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 <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

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.

Combination Therapy With Stavudine and Didanosine in Children With Advanced Human Immunodeficiency Virus Infection: Pharmacokinetic Properties, Safety, and Immunologic and Virologic Effects

PEDIATRICS ◽  
1996 ◽  
Vol 97 (6) ◽  
pp. 886-890
Author(s):  
Mark W. Kline ◽  
Courtney V. Fletcher ◽  
Marianne E. Federici ◽  
Alice T. Harris ◽  
Kim D. Evans ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Combination Therapy ◽  
Lymphocyte Count ◽  
Hiv Disease ◽  
Hiv Rna ◽  
Immunodeficiency Virus ◽  
Pharmacokinetic Properties ◽  
Cd4 Lymphocyte Count ◽  
Cd4 Lymphocyte ◽  
Advanced Hiv Disease

Objectives. To obtain preliminary information on the pharmacokinetic properties, tolerance, safety, and antiviral activity of combination therapy with stavudine and didanosine in children with advanced human immunodeficiency virus (HIV) infection. Methods. Eight children (median age, 6.6 years; range, 2.8 to 12 years) with advanced HIV disease (median CD4+ lymphocyte count at baseline, 42 cells/µL; range, 8 to 553 cells/µL) were treated with stavudine (2 mg/kg per day in two divided doses) and didanosine (180 mg/m2 per day in two divided doses) for 24 weeks. Seven children had histories of prior zidovudine therapy. All children had received stavudine alone for 19 to 33 months before the addition of didanosine to the treatment regimen. Children were assessed clinically and with laboratory studies at baseline, weekly through week 4 of combination therapy, and every 4 weeks thereafter. Results. Analysis of stavudine and didanosine plasma half-life values, clearances, and area under the plasma concentration-versus-time curves revealed no obvious clinical pharmacokinetic interaction between the drugs through study week 12. Combination therapy was well tolerated, and there were no drug-associated clinical or laboratory adverse events. Signs and symptoms of peripheral neuropathy were not observed. All three children with baseline CD4+ lymphocyte counts greater than 50 cells/µL had greater than 20% increases in their counts within the first 12 weeks of therapy; CD4+ lymphocyte count increases were not observed in the other children. Plasma HIV RNA concentrations showed median declines of 0.88 log10 (range, -3.41 log10 to 0.31 log10) and 0.30 log10 (range, -0.63 log10 to 0.89 log10) at study weeks 12 and 24, respectively. Conclusions. Combination therapy with stavudine and didanosine was well tolerated and safe in this small group of children with advanced HIV disease. Plasma HIV RNA concentration declines suggest a favorable effect of therapy on virus load. These findings should be confirmed, and the regimen's clinical efficacy should be examined, in controlled studies of HIV-infected children with less-advanced disease.

scholarly journals Impact of Next-generation Sequencing Defined Human Immunodeficiency Virus Pretreatment Drug Resistance on Virological Outcomes in the ANRS 12249 Treatment-as-Prevention Trial

2018 ◽  
Vol 69 (2) ◽  
pp. 207-214 ◽  
Author(s):  
Anne Derache ◽  
Collins C Iwuji ◽  
Kathy Baisley ◽  
Siva Danaviah ◽  
Anne-Geneviève Marcelin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Clinical Trials ◽  
Transcriptase Inhibitor ◽  
Hiv Positive ◽  
Treatment As Prevention ◽  
Kwazulu Natal ◽  
Immunodeficiency Virus ◽  
Virological Outcomes ◽  
Reverse Transcriptase Inhibitor ◽  
Generation Sequencing

Abstract Background Previous studies in human immunodeficiency virus (HIV)-positive individuals on thymidine analogue backbone antiretroviral therapy (ART) with either nevirapine or efavirenz have suggested poorer virological outcomes in the presence of pretreatment drug resistance (PDR). We assessed the impact of PDR on virological suppression (VS; <50 copies/mL) in individuals prescribed primarily tenofovir/emtricitabine/efavirenz in rural KwaZulu-Natal within a treatment-as-prevention trial. Methods Among 1557 HIV-positive individuals who reported no prior ART at study entry and provided plasma samples, 1328 individuals with entry viral load (VL) >1000 copies/mL had next-generation sequencing (NGS) of the HIV pol gene with MiSeq technology. Results were obtained for 1148 individuals, and the presence of PDR was assessed at 5% and 20% detection thresholds. Virological outcome was assessed using Cox regression in 837 of 920 ART initiators with at least 1 follow-up VL after ART initiation. Results PDR prevalence was 9.5% (109/1148) and 12.8% (147/1148) at 20% and 5% thresholds, respectively. After a median of 1.36 years (interquartile range, 0.91–2.13), mostly on fixed-dose combination tenofovir/emtricitabine/efavirenz, presence of both nonnucleoside reverse transcriptase inhibitor (NNRTI)/nucleoside reverse transcriptase inhibitor PDR vs no PDR was associated with longer time to VS (adjusted hazard ratio [aHR], 0.32; 95% confidence interval [CI], 0.12–0.86), while there was no difference between those with only NNRTI PDR vs no PDR (aHR, 1.05; 95% CI, 0.82–1.34) at the 5% threshold. Similar differences were observed for mutations detected at the 20% threshold, although without statistical significance. Conclusions NGS uncovered a high prevalence of PDR among participants enrolled in trial clinics in rural KwaZulu-Natal. Dual-class PDR to a mainly tenofovir/emtricitabine/efavirenz regimen was associated with poorer VS. However, there was no impact of NNRTI PDR alone. Clinical Trials Tegistration NCT01509508; South African National Clinical Trials Register: DOH-27-0512-3974.

scholarly journals A human immunodeficiency virus 1 (HIV-1) clade A vaccine in clinical trials: stimulation of HIV-specific T-cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans

2004 ◽  
Vol 85 (4) ◽  
pp. 911-919 ◽  
Author(s):  
Matilu Mwau ◽  
Inese Cebere ◽  
Julian Sutton ◽  
Priscilla Chikoti ◽  
Nicola Winstone ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Clinical Trials ◽  
Vaccinia Virus ◽  
Mononuclear Cells ◽  
Vaccine Development ◽  
Cell Mediated Immunity ◽  
Phase I Clinical Trials ◽  
Modified Vaccinia Virus Ankara ◽  
Immunodeficiency Virus ◽  
Hiv 1

The immunogenicities of candidate DNA- and modified vaccinia virus Ankara (MVA)-vectored human immunodeficiency virus (HIV) vaccines were evaluated on their own and in a prime–boost regimen in phase I clinical trials in healthy uninfected individuals in the United Kingdom. Given the current lack of approaches capable of inducing broad HIV-neutralizing antibodies, the pTHr.HIVA DNA and MVA.HIVA vaccines focus solely on the induction of cell-mediated immunity. The vaccines expressed a common immunogen, HIVA, which consists of consensus HIV-1 clade A Gag p24/p17 proteins fused to a string of clade A-derived epitopes recognized by cytotoxic T lymphocytes (CTLs). Volunteers' fresh peripheral blood mononuclear cells were tested for HIV-specific responses in a validated gamma interferon enzyme-linked immunospot (ELISPOT) assay using four overlapping peptide pools across the Gag domain and three pools of known CTL epitopes present in all of the HIVA protein. Both the DNA and the MVA vaccines alone and in a DNA prime–MVA boost combination were safe and induced HIV-specific responses in 14 out of 18, seven out of eight and eight out of nine volunteers, respectively. These results are very encouraging and justify further vaccine development.

scholarly journals Pharmacologic Characteristics of Indinavir, Didanosine, and Stavudine in Human Immunodeficiency Virus-Infected Children Receiving Combination Therapy

2000 ◽  
Vol 44 (4) ◽  
pp. 1029-1034 ◽  
Author(s):  
Courtney V. Fletcher ◽  
Richard C. Brundage ◽  
Rory P. Remmel ◽  
Linda M. Page ◽  
Dennis Weller ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Trough Concentration ◽  
Area Under The Curve ◽  
Hiv Protease ◽  
Pharmacokinetic Parameters ◽  
Hiv Protease Inhibitors ◽  
Hiv Rna ◽  
Immunodeficiency Virus ◽  
Dosing Regimens ◽  
Outcomes For Children

ABSTRACT The use of human immunodeficiency virus (HIV) protease inhibitors in children has lagged behind that in adults because of the lack of suitable pediatric formulations and information on safe and effective dosing regimens. This study was designed to obtain pharmacokinetic information on indinavir, administered to HIV-infected children also receiving therapy with two nucleoside agents, and to explore relationships between pharmacokinetic parameters and anti-HIV effect. Indinavir was initiated at a dose of 500 mg/m2 every 8 h. Plasma indinavir concentrations were measured every 4 weeks; the dose or dosing interval was adjusted to maintain trough concentrations of ≥0.1 mg/liter. All children were evaluated clinically at baseline and every 4 weeks. Plasma HIV RNA was quantitated at baseline and at weeks 4, 12, and 24. Eighteen children participated in this study. The average daily dose of indinavir was 2,043 mg/m2; nine children received indinavir at 6-h intervals. Pharmacokinetic characteristics of indinavir (mean ± standard deviation) were the following: oral clearance, 1.4 ± 0.5 liters/h/kg; half-life, 1.1 ± 0.43 h; and trough concentration, 0.29 ± 0.32 mg/liter. In nine children that completed 24 weeks of therapy, the baseline-to-week-24 change in HIV RNA level was related to indinavir trough concentration and didanosine area under the curve. This study illustrates the ability to obtain pharmacokinetic information from children during routine clinic visits and to use this information to provide a safeguard against underdosing. The incorporation of pharmacologic knowledge with virologic, immunologic, and behavioral considerations should result in improved clinical outcomes for children infected with HIV.

Sign in / Sign up

Export Citation Format

Share Document