Raltegravir Versus Efavirenz Regimens in Treatment-Naive HIV-1–Infected Patients: 96-Week Efficacy, Durability, Subgroup, Safety, and Metabolic Analyses

Lennox, Jeffrey L.; DeJesus, Edwin; Berger, Daniel; Lazzarin, Adriano; Pollard, Richard B.; Madruga, José Valdez; Zhao, Jing; Wan, Hong; Gilbert, Christopher L.; Teppler, Hedy; Rodgers, Anthony; Barnard, Richard; Miller, Michael D.; DiNubile, Mark J.; Nguyen, Bach Yen; Leavitt, Randi Y.; Sklar, Peter

doi:10.1097/qai.0b013e3181da1287

Cited by 218 publications

(181 citation statements)

References 19 publications

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“…28,84 Recently, the integrase inhibitor raltegravir has been shown to induce a greater increase in CD4 count in treatment-naive patients at week 48 but not at week 96 compared with efavirenz. 85 The same result was reported at week 48 for the CCR5 antagonist maraviroc, which persisted at week 96. 86 CD4 ؉ T-cell nadir.…”

Section: Other Causessupporting

confidence: 73%

Immune reconstitution under antiretroviral therapy: the new challenge in HIV-1 infection

Corbeau

Reynes

2011

Blood

182

165

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Although highly active antiretroviral therapy has enabled constant progress in reducing HIV-1 replication, in some patients who are "aviremic" during treatment, the problem of insufficient immune restoration remains, and this exposes them to the risk of immune deficiencyassociated pathologies. Various mechanisms may combine and account for this impaired immunologic response to treatment. A first possible mechanism is immune activation, which may be because of residual HIV production, microbial translocation, co-infections, immunosenescence, or lymphopenia per se. A second mechanism is ongoing HIV replication. Finally, deficient thymus output, sex, and genetic polymorphism influencing apoptosis may impair immune reconstitution. In this review we will discuss the tools at our disposal to identify the various mechanisms at work in a given patient and the specific therapeutic strategies we could propose based on this etiologic diagnosis. (Blood. 2011;117(21): 5582-5590)

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Section: Other Causessupporting

confidence: 73%

Immune reconstitution under antiretroviral therapy: the new challenge in HIV-1 infection

Corbeau

Reynes

2011

Blood

182

165

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“…Even though 3= processing may be a suitable therapeutic target, the integrase inhibitors developed so far are integrase strand transfer inhibitors (INSTIs) that preferentially inhibit strand transfer while only modestly affecting 3= processing (18,24,26). Raltegravir (RAL) was the first INSTI to be approved for therapy in 2007 (64) and is safe and efficient in both treatment-naïve and treatment-experienced subjects (11,17,23,35,49,62,63). Elvitegravir (EVG) is another INSTI currently in advanced clinical trials (10,12,77).…”

mentioning

confidence: 99%

Characterization of the R263K Mutation in HIV-1 Integrase That Confers Low-Level Resistance to the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir

Quashie

Mésplède

Han

et al. 2012

J Virol

214

306

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Integrase (IN) strand transfer inhibitors (INSTIs) have been developed to inhibit the ability of HIV-1 integrase to irreversibly link the reverse-transcribed viral DNA to the host genome. INSTIs have proven their high efficiency in inhibiting viral replication in vitro and in patients. However, first-generation INSTIs have only a modest genetic barrier to resistance, allowing the virus to escape these powerful drugs through several resistance pathways. Second-generation INSTIs, such as dolutegravir (DTG, S/GSK1349572), have been reported to have a higher resistance barrier, and no novel drug resistance mutation has yet been described for this drug. Therefore, we performed in vitro selection experiments with DTG using viruses of subtypes B, C, and A/G and showed that the most common mutation to emerge was R263K. Further analysis by site-directed mutagenesis showed that R263K does confer low-level resistance to DTG and decreased integration in cell culture without altering reverse transcription. Biochemical cell-free assays performed with purified IN enzyme containing R263K confirmed the absence of major resistance against DTG and showed a slight decrease in 3= processing and strand transfer activities compared to the wild type. Structural modeling suggested and in vitro IN-DNA binding assays show that the R263K mutation affects IN-DNA interactions.T he high mutation rate of HIV-1 reverse transcriptase (RT) allows the virus to escape pressure through adaptive mutations that include drug resistance mutations that limit the effectiveness of antiretroviral drugs (5,31,66,69,70). The use of multiple drugs in combination can hamper this process by restraining viral replication, limiting the emergence of resistant strains. The addition of integrase inhibitors to the arsenal of drugs against HIV-1 is important since these inhibitors are active against viruses resistant to other drug classes (16,49,63).The HIV-1 integrase enzyme catalyzes two reactions. The first is 3= processing, which consists of cleavage of a dinucleotide at both 3= ends of the reverse-transcribed linear viral DNA and results in the exposure of reactive hydroxyl groups. The second step termed "strand transfer" is carried out through a nucleophilic attack by exposed 3= hydroxyl groups on host genomic DNA (26, 47). Even though 3= processing may be a suitable therapeutic target, the integrase inhibitors developed so far are integrase strand transfer inhibitors (INSTIs) that preferentially inhibit strand transfer while only modestly affecting 3= processing (18,24,26). Raltegravir (RAL) was the first INSTI to be approved for therapy in 2007 (64) and is safe and efficient in both treatment-naïve and treatment-experienced subjects (11,17,23,35,49,62,63). Elvitegravir (EVG) is another INSTI currently in advanced clinical trials (10,12,77).Although first-generation INSTIs strongly inhibit HIV-1 replication, they possess only a modest genetic barrier to resistance. Three main resistance pathways have been identified for RAL, involving initial mutations of the N1...

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“…RAL specifically inhibits the strand transfer activity of IN in a manner similar to that of several predecessor compounds (14,30). The approval of RAL by the Food and Drug Administration (FDA) for the treatment of antiretroviral (ARV) drug-experienced and ARV drug-naïve HIV-1-infected patients has added a potent new drug to the armament of ARV drugs used to control HIV-1 replication (4,18).…”

mentioning

confidence: 99%

Substitutions at Amino Acid Positions 143, 148, and 155 of HIV-1 Integrase Define Distinct Genetic Barriers to Raltegravir Resistance In Vivo

Fransen¹,

Gupta²,

Frantzell³

et al. 2012

J Virol

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Mutations at amino acids 143, 148, and 155 in HIV-1 integrase (IN) define primary resistance pathways in subjects failing raltegravir (RAL)-containing treatments. Although each pathway appears to be genetically distinct, shifts in the predominant resistant virus population have been reported under continued drug pressure. To better understand this dynamic, we characterized the RAL susceptibility of 200 resistant viruses, and we performed sequential clonal analysis for selected cases. Patient viruses containing Y143R, Q148R, or Q148H mutations consistently exhibited larger reductions in RAL susceptibility than patient viruses containing N155H mutations. Sequential analyses of virus populations from three subjects revealed temporal shifts in subpopulations representing N155H, Y143R, or Q148H escape pathways. Evaluation of molecular clones isolated from different time points demonstrated that Y143R and Q148H variants exhibited larger reductions in RAL susceptibility and higher IN-mediated replication capacity (RC) than N155H variants within the same subject. Furthermore, shifts from the N155H pathway to either the Q148R or H pathway or the Y143R pathway were dependent on the amino acid substitution at position 148 and the secondary mutations in Y143R-or Q148R-or H-containing variants and correlated with reductions in RAL susceptibility and restorations in RC. Our observations in patient viruses were confirmed by analyzing site-directed mutations. In summary, viruses that acquire mutations defining the 143 or 148 escape pathways are less susceptible to RAL and exhibit greater RC than viruses containing 155 pathway mutations. These selective pressures result in the displacement of N155H variants by 143 or 148 variants under continued drug exposure.

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Raltegravir Versus Efavirenz Regimens in Treatment-Naive HIV-1–Infected Patients: 96-Week Efficacy, Durability, Subgroup, Safety, and Metabolic Analyses

Cited by 218 publications

References 19 publications

Immune reconstitution under antiretroviral therapy: the new challenge in HIV-1 infection

Immune reconstitution under antiretroviral therapy: the new challenge in HIV-1 infection

Characterization of the R263K Mutation in HIV-1 Integrase That Confers Low-Level Resistance to the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir

Substitutions at Amino Acid Positions 143, 148, and 155 of HIV-1 Integrase Define Distinct Genetic Barriers to Raltegravir Resistance In Vivo

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