scholarly journals Noninferiority of Simplified Dolutegravir Monotherapy Compared to Continued Combination Antiretroviral Therapy That Was Initiated During Primary Human Immunodeficiency Virus Infection: A Randomized, Controlled, Multisite, Open-label, Noninferiority Trial

2019 ◽  
Vol 69 (9) ◽  
pp. 1489-1497 ◽  
Author(s):  
Dominique L Braun ◽  
Teja Turk ◽  
Fabian Tschumi ◽  
Christina Grube ◽  
Benjamin Hampel ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Pilot Study ◽  
Latent Reservoir ◽  
Combination Antiretroviral Therapy ◽  
Open Label ◽  
Once Daily ◽  
Noninferiority Trial ◽  
Immunodeficiency Virus ◽  
Hiv 1

Abstract Background Patients who start combination antiretroviral therapy (cART) during primary human immunodeficiency virus type 1 (HIV-1) infection show a smaller HIV-1 latent reservoir, less immune activation, and less viral diversity compared to patients who start cART during chronic infection. We conducted a pilot study to determine whether these properties would allow sustained virological suppression after simplification of cART to dolutegravir monotherapy. Methods EARLY-SIMPLIFIED is a randomized, open-label, noninferiority trial. Patients who started cART <180 days after a documented primary HIV-1 infection and had an HIV-1 RNA <50 copies/mL plasma for at least 48 weeks were randomized (2:1) to monotherapy with dolutegravir 50 mg once daily or to continuation of cART. The primary efficacy endpoint was the proportion of patients with <50 HIV-1 RNA copies/mL on or before week 48; noninferiority margin 10%. Results Of the 101 patients randomized, 68 were assigned to simplification to dolutegravir monotherapy and 33 to continuation of cART. At week 48 in the per-protocol population, 67/67 (100%) had virological response in the dolutegravir monotherapy group vs 32/32 (100%) in the cART group (difference, 0.00%; 95% confidence interval, –100%, 4.76%). This showed noninferiority of the dolutegravir monotherapy at the prespecified level. Conclusion In this pilot study consisting of patients who initiated cART during primary HIV-1 infection and had <50 HIV-1 RNA copies/mL for at least 48 weeks, monotherapy with once-daily dolutegravir was noninferior to cART. Our results suggest that future simplification studies should use a stratification according to time of HIV infection and start of first cART. Clinical Trials Registration NCT02551523.

scholarly journals A Randomized Switch From Nevirapine-Based Antiretroviral Therapy to Single Tablet Rilpivirine/Emtricitabine/Tenofovir Disoproxil Fumarate in Virologically Suppressed Human Immunodeficiency Virus-1-Infected Rwandans

2016 ◽  
Vol 3 (3) ◽  
Author(s):  
Sean E. Collins ◽  
Philip M. Grant ◽  
Francois Uwinkindi ◽  
Annie Talbot ◽  
Eric Seruyange ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Tenofovir Disoproxil Fumarate ◽  
Sub Saharan Africa ◽  
Current Therapy ◽  
Virologic Suppression ◽  
Open Label ◽  
Immunodeficiency Virus ◽  
Sub Saharan ◽  
Hiv 1

Abstract Background.  Many human immunodeficiency virus (HIV)-infected patients remain on nevirapine-based antiretroviral therapy (ART) despite safety and efficacy concerns. Switching to a rilpivirine-based regimen is an alternative, but there is little experience with rilpivirine in sub-Saharan Africa where induction of rilpivirine metabolism by nevirapine, HIV subtype, and dietary differences could potentially impact efficacy. Methods.  We conducted an open-label noninferiority study of virologically suppressed (HIV-1 ribonucleic acid [RNA] < 50 copies/mL) HIV-1-infected Rwandan adults taking nevirapine plus 2 nucleos(t)ide reverse-transcriptase inhibitors. One hundred fifty participants were randomized 2:1 to switch to coformulated rilpivirine-emtricitabine-tenofovir disoproxil fumarate (referenced as the Switch Arm) or continue current therapy. The primary efficacy endpoint was HIV-1 RNA < 200 copies/mL at week 24 assessed by the US Food and Drug Administration Snapshot algorithm with a noninferiority margin of 12%. Results.  Between April and September 2014, 184 patients were screened, and 150 patients were enrolled; 99 patients switched to rilpivirine-emtricitabine-tenofovir, and 51 patients continued their nevirapine-based ART. The mean age was 42 years and 43% of participants were women. At week 24, virologic suppression (HIV-1 RNA level <200 copies/mL) was maintained in 93% and 92% in the Switch Arm versus the continuation arm, respectively. The Switch Arm was noninferior to continued nevirapine-based ART (efficacy difference 0.8%; 95% confidence interval, −7.5% to +12.0%). Both regimens were generally safe and well tolerated, although 2 deaths, neither attributed to study medications, occurred in participants in the Switch Arm. Conclusions.  A switch from nevirapine-based ART to rilpivirine-emtricitabine-tenofovir disoproxil fumarate had similar virologic efficacy to continued nevirapine-based ART after 24 weeks with few adverse events.

scholarly journals The dynamics of the HIV-1 latent reservoir – considering the heterogeneous subpopulations

2019 ◽  
Author(s):  
Ruian Ke ◽  
Kai Deng
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Latent Reservoir ◽  
Major Barrier ◽  
Clinical Observations ◽  
Wide Range ◽  
Immunodeficiency Virus ◽  
Latently Infected ◽  
Ctl Escape ◽  
Hiv 1

AbstractA major barrier to finding a cure for human immunodeficiency virus type-I (HIV-1) infection is the existence and persistence of the HIV-1 latent reservoir. Although the size of the reservoir is shown to be extremely stable under effective antiretroviral therapy, multiple lines of evidence suggest that the reservoir is composed of dynamic and heterogeneous subpopulations. Quantifying the dynamics of these subpopulations and the processes that maintain the latent reservoir is crucial to the development of effective strategies to eliminate this reservoir. Here, we constructed a mathematical model to consider four latently infected subpopulations, according to their ability to proliferate and the type of virus they are infected. Our model explains a wide range of clinical observations, including variable estimates of the reservoir half-life and dynamical turnover of cytotoxic T lymphocyte (CTL) escape viruses in the reservoir. It suggests that very early treatment leads to a reservoir that is small in size and is composed of less stable latently infected cells (compared to the reservoir in chronically infected individuals). The shorter half-lives estimated from individuals treated during acute infection is likely driven by cells that are less prone to proliferate; in contrast, the remarkably consistent estimate of the long half-lives in individuals who are treated during chronic infection are driven by fast proliferating cells that are likely to be infected by CTL escape mutants. Our model shed light on the dynamics of the reservoir in the absence and presence of antiretroviral therapy. More broadly, it can be used to estimate the turnover rates of subpopulations of the reservoir as well as to design and evaluate the impact of various therapeutic interventions to purge the HIV-1 reservoir.Author summaryHuman immunodeficiency virus (HIV) infects tens of millions of people globally and causes approximately a million death each year. Current treatment for HIV infection suppresses viral load but does not eradicates the virus. A major barrier to cure HIV infection is the existence and persistence of populations of cells that are latently infected by HIV, i.e. the HIV latent reservoir. Understanding and quantifying the kinetics of the reservoir is therefore critical for developing and evaluating effective therapies to purge the reservoir. Recent studies suggested that this reservoir is heterogenous in their population dynamics; yet most previous mathematical models consider this reservoir as a homogenous population. Here we developed a model explicitly tracking the heterogenous subpopulations of the reservoir. We show that this model explains a wide range of clinical observations, and then demonstrate its utility to make quantitative predictions about varies interventions that aim to restrict or reduce the size of the reservoir.

scholarly journals Quantitation of Human Immunodeficiency Virus Type 1 DNA Forms with the Second Template Switch in Peripheral Blood Cells Predicts Disease Progression Independently of Plasma RNA Load

2002 ◽  
Vol 76 (20) ◽  
pp. 10099-10108 ◽  
Author(s):  
Leondios G. Kostrikis ◽  
Giota Touloumi ◽  
Rose Karanicolas ◽  
Nikos Pantazis ◽  
Cleo Anastassopoulou ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Clinical Outcome ◽  
Peripheral Blood ◽  
Combination Antiretroviral Therapy ◽  
Immunodeficiency Virus ◽  
Template Switch ◽  
Hiv 1

ABSTRACT There are several forms of human immunodeficiency virus type 1 (HIV-1) DNA in peripheral blood T cells and lymph nodes in untreated HIV-1-infected individuals and in patients whose plasma HIV-1 RNA levels are suppressed by long-term combination antiretroviral therapy. However, it remains to be established whether the concentration of HIV-1 DNA in cells predicts the clinical outcome of HIV-1 infection. In this report, we measured the concentration of HIV-1 DNA forms which has undergone the second template switch (STS DNA) and 2-long-terminal-repeat DNA circles in peripheral blood mononuclear cell (PBMC) samples. To do this, we used molecular-beacon-based real-time PCR assays and studied 130 patients with hemophilia in the Multicenter Hemophilia Cohort Study. We assessed the influence of baseline HIV-1 STS DNA levels on the progression of HIV-1 disease in the absence of combination antiretroviral therapy by Kaplan-Meier and Cox regression analysis. Among the patients who progressed to AIDS, the median levels (interquartile ranges) of STS HIV-1 DNA in PBMC were significantly higher than those of patients who remained AIDS free during the 16 years of follow-up (1,017 [235 to 6,059] and 286 [31 to 732] copies per 106 PBMC, respectively; P < 0.0001). Rates of progression to death and development of AIDS varied significantly (log rank P < 0.001) by quartile distribution of HIV-1 STS DNA levels. After adjustment for age at seroconversion, baseline CD4+ T-cell counts, plasma viral load, and T-cell-receptor excision circles, the relative hazards (RH) of death and AIDS were significantly increased with higher HIV-1 STS DNA levels (adjusted RH, 1.84 [95% confidence interval {CI}, 1.30 to 2.59] and 2.62 [95% CI, 1.75 to 3.93] per 10-fold increase per 106 PBMC, respectively). HIV-1 STS DNA levels in each individual remained steady in longitudinal PBMC samples during 16 years of follow-up. Our findings show that the concentration of HIV-1 STS DNA in PBMC complements the HIV-1 RNA load in plasma in predicting the clinical outcome of HIV-1 disease. This parameter may have important implications for understanding the virological response to combination antiretroviral therapy.

scholarly journals Suppression of Virus Load by Highly Active Antiretroviral Therapy in Rhesus Macaques Infected with a Recombinant Simian Immunodeficiency Virus Containing Reverse Transcriptase from Human Immunodeficiency Virus Type 1

2005 ◽  
Vol 79 (12) ◽  
pp. 7349-7354 ◽  
Author(s):  
Thomas W. North ◽  
Koen K. A. Van Rompay ◽  
Joanne Higgins ◽  
Timothy B. Matthews ◽  
Debra A. Wadford ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Rhesus Macaques ◽  
Once Daily ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We have modeled highly active antiretroviral therapy (HAART) for AIDS in rhesus macaques infected with a chimera (RT-SHIV) of simian immunodeficiency virus containing reverse transcriptase from human immunodeficiency virus type-1 (HIV-1). Seven RT-SHIV-infected macaques were treated with a combination of efavirenz (200 mg orally once daily), lamivudine (8 mg/kg subcutaneously once daily), and tenofovir (30 mg/kg subcutaneously once daily). Plasma viral RNA levels in all animals were reduced by more than 1,000-fold after 4 weeks and, in six of the seven animals, were reduced to undetectable levels after 10 weeks. Virus loads increased slightly between 12 and 16 weeks of treatment, associated with problems with the administration of efavirenz. After a change in the method of efavirenz administration, virus loads declined again and remained undetectable in the majority of animals for the duration of therapy. Treatment was stopped for three animals after 36 weeks of therapy, and virus loads increased rapidly. Posttreatment RT-SHIV isolates had no mutations associated with resistance to any of the three drugs. Efavirenz treatment was stopped, but lamivudine and tenofovir treatment for two other macaques was continued. The virus load in one of these two animals rebounded; virus from this animal was initially free of drug-resistance mutations but acquired the K65R mutation in reverse transcriptase at 11 weeks after efavirenz treatment was withdrawn. These results mimic HAART of HIV-1-infected humans. The RT-SHIV/rhesus macaque model should be useful for studies of tissue reservoirs and sites of residual replication that are not possible or practical with humans.

scholarly journals Impact of Raltegravir or Efavirenz on Cell-Associated Human Immunodeficiency Virus-1 (HIV-1) Deoxyribonucleic Acid and Systemic Inflammation in HIV-1/Tuberculosis Coinfected Adults Initiating Antiretroviral Therapy

2020 ◽  
Vol 7 (2) ◽  
Author(s):  
Héloïse M Delagreverie ◽  
Claire Bauduin ◽  
Nathalie De Castro ◽  
Beatriz Grinsztejn ◽  
Marc Chevrier ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Deoxyribonucleic Acid ◽  
Randomized Study ◽  
High Sensitivity ◽  
Open Label ◽  
Art Initiation ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
D Dimer

Abstract Background In view of the fast viremia decline obtained with integrase inhibitors, we studied the respective effects of initiating efavirenz (EFV) or raltegravir (RAL)-based antiretroviral therapy (ART) regimens on human immunodeficiency virus (HIV)-1 deoxyribonucleic acid (DNA) levels and inflammation biomarkers in the highly inflammatory setting of advanced HIV-1 disease with tuberculosis (TB) coinfection. Methods We followed cell-associated HIV-1 DNA, high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), soluble CD14 and D-Dimer levels for 48 weeks after ART initiation in the participants to the ANRS12-180 REFLATE-TB study. This phase II open-label randomized study included ART-naive people with HIV and TB treated with rifampicin to receive RAL 400 mg twice daily (RAL400), RAL 800 mg twice daily (RAL800) or EFV 600 mg QD with tenofovir and lamivudine. Results In 146 participants, the median (interquartile range [IQR]) week (W)0 HIV-1 DNA level was 4.7 (IQR, 4.3–5.1) log10 copies/106 CD4+, and the reduction by W48 was −0.8 log10 copies/106 CD4+ on EFV, −0.9 on RAL400, and −1.0 on RAL800 (P = .74). Baseline median (IQR) hsCRP, IL-6, sCD14, and D-Dimer levels were 6.9 (IQR, 3.3–15.6) mg/L, 7.3 (IQR, 3.5–12.3) pg/mL, 3221 (IQR, 2383–4130) ng/mL, and 975 (IQR, 535–1970) ng/mL. All biomarker levels decreased over the study: the overall W0–W48 mean (95% confidence interval) fold-change on ART was 0.37 (IQR, 0.28–0.48) for hsCRP, 0.42 (IQR, 0.35–0.51) for IL-6, 0.51 (IQR, 0.47–0.56) for sCD14, and 0.39 (IQR, 0.32–0.47) for D-Dimers. There were no differences in biomarker reduction across treatment arms. Conclusions In participants with HIV and TB, EFV, RAL400, or RAL800 effectively and equally reduced inflammation and HIV-1 DNA levels.

scholarly journals Effect of combination antiretroviral therapy on human immunodeficiency virus 1 specific antibody responses in subtype-C infected children

2020 ◽  
Vol 101 (12) ◽  
pp. 1289-1299
Author(s):  
Sanjeev Kumar ◽  
Himanshu Batra ◽  
Swarandeep Singh ◽  
Himanshi Chawla ◽  
Ravinder Singh ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
Antiretroviral Therapy ◽  
Antibody Responses ◽  
Combination Antiretroviral Therapy ◽  
Subtype C ◽  
Effector Functions ◽  
Cart Initiation ◽  
Immunodeficiency Virus ◽  
Hiv 1

Protective antibody responses to human immunodeficiency virus (HIV)-1 infection evolve only in a fraction of infected individuals by developing broadly neutralizing antibodies (bnAbs) and/or effector functions such as antibody-dependent cellular cytotoxicity (ADCC). HIV-1 chronically infected adults and children on combination antiretroviral therapy (cART) showed a reduction in ADCC activity and improvement in HIV-1 specific neutralizing antibody (nAb) responses. Early initiation of cART in infected adults is found to be beneficial in reducing the viral load and delaying disease progression. Herein, we longitudinally evaluated the effect of cART on HIV-1 specific plasma ADCC and nAb responses in a cohort of 20 perinatally HIV-1 subtype-C infected infants and children ≤2 years of age, pre-cART and up to 1 year post-cART initiation. Significant reductions in HIV-1 specific plasma ADCC responses to subtype-C and subtype-B viruses and improvement in HIV-1 neutralization were observed in HIV-1 infected children 1 year post-cART initiation. A positive correlation between reduction in viral load and the loss of ADCC response was observed. This study provides information aiding the understanding of the effects of early initiation of cART on antibody effector functions and viral neutralization in HIV-1 infected children, which needs to be further evaluated in large cohorts of HIV-1 infected children on cART to plan future intervention strategies.

scholarly journals Is ventricular arrhythmias the end for all conditions ?

2021 ◽  
Author(s):  
Ahmet Goktug Ertem ◽  
Mehmet Akif Erdol ◽  
Koray Demirtas ◽  
Sefa Unal ◽  
Mustafa Karanfil ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Risk Factor ◽  
Antiretroviral Therapy ◽  
Ventricular Arrhythmias ◽  
Combination Antiretroviral Therapy ◽  
T Wave ◽  
Medical Status ◽  
Immunodeficiency Virus ◽  
Duration Of Disease ◽  
Severity Of The Disease

Dear Editor, We read the article entitled “Abnormal Dispersion of Ventricular Repolarization as a Risk Factor in Patients with Human Immunodeficiency Virus: Tp-e Interval, Tp-e/QTc Ratio” by Unal Evren et al. with interest[1]. The authors evaluated the changes in Tp-e interval, Tp-e/QT and Tp-e/corrected QT (QTc) ratios, and traditional electrocardiographic features of electrical dispersion in adults infected with Human Immunodeficiency Virus (HIV) and their study revealed that the cTp-e interval, Tp-e/QT and Tp-e/QTc ratios were prolonged and correlated to the severity of the disease in HIV-infected patients. Previous studies have revealed that the Tp–e interval, the Tpeak-Tend interval (Tpe), the interval from the T-wave peak to the end of the T wave, has been related to arrhythmogenesis, is specified as an index of totaldispersion of repolarization[2]. Prolonged Tp–e interval is predictable for ventricular arrhythmias and mortality [3]. Unal et al. showed that HIV-infected patients receiving combination antiretroviral therapy (cART) were associated withlonger Tp–e interval and Tp–e/QTc ratio and correlated positively with the duration of disease and the electrophysiologicalabnormalities, and negatively with CD4 count[4]. There were no informations about medical status of patients with HIV, duration of the disease and why hsCRP is higher in patients’ group. The patients were in active phases of infection. We think that these are important datas for results of the study. We thank the authors for adding this article to the literature

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