24 research outputs found
Resistance mutations outside the integrase coding region have an effect on human immunodeficiency virus replicative fitness but do not affect its susceptibility to integrase strand transfer inhibitors.
Most studies describing phenotypic resistance to integrase strand transfer inhibitors have analyzed viruses carrying only patient-derived HIV-1 integrase genes (INT-recombinant viruses). However, to date, many of the patients on INSTI-based treatment regimes, such as raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) are infected with multidrug-resistant HIV-1 strains. Here we analyzed the effect of drug resistance mutations in Gag (p2/NCp7/p1/p6), protease (PR), reverse transcriptase (RT), and integrase (IN) coding regions on susceptibility to INSTIs and viral replicative fitness using a novel HIV-1 phenotyping assay. Initial characterization based on site-directed mutant INSTI-resistant viruses confirmed the effect of a series of INSTI mutations on reduced susceptibility to EVG and RAL and viral replicative fitness (0.6% to 99% relative to the HIV-1NL4-3 control). Two sets of recombinant viruses containing a 3,428-bp gag-p2/NCp7/p1/p6/pol-PR/RT/IN (p2-INT) or a 1,088 bp integrase (INT) patient-derived fragment were constructed from plasma samples obtained from 27 virologic failure patients participating in a 48-week dose-ranging study of elvitegravir, GS-US-183-0105. A strong correlation was observed when susceptibility to EVG and RAL was assayed using p2-INT- vs. INT-recombinant viruses (Pearson coefficient correlation 0.869 and 0.918, P<0.0001 for EVG and RAL, respectively), demonstrating that mutations in the protease and RT have limited effect on susceptibility to these INSTIs. On the other hand, the replicative fitness of viruses harboring drug resistance mutations in PR, RT, and IN was generally impaired compared to viruses carrying only INSTI-resistance mutations. Thus, in the absence of drug pressure, drug resistance mutations in the PR and RT contribute to decrease the replicative fitness of the virus already impaired by mutations in the integrase. The use of recombinant viruses containing most or all HIV-1 regions targeted by antiretroviral drugs might be essential to understand the collective effect of epistatic interactions in multidrug-resistant viruses
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Tenofovir Disoproxil Fumarate, Emtricitabine, and Efavirenz Versus Fixed-Dose Zidovudine/Lamivudine and Efavirenz in Antiretroviral-Naive Patients: Virologic, Immunologic, and Morphologic Changes-A 96-Week Analysis
BACKGROUND:In antiretroviral-naive patients, tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and efavirenz (EFV) demonstrated superior outcomes compared with fixed-dose zidovudine (ZDV)/lamivudine (3TC) and EFV through 48 weeks. Results through a 96-week extension phase are presented.
METHODS:In this randomized, open-label, noninferiority trial, 517 antiretroviral-naive HIV-infected patients received TDF, FTC, and EFV (TDF + FTC + EFV) or ZDV/3TC and EFV (ZDV/3TC + EFV). The primary endpoint was the proportion of patients with an HIV RNA level <400 copies/mL in patients without baseline nonnucleoside resistance.
RESULTS:Through week 96, significantly more patients receiving TDF + FTC + EFV achieved and maintained an HIV RNA level <400 copies/mL (75% receiving TDF + FTC + EFV vs. 62% receiving ZDV/3TC + EFV; P = 0.004). There was a trend toward greater virologic suppression to <50 copies/mL in the TDF + FTC + EFV group (67% vs. 61%; P = 0.16). The TDF + FTC + EFV group demonstrated a significantly greater increase in CD4 count (270 vs. 237 cells/mm; P = 0.036). No patient developed the K65R mutation. Limb fat at week 96 was significantly greater in the TDF + FTC + EFV group versus the ZDV/3TC + EFV group (7.7 vs. 5.5 kg; P < 0.001).
CONCLUSION:Over 96 weeks, the combination of TDF, FTC, and EFV was superior to fixed-dose ZDV/3TC + EFV for achieving and maintaining an HIV RNA level <400 copies/mL and an increase in CD4 cells
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Tenofovir Disoproxil Fumarate, Emtricitabine, and Efavirenz Compared With Zidovudine/Lamivudine and Efavirenz in Treatment-Naive Patients : 144-Week Analysis
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Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV
Durable suppression of replication of the human immunodeficiency virus (HIV) depends on the use of potent, well-tolerated antiretroviral regimens to which patients can easily adhere.
We conducted an open-label, noninferiority study involving 517 patients with HIV infection who had not previously received antiretroviral therapy and who were randomly assigned to receive either a regimen of tenofovir disoproxil fumarate (DF), emtricitabine, and efavirenz once daily (tenofovir-emtricitabine group) or a regimen of fixed-dose zidovudine and lamivudine twice daily plus efavirenz once daily (zidovudine-lamivudine group). The primary end point was the proportion of patients without baseline resistance to efavirenz in whom the HIV RNA level was less than 400 copies per milliliter at week 48 of the study.
Through week 48, significantly more patients in the tenofovir-emtricitabine group reached and maintained the primary end point of less than 400 copies of HIV RNA per milliliter than did those in the zidovudine-lamivudine group (84 percent vs. 73 percent, respectively; 95 percent confidence interval for the difference, 4 to 19 percent; P=0.002). This difference excludes the inferiority of the tenofovir DF, emtricitabine, and efavirenz regimen, indicating a significantly greater response with this regimen. Significant differences were also seen in the proportion of patients with HIV RNA levels of less than 50 copies per milliliter (80 percent in the tenofovir-emtricitabine group vs. 70 percent in the zidovudine-lamivudine group; 95 percent confidence interval for the difference, 2 to 17 percent; P=0.02) and in increases in CD4 cell counts (190 vs. 158 cells per cubic millimeter, respectively; 95 percent confidence interval for the difference, 9 to 55; P=0.002). More patients in the zidovudine-lamivudine group than in the tenofovir-emtricitabine group had adverse events resulting in discontinuation of the study drugs (9 percent vs. 4 percent, respectively; P=0.02). In none of the patients did the K65R mutation develop.
Through week 48, the combination of tenofovir DF and emtricitabine plus efavirenz fulfilled the criteria for noninferiority to a fixed dose of zidovudine and lamivudine plus efavirenz and proved superior in terms of virologic suppression, CD4 response, and adverse events resulting in discontinuation of the study drugs. (ClinicalTrials.gov number, NCT00112047.
Clinical and virological parameters of 27 HIV-infected individuals participating in the GS-US-183-0105 study of elvitegravir.
a<p>Major mutations associated with resistance to INSTI as described <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065631#pone.0065631-McColl1" target="_blank">[4]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065631#pone.0065631-Blanco1" target="_blank">[11]</a>.</p>b<p>Plasma HIV viral load (log10 copies/ml).</p><p>INSTI-R, mutations associated with resistance to INSTI; PI (1), number of primary mutations associated with resistance to PI; PI (2), number of secondary mutations associated with resistance to PI; #TAMs, number of thymidine analogue-associated mutations; #NAMs, number of nucleoside analogue-associated mutations; NNRTI (1), number of primary mutations associated with resistance to NNRTI. EC<sub>50</sub> FC, based on VIRALARTS™HIV three independent EC<sub>50</sub> replicates for each drug were used to calculate the fold changes (FC) of the query viruses relative to the HIV-1<sub>NL4-3</sub> control and the mean EC<sub>50</sub> FC is indicated. MAX, complete virus inhibition was not achieved using the maximum drug concentration, i.e., virus was completely resistant to the respective antiretroviral drug.</p
Replicative fitness of p2-INT-recombinant viruses carrying mutations associated with resistance to INSTIs in the absence and presence of EVG or RAL.
<p>(A) Fifteen p2-INT-recombinant viruses (i.e., 14 INSTI-resistance and the HIV-1<sub>NL4-3</sub> wild-type virus) were evaluated for their ability to replicate in MT-4 cells in the absence of drug pressure. Virus replication was quantified by measuring reverse transcriptase (RT) activity in the cell-free supernatant. Error bars indicate the range of values obtained from three independent experiments. (B) Viral replication slopes were calculated using the slopes between RLU values at days 0 & 3, 0 & 4, 0 & 5, and 0 & 6. All four slope values for each virus were used to calculate the mean, standard deviation, and 10<sup>th</sup> & 90<sup>th</sup> percentiles. Differences in the mean values were calculated using a One Way Analysis of Variance test and the significance difference from HIV-1<sub>NL4-3</sub> calculated using the Bonferroni’s Multiple Comparison Test. The replication kinetics of viruses marked with an asterisk (*) were significantly different from the HIV-1<sub>NL4-3</sub> control (p<0.05, 95% CI). Each p2-INT-recombinant virus was competed against the HIV-1<sub>NL4-3</sub> control in the absence (C) or presence (D) of EVG (0.01 nM) or RAL (1 nM) and their replicative fitness calculated and expressed as a percentage of the replicative fitness of the reference virus (HIV-1<sub>NL4-3</sub>) as described <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065631#pone.0065631-Weber4" target="_blank">[55]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065631#pone.0065631-Weber5" target="_blank">[69]</a>. The Ratio of Replicative Fitness was calculated dividing the % Replicative Fitness in the presence of drug (EVG or RAL) by the % Replicative Fitness in the absence of drug pressure; e.g., 105.5% ÷ 0.6% = 176x, for Q148R. Values represent results obtained from single growth competition experiments.</p