Efficacy of once daily darunavir/ritonavir 800/100 mg in PI/r-experienced HIV-1 infected patients with suppressed HIV-1 replication: the RADAR study

International audiencen.

Impact of lopinavir/ritonavir use on antiretroviral resistance in recent clinical practice

Objectives This observational study was requested by French health authorities to determine the impact of lopinavir/ritonavir (Kaletra®) on antiretroviral resistance in clinical practice. Virological failures of lopinavir/ritonavir and their effects on the resistance to protease inhibitors and reverse transcriptase inhibitors were evaluated in protease inhibitor-experienced patients.Patients and methods Virological failure was defined as an HIV-1 plasma viral load >50 copies/mL after at least 3 months of lopinavir/ritonavir-containing antiretroviral therapy. For all patients, a resistance genotypic test was available at failure and before lopinavir/ritonavir treatment. Data from 72 patients with inclusion criteria were studied. Results The mean viral load at baseline was 4 log10 copies/mL (1.6–6.5). Mutations in the protease gene significantly selected between baseline and failure were L10V, K20R, L33F, M36I, I47V, I54V, A71V and I85V (P < 0.05). Patients who had more than seven protease inhibitor mutations at baseline showed a significantly increased risk of occurrence of protease inhibitor mutations. The proportion of viruses susceptible to atazanavir, fosamprenavir and darunavir decreased significantly between baseline and failure (P < 0.05). Among patients with a virus susceptible to atazanavir at day 0, 26% (n = 14) exhibited a virus resistant or possibly resistant at the time of failure. This proportion was 32% (n = 16) for fosamprenavir and 16% (n = 7) for darunavir. Conclusions A darunavir-based regimen appears to be a sequential option in the case of lopinavir/ritonavir failure. To compare and determine the best treatment sequencing, similar studies should be performed for darunavir/ritonavir and atazanavir/ritonavir

HIV Reservoirs and Immune Surveillance Evasion Cause the Failure of Structured Treatment Interruptions: A Computational Study

Continuous antiretroviral therapy is currently the most effective way to treat HIV infection. Unstructured interruptions are quite common due to side effects and toxicity, among others, and cannot be prevented. Several attempts to structure these interruptions failed due to an increased morbidity compared to continuous treatment. The cause of this failure is poorly understood and often attributed to drug resistance. Here we show that structured treatment interruptions would fail regardless of the emergence of drug resistance. Our computational model of the HIV infection dynamics in lymphoid tissue inside lymph nodes, demonstrates that HIV reservoirs and evasion from immune surveillance themselves are sufficient to cause the failure of structured interruptions. We validate our model with data from a clinical trial and show that it is possible to optimize the schedule of interruptions to perform as well as the continuous treatment in the absence of drug resistance. Our methodology enables studying the problem of treatment optimization without having impact on human beings. We anticipate that it is feasible to steer new clinical trials using computational models

Antiretroviral-naive and -treated HIV-1 patients can harbour more resistant viruses in CSF than in plasma

Objectives The neurological disorders in HIV-1-infected patients remain prevalent. The HIV-1 resistance in plasma and CSF was compared in patients with neurological disorders in a multicentre study. Methods Blood and CSF samples were collected at time of neurological disorders for 244 patients. The viral loads were >50 copies/mL in both compartments and bulk genotypic tests were realized. Results On 244 patients, 89 and 155 were antiretroviral (ARV) naive and ARV treated, respectively. In ARV-naive patients, detection of mutations in CSF and not in plasma were reported for the reverse transcriptase (RT) gene in 2/89 patients (2.2%) and for the protease gene in 1/89 patients (1.1%). In ARV-treated patients, 19/152 (12.5%) patients had HIV-1 mutations only in the CSF for the RT gene and 30/151 (19.8%) for the protease gene. Two mutations appeared statistically more prevalent in the CSF than in plasma: M41L (P = 0.0455) and T215Y (P = 0.0455). Conclusions In most cases, resistance mutations were present and similar in both studied compartments. However, in 3.4% of ARV-naive and 8.8% of ARV-treated patients, the virus was more resistant in CSF than in plasma. These results support the need for genotypic resistance testing when lumbar puncture is performe

Usefulness of an HIV DNA resistance genotypic test in patients who are candidates for a switch to the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination

International audienceObjectives In the context of a rilpivirine/emtricitabine/tenofovir disoproxil fumarate switch in HIV-1-infected patients with at least 1 year of virological success, we determined whether proviral DNA is an alternative to plasma HIV RNA for resistance genotyping.Methods Resistance-associated mutations (RAMs) in DNA after at least 1 year of virological success [viral load (VL) 50 copies/mL). Kappa's coefficient was used to measure agreement between the DNA and RNA genotypes.Results In patients without VF (n = 130) and with VF (n = 114), RNA and DNA showed resistance to at least one drug of the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination in 8% and 9% and in 60% and 45%, respectively. For rilpivirine RAMs, correlation between RNA and DNA was higher in patients without VF than in patients with VF (kappa = 0.60 versus 0.19, P = 0.026). Overall, the prevalence of RAMs was lower in DNA than in RNA.Conclusions Incomplete information provided by the DNA genotypic test is more notable in patients with VF, suggesting that all resistance mutations associated with prior VF have not been archived in the proviral DNA or decreased to a level below the threshold of detection. In the case where no historical plasma genotypic test is available, DNA testing might be useful to rule out switching to rilpivirine/emtricitabine/tenofovir disoproxil fumarate

Clin Infect Dis

Background: We pooled the results of three randomized trials that compared the efficacy of PI/r monotherapy and standard triple therapy as maintenance therapy and evaluated: 1) the distribution of ultrasensitive viral load (USVL) at week 96 (W96), 2) factors associated with virological success (VL50 copies/mL and was analyzed in intention-to-treat. USVL was measured with commercial standard Roche assay. A logistic model was used to investigate which variables were predictive of VF. The Fisher exact test was used to investigate differences in USVL at W96. Results: Among 609 patients, 73% were male with a median age of 44.4 years (IQR 39.8-52.1), the treatment duration was four years, (2.4-7.6), baseline CD4/CD8 ratio 0.8 (0.6-1.10), baseline CD4 cell count 564/mm3 (422-707), and 59% presented a baseline USVL<1 copy/mL. At W96, the proportion of USVL<1 copy/mL was significantly lower for PI/r monotherapy than triple therapy (65% versus 74%; p=0.04). Overall, baseline USVL<1 copy/mL, triple therapy, and being female were associated with an USVL<1 copy/mL at W96 (p<0.0001, p=0.049 and p=0.006). For PI/r monotherapy, receiving DRV/r rather than LPV/r was associated with an USVL<1 copy/mL at W96 (p=0.03). Factors associated with virological success at W96 were higher baseline CD4 cell count (p=0.034) and baseline USVL<1 copy/mL (p=0.0005). Conclusion: Although PI/r monotherapy is not widely recommended, this strategy is still sometimes used and USVL determination for virologically-controlled patients may help to select the best candidates for PI/r monotherapy

Switching to darunavir/ritonavir 800/100 mg once-daily containing regimen maintains virological control in fully suppressed pre-treated patients infected with HIV-1

Item does not contain fulltextThe objective of this study was to evaluate the switch to once-daily darunavir/ritonavir 800/100 mg in treatment-experienced patients with suppressed HIV-1 replication on a twice-daily ritonavir-boosted protease-inhibitor (bid PI/r) containing regimen, that is in a setting where genotypic resistance test cannot be performed. In this open label, non-comparative, multicenter study, patients on a bid PI/r-containing triple combination, with suppressed viral replication, were switched to once-daily darunavir/r 800/100 mg containing triple combination. The primary endpoint was the proportion of patients with plasma HIV-RNA < 50 copies/ml 24 weeks after the switch. Intensive darunavir pharmacokinetic evaluation was performed at Week 4 (W4) in 11 patients. Eighty-five patients were enrolled. All had HIV-RNA < 50 copies/ml at screening with a pre-exposure to a median of 2 PI/r (1-5). By intent-to-treat analysis (missing = failure), 78/85 patients (92%, 95% CI [83;96]) maintained an HIV-RNA < 50 copies/ml at W24. Seven patients experienced protocol-defined treatment failure between baseline and W24: Two had confirmed low-level viral rebound, one discontinued study treatment for adverse event, three withdrew their consent, and one was lost to follow-up. By on-treatment analysis, 78/80 patients (97%, 95% CI [91;99]) maintained an HIV-RNA < 50 copies/ml at W24. Results were similar at Week 48. The median area under the darunavir plasma concentration-time curve measured in 11 patients was 61,380 ng hr/ml; darunavir median trough concentration 1,340 ng/ml and darunavir half-life was 12.2 hr. Tolerability of once-daily darunavir/r 800/100 mg was excellent. Optimally suppressed, treatment-experienced patients can switch safely from a twice-daily PI/r regimen to a once-daily darunavir/r 800/100 mg containing regimen

New resistance mutations to nucleoside reverse transcriptase inhibitors at codon 184 of HIV-1 reverse transcriptase (M184L and M184T)

Mutations at HIV-1 reverse transcriptase (RT) codon 184 such as M184V confer resistance to two nucleos(t)ide RT inhibitors (NRTI), lamivudine (3TC) and emtricitabine (FTC). The prevalence of mutations at HIV-1 RT codon 184 was evaluated using three independent RT sequence databases from treatment-experienced (TE) and treatment-naive (TN) individuals. Data were collected retrospectively from three centers: one in Italy and two in France between 1997 and 2016. In order to highlight the role of these mutations in conferring drug resistance, structural and thermodynamic analyses were conducted by means of computational approaches. Among 32,440 RT sequences isolated from TE and 12,365 isolated from TN patients, the prevalence of HIV-1 RT codon 184 substitutions in each group was 31.21% and 0.72%, respectively. The mutations M184L and M184T have been observed only in TE patients. In all cases but four, M184L and M184T mutations were present during NRTI treatment. Molecular recognition studies on M184L and M184T structures showed both FTC and 3TC thermodynamic profiles unfavorable in comparison with the wild-type sequence, corroborated by molecular dynamic simulations (MDS). In this study, we highlighted two new resistance mutations in vivo for NRTI resistance. The low frequency of this pathway can be related to high impairment of replicative capacity mediated by these mutations