphisms at protease codons 10I/V and 33F potentially associated with resistance were observed in 18.8% and 1% of patients, respectively. Several polymorphisms in the C-terminal domain of reverse transcriptase were observed: A371V (in 63.4% of patients), G335D (76.2%), E399D (10.9%) and G333E (1%). Conclusion Primary resistance was seen in 9.9% of subjects, which is higher than previously reported in Mali. Taking into consideration other polymorphisms in protease such as L10I/V and 33F, primary resistance could reach 28.7% (95% CI 19.9-37.5%). Our study reflects the need to monitor the evolution of resistance on a regular basis and trends of transmitted resistance.

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Section: Discussionmentioning

confidence: 99%

High level of primary drug resistance in Mali

et al. 2010

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“…The VR was defined here as a decrease of at least 1.5 log 10 copies/ml and/or HIV-1 RNA at Ͻ50 copies/ml at month 2, which is a criterion currently used in such studies (7,(14)(15)(16). Month 2 has been chosen as an endpoint because the impact of mutations on the response needs to be measured early after initiation of a new agent to avoid possible interference of drug discontinuation, dropout, toxicity, and adherence to the regimen in the VR.…”

Section: Discussionmentioning

confidence: 99%

Factors Associated with Virological Response to Etravirine in Nonnucleoside Reverse Transcriptase Inhibitor-Experienced HIV-1-Infected Patients

Marcelin

Flandre

Descamps

et al. 2010

Antimicrob Agents Chemother

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To identify factors associated with virological response (VR) to an etravirine (ETR)-based regimen, 243 patients previously treated with nonnucleoside reverse transcriptase inhibitors (NNRTIs) were studied. The impact of baseline HIV-1 RNA, CD4 cell count, past NNRTIs used, 57 NNRTI resistance mutations, genotypic sensitivity score (GSS) for nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), and the number of new drugs used with ETR for the first time on the VR to an ETR regimen were investigated. Among the 243 patients, the median baseline HIV-1 RNA level was 4.4 log 10 copies/ml (interquartile range [IQR], 3.7 to 4.9) and the median CD4 count was 175 cells/mm 3 (IQR, 69 to 312). Patients had been previously exposed to a median of 6 NRTIs, 1, NNRTI, and 5 PIs. Overall, 82% of patients achieved a VR at month 2, as defined by a decrease of at least 1.5 log 10 copies/ml and/or HIV-1 RNA level of <50 copies/ml. No difference in VR was observed between patients receiving or not a boosted PI in combination with ETR. Factors independently associated with a better VR to ETR were the number of drugs (among enfuvirtide, darunavir, or raltegravir) used for the first time in combination with ETR and the presence of the K103N mutation at baseline. Mutations Y181V and E138A were independently associated with poor VR, whereas no effect of the Y181C on VR was observed. In conclusion, ETR was associated with high response rates in NNRTI-experienced patients in combination with other active drugs regardless of the therapeutic class used.

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“…Comparisons for ART and PI-experienced children are more complicated because of treatment history differences and variability in the types and number of resistance mutation that may have been selected and/or archived during earlier VF. Data from treatment-experienced adults from the CONTEXT and TRIAD studies demonstrated that mutations selected during prior PI treatment can impact response to subsequent FPV treatment [ 4 , 5 ]. In APV29005 and APV20002, almost half of the ART-experienced children who met VF criteria received regimens that contained ≤2 phenotypically active drugs at baseline.…”

Section: Discussionmentioning

confidence: 99%

“…Protease inhibitors are used in potent combination antiretroviral therapy (ART) to inhibit viral replication in HIV-infected patients. The efficacy, safety, and resistance profile of fosamprenavir (FPV), the phosphate ester pro-drug of the protease inhibitor (PI) amprenavir, has previously been evaluated in HIV-infected ART-naïve and ART-experienced adults [ 1 - 5 ].…”

Section: Introductionmentioning

confidence: 99%

Treatment-Emergent Mutations and Resistance in HIV-Infected Children Treated with Fosamprenavir-Containing Antiretroviral Regimens

et al. 2015

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Treatment-emergent mutations and drug resistance were analyzed in virus from HIV-infected children meeting virologic failure (VF) criteria over 48 weeks following treatment with unboosted fosamprenavir or fosamprenavir/ritonavir-containing regimens in studies APV20002 and APV29005. Both antiretroviral therapy (ART)-naïve and ART-experienced patients were enrolled. Patients met VF criteria by either failing to suppress HIV-RNA to <400 copies/mL through week 24 or after confirmed viral rebound (≥400 copies/mL) anytime through week 48. Viral isolates were analyzed for treatment-emergent mutations or reduced drug susceptibility. Through week 48, 25/109 (23%) of APV29005 and 9/54 (17%) APV20002 study patients met VF. VF was more common in ART-experienced patients (68% and 78%, respectively). Major or minor treatment-emergent mutations were detected at VF in virus from 3 patients receiving unboosted fosamprenavir-containing regimens and in virus from 10 patients receiving fosamprenavir/ritonavir-containing regimens across the two studies. Major protease inhibitor mutations and the reverse transcriptase mutation M184V were detected at VF in virus from 4 and 5 patients, respectively, across both studies. Reduced drug susceptibility to any drug emerged in virus from 9 patients at VF, although reduced fosamprenavir susceptibility emerged in virus from only 4 patients (2 ART-naïve and 2 ART-experienced). No cross-resistance to the protease inhibitor darunavir was observed.In conclusion, given the high proportion of ART-experienced children (71%) in these two studies, the overall incidence of children meeting VF criteria through 48 weeks was relatively low (21%) and development of fosamprenavir reduced drug susceptibility at VF was uncommon, further supporting the use of fosamprenavir-containing ART regimens in HIV-infected children.

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Genotypic Resistance Analysis of the Virological Response to Fosamprenavir-Ritonavir in Protease Inhibitor-Experienced Patients in CONTEXT and TRIAD Clinical Trials

Cited by 8 publications

References 19 publications

High level of primary drug resistance in Mali

High level of primary drug resistance in Mali

Factors Associated with Virological Response to Etravirine in Nonnucleoside Reverse Transcriptase Inhibitor-Experienced HIV-1-Infected Patients

Treatment-Emergent Mutations and Resistance in HIV-Infected Children Treated with Fosamprenavir-Containing Antiretroviral Regimens

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