Dolutegravir Monotherapy Versus Dolutegravir/Abacavir/Lamivudine for Virologically Suppressed People Living With Chronic Human Immunodeficiency Virus Infection: The Randomized Noninferiority MONotherapy of TiviCAY Trial

2019 ◽  
Vol 69 (9) ◽  
pp. 1498-1505 ◽  
Author(s):  
Laurent Hocqueloux ◽  
François Raffi ◽  
Thierry Prazuck ◽  
Louis Bernard ◽  
Simon Sunder ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Triple Therapy ◽  
Virologic Failure ◽  
Resistance Mutation ◽  
Data Safety Monitoring Board ◽  
Rank Test ◽  
Strand Transfer ◽  
Open Label ◽  
Hiv Rna ◽  
Immunodeficiency Virus

Abstract Background We investigated whether dolutegravir (DTG) monotherapy could be used to maintain virological suppression in people living with human immunodeficiency virus (HIV) on a successful dolutegravir-based triple therapy. Methods MONCAY (MONotherapy of TiviCAY) was a 48-week, multicentric, randomized, open-label, 12% noninferiority margin trial. Patients with CD4 nadir >100/μL, plasma HIV-1 RNA <50 copies/mL for ≥12 months, and stable regimen with DTG/abacavir (ABC)/lamivudine (3TC) were 1:1 randomized to continue their regimen or to DTG monotherapy. The primary endpoint was the proportion of patients with HIV RNA <50 copies/mL at week 24 in intention-to-treat snapshot analysis. Virologic failure (VF) was defined as 2 consecutive HIV RNA >50 copies/mL within 2 weeks apart. Results Seventy-eight patients were assigned to DTG monotherapy and 80 to continue DTG/ABC/3TC. By week 24, 2 patients in the DTG group experienced VF without resistance to the integrase strand transfer inhibitor (INSTI) class; 1 patient discontinued DTG/ABC/3TC due to an adverse event. The success rate at week 24 was 73/78 (93.6%) in the DTG arm and 77/80 (96.3%) in the DTG/ABC/3TC arm (difference, 2.7%; 95% confidence interval [CI], –5.0 to 10.8). During subsequent follow-up, 5 additional VFs occurred in the DTG arm (2 of which harbored emerging resistance mutation to INSTI). The cumulative incidence of VF at week 48 was 9.7% (95% CI, 2.8 to 16.6) in the DTG arm compared with 0% in the DTG/ABC/3TC arm (P = .005 by the log-rank test). The Data Safety Monitoring Board recommended to reintensify the DTG arm with standardized triple therapy. Conclusions Because the risk of VF with resistance increases over time, we recommend avoiding DTG monotherapy as a maintenance strategy among people living with chronic HIV infection. Clinical Trials Registration NCT02596334 and EudraCT 2015-002853-36.

scholarly journals Genotypic Changes in Human Immunodeficiency Virus Type 1 Associated with Loss of Suppression of Plasma Viral RNA Levels in Subjects Treated with Ritonavir (Norvir) Monotherapy

1998 ◽  
Vol 72 (6) ◽  
pp. 5154-5164 ◽  
Author(s):  
P. Scott Eastman ◽  
John Mittler ◽  
Reed Kelso ◽  
Chris Gee ◽  
Eric Boyer ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Resistance Mutation ◽  
Virologic Response ◽  
Hiv Rna ◽  
Immunodeficiency Virus ◽  
Plasma Rna ◽  
Doubling Times ◽  
Rna Levels

ABSTRACT Ten subjects received 600 to 1,200 mg of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor ritonavir per day. Following 2 weeks of therapy, plasma HIV RNA levels decreased by a mean of 1.57 (range, 0.89 to 1.96) log units. With continued therapy, HIV RNA levels began to rise in eight subjects. The initial rise in plasma RNA levels was temporally associated with the development and quantitative increase in the V82 resistance mutation. Doubling times of the V82A mutant virus were estimated to be 2.4 to 4.8 days. An L63P/A mutation was commonly present at baseline even in subjects with a durable virologic response. The concomitant acquisition of an L63P/A mutation with the V82A/F mutation at the time when plasma RNA levels rebounded suggests a role for the L63P/A mutation in improving the fitness of the V82A/F mutation. Subsequent additional genotypic changes at codons 54 and 84 were often associated with further increases in plasma RNA levels. Ongoing viral replication in the presence of drugs resulted in the appearance of additional genotypic changes, including the L90M saquinavir resistance mutation, and decreased phenotypic susceptibility. The relative fitness of the protease V82A ritonavir resistance mutation and reverse transcriptase T215Y/F zidovudine resistance mutation following drug withdrawal were estimated to be 96 to 98% that of the wild type. Durability of the virologic response was associated with plasma RNA levels at the nadir. A virologic response beyond 60 days was not observed unless plasma HIV RNA levels were suppressed below 2,000 copies/ml, consistent with estimates from V82A doubling times for selection of a single resistance mutation to dominate the replicating population.

Genital Human Immunodeficiency Virus–1 RNA and DNA Shedding in Virologically Suppressed Individuals Switching From Triple- to Dual- or Monotherapy: Pooled Results From 2 Randomized, Controlled Trials

2019 ◽  
Vol 70 (9) ◽  
pp. 1973-1979
Author(s):  
Laurent Hocqueloux ◽  
Camélia Gubavu ◽  
Thierry Prazuck ◽  
Barbara De Dieuleveult ◽  
Jérôme Guinard ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Clinical Trials ◽  
Triple Therapy ◽  
Dual Therapy ◽  
Pooled Analysis ◽  
Similar Proportion ◽  
Hiv Rna ◽  
Immunodeficiency Virus ◽  
Lower Drug ◽  
Genital Shedding

Abstract Background Increasingly, people living with human immunodeficiency virus (HIV) benefit from lower drug regimens (LDRs). Exploring viral genital shedding during LDRs is crucial to ensure their safety. Methods We pooled genital sub-studies from 2 clinical trials in this area. Patients were randomized 1:1 to continue abacavir/lamivudine/dolutegravir or switch to dolutegravir (MONCAY trial), or to continue tenofovir/emtricitabine + a third agent or switch to tenofovir/emtricitabine (TRULIGHT trial). Participants whose plasma HIV-RNA remained &lt;50 copies/mL had sperm or cervicovaginal lavage collected between Weeks 24 and 48. HIV-RNA and HIV-DNA were amplified by ultrasensitive polymerase chain reaction. The main objective was to measure the proportion of participants who had no detectable HIV in genital fluids, both according to each strategy and then in an aggregated analysis (LDR versus triple therapies). Results There were 64 participants (35 males, 29 females) included: 16 received dual therapies and 16 received triple therapies in TRULIGHT; and 16 received monotherapies and 16 received triple therapies in MONCAY. In TRULIGHT, 13/15 (87%) of evaluable participants on dual therapy had no detectable HIV in their genital fluid, versus 14/15 (93%) under triple therapy (P = 1.0). In MONCAY, these figures were 12/15 (80%) on monotherapy versus 13/16 (81%) on triple therapy (P = 1.0). In the pooled analysis, a similar proportion of participants in the LDR and triple therapy groups had no detectable HIV: 25/30 (83%) and 27/31 (87%), respectively (P = .73). Conclusions There was no evidence of increased HIV-RNA and/or -DNA shedding in the genital fluids of people who maintained undetectable plasma HIV-RNA during LDRs. Clinical Trials Registration NCT02302547 and NCT02596334

scholarly journals Safety and Efficacy of Enfuvirtide in Combination with Darunavir-Ritonavir and an Optimized Background Regimen in Treatment-Experienced Human Immunodeficiency Virus-Infected Patients: the Below the Level of Quantification Study

2008 ◽  
Vol 52 (12) ◽  
pp. 4315-4319 ◽  
Author(s):  
Edwin DeJesus ◽  
Michael S. Gottlieb ◽  
Joseph C. Gathe ◽  
Michael L. Greenberg ◽  
Carol Jean Guittari ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
Baseline Viral Load ◽  
Open Label ◽  
Coreceptor Tropism ◽  
Viral Loads ◽  
Immunological Responses ◽  
Hiv Rna ◽  
Background Regimen ◽  
Immunodeficiency Virus

ABSTRACT Enfuvirtide is the first fusion and entry inhibitor approved for use for the treatment of human immunodeficiency virus (HIV) type 1 infection and as such represents a novel class of agents. For the population of patients experienced with three antiretroviral classes, enfuvirtide provides an additional option for treatment. This prospective, open-label, 24-week, single-arm trial assessed the efficacy and safety of enfuvirtide (90 mg injected subcutaneously twice daily) in combination with darunavir-ritonavir (600/100 mg administered orally twice daily) in triple-antiretroviral-class-experienced adults failing their current regimen. The primary efficacy endpoint was the proportion of participants with plasma HIV RNA loads of <50 copies/ml. Other virological and immunological measures were also evaluated, as were the effects of the baseline viral coreceptor tropism and darunavir phenotype sensitivity scores on the outcomes. At week 24, 60.3%, 72.5%, and 84.0% of 131 participants achieved viral loads of <50 copies/ml and <400 copies/ml and a change from the baseline load of ≥1 log10 copies/ml, respectively. A baseline viral load of ≤5 log10 copies/ml was a significant predictor of achieving a viral load of <50 copies/ml at 24 weeks; however, neither background genotype sensitivity nor darunavir phenotype sensitivity was a significant predictor of the achievement of viral loads of <50 copies/ml. Although these findings are limited by the relatively small numbers of participants with darunavir susceptibility changes of ≥10-fold, they suggest that combining enfuvirtide and darunavir-ritonavir with an optimized background regimen in triple-class experienced participants naïve to these agents can result in positive virological and immunological responses regardless of most baseline parameters.

scholarly journals Human Immunodeficiency Virus-1 Sequence Changes and Drug Resistance Mutation Among Virologic Failures of Lopinavir/Ritonavir Monotherapy: AIDS Clinical Trials Group Protocol A5230

2016 ◽  
Vol 3 (3) ◽  
Author(s):  
Saran Vardhanabhuti ◽  
David Katzenstein ◽  
John Bartlett ◽  
Nagalingeswaran Kumarasamy ◽  
Carole L. Wallis
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Genetic Distance ◽  
Hamming Distance ◽  
Virologic Failure ◽  
Resistance Mutation ◽  
Drug Resistance Mutation ◽  
Immunodeficiency Virus ◽  
Human Immunodeficiency Virus 1

Abstract Background.  The mechanism of virologic failure (VF) of lopinavir/ritonavir (LPV/r) monotherapy is not well understood. We assessed sequence changes in human immunodeficiency virus-1 reverse-transcriptase (RT) and protease (PR) regions. Methods.  Human immunodeficiency virus-1 pol sequences from 34 participants who failed second-line LPV/r monotherapy were obtained at study entry (SE) and VF. Sequence changes were evaluated using phylogenetic analysis and hamming distance. Results.  Human immunodeficiency virus-1 sequence change was higher over drug resistance mutation (DRM) sites (median genetic distance, 2.2%; Q1 to Q3, 2.1%–2.5%) from SE to VF compared with non-DRM sites (median genetic distance, 1.3%; Q1 to Q3, 1.0%–1.4%; P &lt; .0001). Evolution over DRM sites was mainly driven by changes in the RT (median genetic distance, 2.7%; Q1 to Q3, 2.2%–3.2%) compared with PR (median genetic distance, 1.1%; Q1 to Q3, 0.0%–1.1%; P &lt; .0001). Most RT DRMs present at SE were lost at VF. At VF, 19 (56%) and 26 (76%) were susceptible to efavirenz/nevirapine and etravirine (ETV)/rilpivirine (RPV), respectively, compared with 1 (3%) and 12 (35%) at SE. Participants who retained nonnucleoside reverse-transcriptase inhibitor (NNRTI) DRMs and those without evolution of LPV/r DRMs had significantly shorter time to VF. Conclusions.  The selection of LPV/r DRMs in participants with longer time to VF suggests better adherence and more selective pressure. Fading NNRTI mutations and an increase in genotypic susceptibility to ETV and RPV could allow for the reuse of NNRTI. Further studies are warranted to understand mechanisms of PR failure.

scholarly journals Minimal Pharmacokinetic Interaction between the Human Immunodeficiency Virus Nonnucleoside Reverse Transcriptase Inhibitor Etravirine and the Integrase Inhibitor Raltegravir in Healthy Subjects

2008 ◽  
Vol 52 (12) ◽  
pp. 4228-4232 ◽  
Author(s):  
Matt S. Anderson ◽  
Thomas N. Kakuda ◽  
William Hanley ◽  
Jutta Miller ◽  
James T. Kost ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Geometric Mean ◽  
Transcriptase Inhibitor ◽  
Strand Transfer ◽  
Open Label ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Adverse Experiences ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor

ABSTRACT Etravirine, a next-generation nonnucleoside reverse transcriptase inhibitor, and raltegravir, an integrase strand transfer inhibitor, have separately demonstrated potent activity in treatment-experienced, human immunodeficiency virus (HIV)-infected patients. An open-label, sequential, three-period study with healthy, HIV-seronegative subjects was conducted to assess the two-way interaction between etravirine and raltegravir for potential coadministration to HIV-infected patients. In period 1, 19 subjects were administered 400 mg raltegravir every 12 h (q12 h) for 4 days, followed by a 4-day washout; in period 2, subjects were administered 200 mg etravirine q12 h for 8 days; and in period 3, subjects were coadministered 400 mg raltegravir and 200 mg etravirine q12 h for 4 days. There was no washout between periods 2 and 3. Doses were administered with a moderate-fat meal. Etravirine had only modest effects on the pharmacokinetics of raltegravir, while raltegravir had no clinically meaningful effect on the pharmacokinetics of etravirine. For raltegravir coadministered with etravirine relative to raltegravir alone, the geometric mean ratio (GMR) and 90% confidence interval (CI) were 0.90 and 0.68 to 1.18, respectively, for the area under the concentration curve from 0 to 12 h (AUC0-12), 0.89 and 0.68 to 1.15, respectively, for the maximum concentration of drug in serum (C max), and 0.66 and 0.34 to 1.26, respectively, for the trough drug concentration (C 12); the GMR (90% CI) for etravirine coadministered with raltegravir relative to etravirine alone was 1.10 (1.03, 1.16) for AUC0-12, 1.04 (0.97, 1.12) for C max, and 1.17 (1.10, 1.26) for C 12. All drug-related adverse clinical experiences were mild and generally transient in nature. No grade 3 or 4 adverse experiences or discontinuations due to adverse experiences occurred. Coadministration of etravirine and raltegravir was generally well tolerated; the data suggest that no dose adjustment for either drug is necessary.

scholarly journals Determinants of Viral Resuppression or Persistent Virologic Failure After Initial Failure With Second-Line Antiretroviral Treatment Among Asian Children and Adolescents With HIV

2019 ◽  
Vol 9 (2) ◽  
pp. 253-256
Author(s):  
Sirinya Teeraananchai ◽  
Stephen J Kerr ◽  
Monica Gandhi ◽  
Viet Chau Do ◽  
Lam Van Nguyen ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Antiretroviral Treatment ◽  
Virologic Failure ◽  
Second Line ◽  
Hiv Rna ◽  
Immunodeficiency Virus ◽  
Asian Children ◽  
Perinatally Acquired

Abstract Of 56 children with perinatally acquired human immunodeficiency virus (HIV) who had been prescribed second-line protease inhibitor–based antiretroviral therapy and had ≥1 previous episode of viral failure (HIV RNA, ≥1000 copies/mL), 46% had ≥1, 34% had ≥2, and 23% had ≥3 consecutive episodes of viral failure during the 2 years of follow-up. Two of these children experienced a major protease inhibitor mutation.

scholarly journals The Successful Application of a National Peer Advisory Committee for Physicians Who Provide Salvage Regimens to Heavily Antiretroviral-Experienced Patients in Mexican Human Immunodeficiency Virus Clinics

2014 ◽  
Vol 1 (2) ◽  
Author(s):  
Juan J. Calva ◽  
Juan Sierra-Madero ◽  
Luis E. Soto-Ramírez ◽  
Pedro Aguilar-Salinas
Keyword(s):  
Human Immunodeficiency Virus ◽  
Advisory Committee ◽  
Virologic Failure ◽  
Clinical Skills ◽  
Virologic Response ◽  
Routine Practice ◽  
Salvage Regimen ◽  
Hiv Rna ◽  
Immunodeficiency Virus

Background.  Designing optimal antiretroviral (ARV) salvage regimens for multiclass drug-resistant, human immunodeficiency virus (HIV)-infected patients demands specific clinical skills. Our aim was to assess the virologic and immunologic effects of the treatment recommendations drafted by a peer advisory board to physicians caring for heavily ARV-experienced patients. Methods.  We conducted a nationwide, HIV clinic-based, cohort study in Mexico. Adults infected with HIV were assessed for a median of 33 months (interquartile range [IQR] = 22–43 months). These patients had experienced the virologic failure of at least 2 prior ARV regimens and had detectable viremia while currently being treated; their physicians had received therapeutic advice, by a panel of experts, regarding the ARV salvage regimen. The primary endpoint was the incidence of loss of virologic response (plasma HIV-RNA levels of &lt;200 copies per mL, followed by levels above this threshold) during the follow-up assessment using an observed-failure competing risks regression analysis. Results.  A total of 611 patients were observed (median ARV therapy exposure = 10.5 years; median prior regimens = 4). The probabilities of virologic failure were 11.9%, 14.4%, 16.9%, and 19.4% at the 12-, 24-, 36-, and 48-month follow-up assessments, respectively. Of the 531 patients who achieved a confirmed plasma HIV-RNA level below 200 copies per mL, the median increase in blood CD4+ T-cell count was 162 cells per mL (IQR = 45–304 cells per mL). Conclusions.  In routine practice, a high rate of patients with extensive ARV experience, who received an optimized salvage regimen recommended by a peer advisory committee, achieved a long-term sustained virologic response and immune reconstitution.

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