Nucleoside reverse transcriptase inhibitor-sparing regimen (nonnucleoside reverse transcriptase inhibitor + protease inhibitor) was more likely associated with resistance comparing to nonnucleoside reverse transcriptase inhibitor or protease inhibitor + nucleoside reverse transcriptase inhibitor in the randomized ANRS 121 trial.

The use of nonnucleoside reverse transcriptase inhibitor (NNRTI) + protease inhibitor regimen for the treatment of antiretroviral-naive patients was less successful than classical nucleoside reverse transcriptase inhibitor (NRTI) based regimen and associated with more resistance for protease inhibitors and NNRTIs. The selection for NNRTI resistance was particularly observed in patients with high viral load (>100 000 copies/ml) and low efavirenz trough levels (<1100 ng/ml). Contrary to the results observed in trials evaluating mono or dual protease inhibitors strategies, gag gene mutations were not involved in the low efficacy of this strategy.

[CCR5 antagonists: a new class of antiretrovirals].

A decade after identification of the chemokine receptor CCR5 as a coreceptor for human immunodeficiency virus (HIV), the first CCR5 antagonist has recently been approved by the European Medicines Evaluation Agency (EMEA) for treatment of HIV infected patients. Maraviroc (Celsentri is a small molecule that specifically inhibits CCR5 and thereby blocks HIV entry into its target cells. Viral tropism testing is mandatory before prescribing maraviroc, due to its unique mode of action limited to CCR5-tropic viruses.

Presence of HIV-1 R5 viruses in cerebrospinal fluid even in patients harboring R5X4/X4 viruses in plasma.

Background: HIV-1 viruses have the ability to use CCR5 or CXCR4 coreceptors either solely (R5 or X4) or in combination (R5X4). The CCR5 antagonists block HIV entry into the cell and are specifically active against HIV-1 R5 strains. The objectives of this study were to investigate the predicted tropism of viruses present in paired cerebrospinal fluid (CSF) and plasma in a group of 22 HIV-1-infected patients with neurological disorders and to search for eventual discordance of predicted virus tropism between both compartments.

Quasispecies variant dynamics during emergence of resistance to raltegravir in HIV-1-infected patients.

Objectives: Raltegravir is the first approved inhibitor of HIV-1 integrase (IN). In most patients, raltegravir failure is associated with mutations in the IN gene, through two different genetic pathways: 155 (N155H) or 148 (Q148K/R/H). The objective of this study was to characterize the dynamics of HIV-1 quasispecies variant populations in patients who failed to respond to raltegravir treatment.

Mutations associated with virological response to darunavir/ritonavir in HIV-1-infected protease inhibitor-experienced patients.

Objective: The aim of the study was to identify a pattern of protease gene mutations associated with the virological response to darunavir/ritonavir-based regimens.

Patients And Methods: We analysed 153 treatment-experienced patients receiving a darunavir/ritonavir salvage regimen as a sole protease inhibitor (PI). Virological response was defined as an HIV-1 RNA load of <200 copies/mL at month 3.

The G140S mutation in HIV integrases from raltegravir-resistant patients rescues catalytic defect due to the resistance Q148H mutation.

Raltegravir (MK-0518) is the first integrase (IN) inhibitor to be approved by the US FDA and is currently used in clinical treatment of viruses resistant to other antiretroviral compounds. Virological failure of Raltegravir treatment is associated with mutations in the IN gene following two main distinct genetic pathways involving either the N155 or Q148 residue. Importantly, in most cases, an additional mutation at the position G140 is associated with the Q148 pathway.

Antiretroviral combinations implicated in emergence of the L74I and L74V resistance mutations in HIV-1-infected patients.

Background: Very little is known about the alternative L74I mutation. This lack of knowledge has led to contradictory and confusing attitudes to L74I; although this mutation is not listed by the International AIDS Society - USA, it is increasingly included in several resistance algorithms.

Objective: To compare and clarify the role of each antiretroviral compound and the resistance background in the emergence of the L74I and L74V mutations.

Size distribution dependence of prion aggregates infectivity.

We consider a model for the polymerization (fragmentation) process involved in infectious prion self-replication and study both its dynamics and non-zero steady state. We address several issues. Firstly, we extend a previous study of the nucleated polymerization model [M.

Genotypic resistance analysis of the virological response to fosamprenavir-ritonavir in protease inhibitor-experienced patients in CONTEXT and TRIAD clinical trials.

The aim of this study was to identify human immunodeficiency virus (HIV) protease mutations associated with virological response (VR) to fosamprenavir-ritonavir (FPV/r) in 113 protease inhibitor (PI)-experienced patients randomized in both CONTEXT and TRIAD clinical trials and receiving the same dose (700/100 mg twice daily) of FPV/r. The impact of each protease mutation on the VR to FPV/r, defined as the decrease in HIV RNA at week 12, was investigated with nonparametric analyses. A step-by-step procedure was done using a Jonckheere-Terpstra (JT) test that retains the group of mutations most strongly associated with the VR.

Primary genotypic resistance of HIV-1 to CCR5 antagonists in CCR5 antagonist treatment-naive patients.

Resistance to CCR5 antagonists can be driven by mutations in gp120. Sequences from 323 anti-CCR5 naive patients were analyzed for the presence of previously described in-vivo or in-vitro resistance mutations to CCR5 antagonists located in the V3 loop of gp120. The V3 loop region was rather polymorphic, and 7.

Impact of gag mutations on selection of darunavir resistance mutations in HIV-1 protease.

Objectives: To search for genetic factors in the protease and gag regions (NC-p1/TFP-p6/p6pol) involved in selection of darunavir resistance mutations.

Patients And Methods: We analysed 48 protease inhibitor (PI)-experienced HIV-infected patients experiencing darunavir treatment failure. Viral genotyping at baseline and months 3 and 6 was used to assess the selection of mutations in the protease and gag regions conferring resistance to PIs.

Initial therapy with nucleoside reverse transcriptase inhibitor-containing regimens is more effective than with regimens that spare them with no difference in short-term fat distribution: Hippocampe-ANRS 121 Trial.

Objectives: The aim of this study was to evaluate the impact on body fat of nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimens compared with NRTI-containing therapy in HIV-1-infected antiretroviral (ARV)-naive patients.

Methods: A randomized, multicentre, open-label trial in ARV-naive patients. Subjects were randomized (2:1:1) to receive: (i) an NRTI-sparing regimen consisting of a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus a boosted protease inhibitor (PI/r); or (ii) an NRTI-containing regimen of (a) a PI/r plus two NRTIs or (b) an NNRTI plus two NRTIs.

Greater viral rebound and reduced time to resume antiretroviral therapy after therapeutic immunization with the ALVAC-HIV vaccine (vCP1452).

Objective: Evaluate immunogenicity and clinical efficacy of two immunization strategies with the ALVAC-HIV-recombinant canarypox vaccine (vCP1452) in treated HIV-infected patients.

Design: Randomized, double-blind, placebo-controlled, phase II study of vCP1452 immunization in chronically HIV-infected patients on therapy with CD4 T-cell count more than 350 cells/microl, CD4 nadir less than 400 cells/microl and pHIV-RNA less than 400 copies/ml. Patients were equally randomized to four injections at weeks 0, 4, 8, 20; three injections at weeks 4, 8, 20; and placebo.

HIV-1-infected patients from the French National Observatory experiencing virological failure while receiving enfuvirtide.

Objectives: We studied gp41 mutations associated with failing enfuvirtide salvage therapy.

Methods: This multicentre study involved patients with HIV-1 plasma viral load (pVL) > 5000 copies/mL after at least 3 months of uninterrupted enfuvirtide therapy and with plasma samples available at inclusion (T0), at initial enfuvirtide failure (T1) and at last follow-up visit during continued failing enfuvirtide therapy (T2). The HR-1 and HR-2 domains of the gp41 gene were sequenced at T0, T1 and T2.

Structural effects of amino acid variations between B and CRF02-AG HIV-1 integrases.

HIV-1 integrase is one of the three essential enzyme required for viral replication and has a great potential as a novel target for anti-HIV drugs. The sequence variability of the entire integrase (IN) was examined in HIV-1 subtype B and CRF02-AG antiretroviral naïve infected patients for the presence of naturally occurring polymorphisms IN gene sequences and protein structures from both subtypes were compared. The phylogenetic analysis showed a total concordance between the 3 pol gene sequences for patients identified as subtype B whereas 3% of patients identified as CRF02-AG showed a mixture of subtypes.

Antiretroviral therapy with a twice-daily regimen containing 400 milligrams of indinavir and 100 milligrams of ritonavir in human immunodeficiency virus type 1-infected women during pregnancy.

We evaluated the safety and efficacy of a twice daily regimen containing 400 mg of indinavir and 100 mg of ritonavir in 32 human immunodeficiency virus (HIV)-infected women during pregnancy. The median indinavir trough concentration was 208 ng/ml during the third trimester. At delivery, 26 of 28 women on indinavir-ritonavir had HIV RNA levels of <200 copies/ml.

Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro.

Raltegravir (MK-0518) is a potent inhibitor of human immunodeficiency virus (HIV) integrase and is clinically effective against viruses resistant to other classes of antiretroviral agents. However, it can select mutations in the HIV integrase gene. Nine heavily pretreated patients who received salvage therapy including raltegravir and who subsequently developed virological failure under raltegravir therapy were studied.

HIV drug resistance after the use of generic fixed-dose combination stavudine/lamivudine/nevirapine as standard first-line regimen.

Early failures to stavudine/lamivudine/nevirapine used as a generic fixed-dose combination in Mali showed resistance mutations in 50% of cases (mostly M184V and Y181C). No thymidine analogue mutations were seen, suggesting that most nucleoside reverse transcriptase inhibitors could be used in a second-line regimen. This highlights the importance of the accessibility of HIV-RNA assays for monitoring treated patients in resource-poor countries to detect early virological failure in order to preserve future therapeutic options.

HIV-1 X4/R5 co-receptor in viral reservoir during suppressive HAART.

As immune recovery during HAART is mainly caused by the expansion of X4-naive cells, we studied the evolution of HIV tropism in the reservoir of 34 patients receiving 48 weeks of HAART. No change in virus tropism was observed over time, but patients with X4 viruses had higher HIV-1 proviral DNA levels than patients with R5 viruses. This suggests that CCR5 antagonist activity should not be compromised in patients harbouring R5 viruses before starting HAART.

Factors associated with the selection of mutations conferring resistance to protease inhibitors (PIs) in PI-experienced patients displaying treatment failure on darunavir.

The objective of this study was to characterize the mutations selected by darunavir (DRV) use in protease inhibitor (PI)-experienced patients and the associated factors. We analyzed treatment failure in 54 PI-experienced human immunodeficiency virus (HIV)-infected patients on a DRV- and ritonavir-containing regimen. Viral genotyping was carried out at the baseline, at between 1 and 3 months of treatment, and at between 3 and 6 months of treatment to search for the selection of mutations conferring resistance to PIs.