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Results for “Viral suppression”

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PubMed2006

Interruption of enfuvirtide in HIV-1 infected adults with incomplete viral suppression on an enfuvirtide-based regimen.

Many antiretroviral drugs continue to exert an anti-human immunodeficiency virus (HIV) benefit in the presence of drug resistance mutations. The degree to which enfuvirtide exerts continued antiviral activity in the presence of incomplete viral suppression has not been defined. To address this question, 25 subjects interrupted enfuvirtide while remaining on a stable background regimen. Enfuvirtide interruption was associated with an immediate but limited increase in plasma HIV-1 RNA levels. Enfuvirtide resistance waned rapidly in the absence of drug pressure and was no longer detectable by week 16 in most individuals. These data indicate that enfuvirtide has measurable antiviral activity in the setting of incomplete viral suppression. Although enfuvirtide resistance mutations are associated with significant fitness defects in vivo, the clinical significance of these mutations remains undefined.

Adult↗

PubMed2003

T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy.

Although T cell activation is associated with disease progression in untreated human immunodeficiency virus type 1 (HIV-1) infection, its significance in antiretroviral-treated patients is unknown. Activated (CD38(+)HLA-DR(+)) T cell counts were measured in 99 HIV-infected adults who had maintained a plasma HIV RNA level <or=1000 copies/mL for a median of 21 months while receiving antiretroviral therapy. Patients with sustained viral suppression had lower levels of T cell activation than untreated patients but higher levels than HIV-uninfected control subjects. Persistent T cell activation was associated with decreased CD4(+) T cell gains during therapy. For every 5% increase in the proportion of activated CD8(+) T cells, 35 fewer CD4(+) T cells/mm(3) were gained. Increased T cell activation was associated with shorter duration of viral suppression, hepatitis C virus coinfection, frequent low-level viremia, and lower nadir CD4(+) T cell counts. Interventions that directly target T cell activation or the determinants of activation may prove to be useful adjuvants to antiretroviral therapy.

Adult↗

PubMed2001

Lymphoid tissue viral burden and duration of viral suppression in plasma.

OBJECTIVES: To assess virological response in lymphoid tissue and its impact on the durability of response in plasma in HIV-1-infected persons who achieved sustained suppression of plasma viraemia with different antiretroviral regimens. METHODS: Consecutive patients on first-line antiretroviral therapy were included if they had a plasma HIV-1 RNA viraemia < 20 copies/ml within the last 6 months and tonsillar tissue accessible for biopsy. First-line therapy contained two nucleoside analogues: alone (2NRTI group, n = 3); plus a HIV-1 protease inhibitor (PI group, n = 11) or plus nevirapine (NVP group; n = 16). Patients were followed until virus was detectable in plasma, they changed therapy or were lost to follow-up. RESULTS: Tonsillar HIV-1 RNA could be detected (> 100 copies/mg) in 10 patients: one in the PI group (9%), six (38%) in the NVP group and in all three patients in the 2NRTI group. Primary resistance mutations could be detected in only 2 of these 10 patients. After a median of 9 months after the biopsies, viral suppression in plasma had failed in 6 of these 10 patients whereas failure had only occurred in 1 out of 20 with initially undetectable viral load in lymphoid tissue (P = 0.01; log rank test). CONCLUSIONS: In patients with sustained viral suppression in plasma, triple therapy including a HIV-1 protease inhibitor was more potent than triple therapy containing nevirapine or dual therapy with nucleoside analogues to reduce viral burden in lymphoid tissue. A worse response in lymphoid tissue could not be explained by local selection of resistance and was associated with a less durable virological response in plasma.

Adult↗

PubMed2005

Inhibition of flavivirus infections by antisense oligomers specifically suppressing viral translation and RNA replication.

RNA elements within flavivirus genomes are potential targets for antiviral therapy. A panel of phosphorodiamidate morpholino oligomers (PMOs), whose sequences are complementary to RNA elements located in the 5'- and 3'-termini of the West Nile (WN) virus genome, were designed to anneal to important cis-acting elements and potentially to inhibit WN infection. A novel Arg-rich peptide was conjugated to each PMO for efficient cellular delivery. These PMOs exhibited various degrees of antiviral activity upon incubation with a WN virus luciferase-replicon-containing cell line. Among them, PMOs targeting the 5'-terminal 20 nucleotides (5'End) or targeting the 3'-terminal element involved in a potential genome cyclizing interaction (3'CSI) exhibited the greatest potency. When cells infected with an epidemic strain of WN virus were treated with the 5'End or 3'CSI PMO, virus titers were reduced by approximately 5 to 6 logs at a 5 muM concentration without apparent cytotoxicity. The 3'CSI PMO also inhibited mosquito-borne flaviviruses other than WN virus, and the antiviral potency correlated with the conservation of the targeted 3'CSI sequences of specific viruses. Mode-of-action analyses showed that the 5'End and 3'CSI PMOs suppressed viral infection through two distinct mechanisms. The 5'End PMO inhibited viral translation, whereas the 3'CSI PMO did not significantly affect viral translation but suppressed RNA replication. The results suggest that antisense PMO-mediated blocking of cis-acting elements of flavivirus genomes can potentially be developed into an anti-flavivirus therapy. In addition, we report that although a full-length WN virus containing a luciferase reporter (engineered at the 3' untranslated region of the genome) is not stable, an early passage of this reporting virus can be used to screen for inhibitors against any step of the virus life cycle.

3' Untranslated Regions↗

PubMed2005

[Treatment interruption in 30 HIV-infected patients with successful viral suppression under highly active antiretroviral treatment].

OBJECTIVE: To evaluate clinical and laboratory results in HIV-infected patients with complete viral suppression under HAART (highly active antiretroviral treatment) for whom treatment was interrupted and to identify risk factors associated with prolonged (i.e., successful) treatment interruption. METHODS: Retrospective study of patients who interrupted therapy while on HAART with a plasma HIV RNA <400 copies/mL. Multivariate regression analysis was performed to identify factors associated with a prolonged interruption (more than 6 months). RESULTS: 36 treatment interruptions in 30 patients were analyzed. Patients' mean age was 42 years, 83% were men, and 60% were infected through homosexual contact. Median CD4 cell count at initiation of HAART was 292/mm3 and median viral load 43,000 copies/mL. Reported reasons for HAART discontinuation included patient or clinician choice (n=21) or drug toxicity (n=15). Median CD4 cell count when treatment interruption began was 606/mm3, and its median duration was 14 months. During treatment interruption, adverse clinical events or laboratory findings occurred in 9 patients (30%), all of whom had a CD4 cell count nadir < 300/mm3. When HAART resumed, median CD4 cell count was 302/mm3, and median viral load 59,800 copies/mL. Plasma HIV RNA dropped to <400 copies/mL in all patients within 4 months of resuming treatment. In multivariate analysis, the factors associated with resuming HAART within 6 month of treatment interruption were: HAART including non-nucleoside analog (adjusted Hazard Ratio [aHR]: 3.6, 95% CI: 1.2-10.6, p = 0.02), a CD4 cell count nadir < 300 (adjusted Hazard Ratio [aHR]: 5.5, 95% CI: 2.0-26, p = 0.0057), undetectable plasma HIV RNA for longer than 21 months at the interruption (aHR: 7.2, 95% CI: 2-26, p = 0.002). This probability was 45.5% in patients with a CD4 cell count nadir < 300 and 14.3% in the others (p 0.10). CONCLUSION: Antiretroviral treatment should be interrupted only with caution in patients with a CD4 cell count nadir <300/mm3 because of the risk of adverse clinical events or laboratory findings.

Adult↗

PubMed2006

Viral failure in HIV-infected patients with long-lasting viral suppression who discontinued enfuvirtide.

The aim of this pilot study was to assess whether enfuvirtide can be discontinued in patients on long-term viral suppression. Eight patients with multidrug-resistant virus were randomly assigned to stop and 10 subjects to continue enfuvirtide. At week 48, viral rebound occurred in five (62.5%) and in no patients, respectively, (P = 0.007). The CD4 cell decrease in failure patients was 5% (P = ns). These results suggest that enfuvirtide should be maintained until new active drugs became available.

ADP-ribosyl Cyclase 1↗

PubMed2005

Characteristics associated with suboptimal viral suppression at delivery in human immunodeficiency virus-1-infected pregnant women.

OBJECTIVE: This study was undertaken to determine clinical characteristics and factors associated with suboptimal viral suppression at delivery in human immunodeficiency virus (HIV)-infected women. STUDY DESIGN: All HIV-infected women who delivered at a single urban tertiary care center from January 1999 to June 2004 were studied. Women were divided into 2 groups based on HIV viral load (VL) proximate to delivery: VL < 1000 copies per milliliter and VL > or = 1000 copies per milliliter. Demographic and clinical factors were analyzed and compared between the 2 groups. RESULTS: A total of 146 women had adequate data available for analysis: 102 (69.9%) had VL < 1000 copies per milliliter and 44 (30.1%) had VL > or = 1000 copies per milliliter at delivery. Women with a viral load > or = 1000 copies per milliliter at delivery were more likely to have a baseline viral load VL > or = 10,000 copies per milliliter (66.7% vs 32%, P < .001) and less likely to report medication adherence, (50% vs 87.8%, P < .001). CONCLUSION: Our findings support the concept that in addition to antiviral medical therapy, intervention to improve adherence and maintaining a low baseline VL are key components to VL suppression in pregnancy.

Adult↗

PubMed2005

Nevirapine plasma exposure affects both durability of viral suppression and selection of nevirapine primary resistance mutations in a clinical setting.

The relationship between nevirapine plasma concentrations and the durability of both viral suppression (VS) and selection of nevirapine primary resistance mutations (PRMs) was evaluated. A nevirapine trough concentration (Ctrough) of >4,300 ng/ml was found to predict longer VS. Patients with nevirapine Ctrough s ranging from 3,100 to 4,300 ng/ml had higher probabilities of developing PRMs than those with nevirapine Ctrough s below and above this concentration interval.

Adult↗

PubMed2003

Continued indinavir versus switching to indinavir/ritonavir in HIV-infected patients with suppressed viral load.

OBJECTIVE: To compare continued indinavir (IDV) 8-hourly (q8h) with switching to indinavir/ritonavir (IDV/RTV) 12-hourly (q12h) in HIV-positive patients having suppressed viral load with IDV q8h plus two nucleoside reverse transcriptase inhibitors (NRTI). DESIGN: Multicentre, international, randomized, open-label study enrolling HIV-1 infected patients on IDV 800 mg q8h plus two NRTI with CD4 cell counts > or = 100 x 106/l and plasma HIV RNA < 500 copies/ml for > or = 3 months. METHODS: Patients were randomized to continue on the same regimen or to switch to IDV plus liquid RTV (IDV/RTV 800 mg/100 mg q12h). Primary endpoint was the proportion of patients remaining < 500 copies/ml at 48 weeks. RESULTS: A total of 323 patients (IDV/RTV, 162; IDV, 161) were evaluable. At 48 weeks, the proportions of patients with plasma HIV RNA < 500 copies/ml were 93%, 88% and 58% in the IDV/RTV arm versus 92% (P = 1), 86% (P = 0.87) and 74% (P = 0.003) in the IDV arm using on-treatment (OT) and intent-to-treat (ITT) [switches included (ITT, S = I) and switches = failure (ITT, S = F)] analyses respectively. Mean increase in CD4 cell count was 88 x 106/cells/l (IDV/RTV arm) and 60 x 106 cells/l (IDV arm) (P = 0.08). More patients discontinued study medication due to adverse events in the IDV/RTV arm than in the IDV arm (P < 0.001). CONCLUSIONS: Equivalence of continuing IDV q8h versus switching to IDV/RTV (liquid) q12h in suppressed stable patients was demonstrated by OT and ITT S = I analyses. However, the IDV q8h arm performed better when discontinuations were classified as failures. IDV/RTV q12h can be convenient and equally effective for patients able to tolerate it.

Adult↗

PubMed1999

HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression.

Identifying the immunologic and virologic consequences of discontinuing antiretroviral therapy in HIV-infected patients is of major importance in developing long-term treatment strategies for patients with HIV-1 infection. We designed a trial to characterize these parameters after interruption of highly active antiretroviral therapy (HAART) in patients who had maintained prolonged viral suppression on antiretroviral drugs. Eighteen patients with CD4(+) T cell counts >/= 350 cells/microliter and viral load below the limits of detection for >/=1 year while on HAART were enrolled prospectively in a trial in which HAART was discontinued. Twelve of these patients had received prior IL-2 therapy and had low frequencies of resting, latently infected CD4 cells. Viral load relapse to >50 copies/ml occurred in all 18 patients independent of prior IL-2 treatment, beginning most commonly during weeks 2-3 after cessation of HAART. The mean relapse rate constant was 0.45 (0.20 log(10) copies) day(-1), which was very similar to the mean viral clearance rate constant after drug resumption of 0.35 (0.15 log(10) copies) day(-1) (P = 0.28). One patient experienced a relapse delay to week 7. All patients except one experienced a relapse burden to >5,000 RNA copies/ml. Ex vivo labeling with BrdUrd showed that CD4 and CD8 cell turnover increased after withdrawal of HAART and correlated with viral load whereas lymphocyte turnover decreased after reinitiation of drug treatment. Virologic relapse occurs rapidly in patients who discontinue suppressive drug therapy, even in patients with a markedly diminished pool of resting, latently infected CD4(+) T cells.

Adult↗

PubMed2003

HIV viral suppression in the era of antiretroviral therapy.

Altogether 42 million people worldwide have been infected with HIV, and 12 million have died over the last 20 years. Effective antiretroviral therapy has lead to sustained HIV viral suppression and immunological recovery in patients who have been infected with the virus. The incidence of AIDS has declined in the Western world with the introduction of effective antiretroviral therapy. Questions on When to start treatment?, What to start with?, How to monitor patients?, remain heavily debated. Adherence to antiretroviral treatment remains the cornerstone of effective treatment, and failure to adhere is the strongest predictor of virological failure. Long term therapy can lead to metabolic complications. Resource poor countries are dealing with difficult issues such as mother to child prevention of HIV transmission. Other treatment options are now available, with the recent introduction of fusion inhibitors, second generation non-nucleoside reverse transcriptase inhibitors, and nucleotide reverse transcriptase inhibitors to clinical practice.

Anti-HIV Agents↗

PubMed2002

Intensification and stimulation therapy for human immunodeficiency virus type 1 reservoirs in infected persons receiving virally suppressive highly active antiretroviral therapy.

Highly active antiretroviral therapy (HAART) has led to significant changes in mortality and morbidity in the human immunodeficiency virus type 1 (HIV-1) epidemic. Nevertheless, because of molecular mechanisms of viral persistence, HAART does not eradicate HIV-1. Didanosine and hydroxyurea were added to the antiretroviral regimens of 3 HIV-1-infected men who were receiving stable HAART and who had HIV-1 RNA levels <50 copies/mL at the initiation of the study protocol, as a novel intensification to attack cryptic viral replication; low-dose OKT3 was then administered, followed by a course of interleukin-2, to stimulate latent provirus. Replication-competent virus was undetectable after treatment, and plasma viral RNA was either undetectable or <5 copies/mL. In trial periods during which no antiretroviral therapy was administered, the patients developed plasma viral rebound. This translational approach combines novel intensification and stimulation therapy to deplete residual HIV-1 reservoirs. Additional experimental approaches must be developed if HIV-1 eradication is to become possible in patients receiving virally suppressive HAART.

Adult↗

PubMedDate not supplied

Study protocol for the evaluation of the potential for durable viral suppression after quadruple HAART with or without HIV vaccination: the QUEST study.

PURPOSE: By protecting and stimulating HIV-specific CD4 cell responses, treatment of primary HIV infection (PHI) with potent quadruple HAART could lead to prolonged suppression of HIV replication after cessation of antiretroviral therapy. The QUEST trial investigates this hypothesis and aims to determine whether addition of a therapeutic vaccine to HAART increases the likelihood of prolonged viral suppression compared to HAART alone. METHOD: 148 patients with PHI were recruited. Participants were treated with open-label HAART for at least 76 weeks. Participants with sustained viremia <50 copies/mL were randomized to one of three 5-month, double-blinded study treatment groups: HAART alone, HAART + ALVAC-HIV (vCP1452), or HAART + ALVAC-HIV (vCP1452) + Remune. After a further month of HAART alone, all treatment was stopped where plasma HIV-1 RNA remained at <50 copies/mL. Intensive virologic and immunologic monitoring during a 24-week observation period followed treatment interruption. Patients who met treatment reintroduction criteria were offered HAART rescue.

AIDS Vaccines↗

PubMed1996

HIV replication in CD4+ T cells of HIV-infected individuals is regulated by a balance between the viral suppressive effects of endogenous beta-chemokines and the viral inductive effects of other endogenous cytokines.

This study demonstrates that the beta-chemokines macrophage inflammatory proteins 1 alpha and 1 beta (MIP-1 alpha and MIP-1 beta) and, RANTES (regulated on activation, normally T-cell expressed and secreted) inhibit human immunodeficiency virus (HIV) replication in anti-CD3 or recall antigen-stimulated peripheral blood mononuclear cells (PBMCs) of asymptomatic HIV-infected subjects. Significant levels of beta-chemokines were produced by both CD4+ and CD8+ PBMC subsets from HIV-infected individuals. Neutralization of endogenous MIP-1 alpha, MIP-1 beta, and RANTES did not rescue HIV replication in cultures to which greater than 10% CD8+ T cells had been added, indicating that the HIV suppressor activity of CD8+ T cells cannot be explained entirely by the beta-chemokines. However, significant enhancement of viral replication was observed upon neutralization of endogenous beta-chemokines in CD8-depleted or CD4+ PBMCs from most donors, particularly in cultures with low inducible levels of HIV production. In contrast, certain endogenous proinflammatory cytokines induced HIV replication in these same cells. These data suggest that the levels of HIV replication in CD4+ PBMC reflect the balance of the opposing effects of endogenous suppressive factors, such as the beta-chemokines, and HIV-inducing cytokines, such as tumor necrosis factor alpha and interleukin 1 beta.

CD4-Positive T-Lymphocytes↗

PubMed2002

Virological, immunological, and clinical impact of switching from protease inhibitors to nevirapine or to efavirenz in patients with human immunodeficiency virus infection and long-lasting viral suppression.

Seventy-seven subjects infected with human immunodeficiency virus were randomized to switch from protease inhibitor (PI) therapy to nevirapine therapy (group A; n=26) or to efavirenz therapy (group B; n=25) or to continue PI therapy (group C; n=26). At month 12, viral suppression had been maintained in 96% of patients in group A, 92% of patients in group B, and 92% of patients in group C. A significant increase in the CD4(+) level was observed in all 3 groups. In group A, lipid profiles improved, whereas levels of gamma-glutamiltransferase and alanine aminotransferase significantly increased; 1 subject interrupted treatment because of hepatotoxicity. In group B, an increase in gamma-glutamiltransferase levels was also observed, and 3 patients interrupted treatment because of central nervous system symptoms. Two patients in group C withdrew therapy. Quality of life significantly improved for groups A and B. In patients receiving effective PI-based therapy, the replacement of the PI with either nevirapine or efavirenz is safe and virologically effective.

Alkynes↗

PubMed2006

Therapy of hepatitis B -- viral suppression or eradication?

The practicing clinician is currently faced with a number of treatment options for chronic hepatitis B. Beginning in 1998 with the licensing of lamivudine and subsequently adefovir, the treatment paradigm shifted from 4 to 6 months of conventional alfa interferon to a year of nucleoside analog therapy. However, prolonged treatment with nucleoside analogs is often needed to optimize virological response. Recently, a 48-week regimen of pegylated interferon for hepatitis B e antigen (HBeAg)-positive and HBeAg-negative chronic hepatitis B has been shown to be effective, and long-term nucleoside analog therapy has been demonstrated to maintain viral suppression. These findings have added to the complexity of decision-making and have raised questions about whether a finite course of pegylated interferon or nucleoside analog therapy, with possible long-term maintenance, is better as first-line therapy. Each of these fundamentally different approaches has advantages and limitations, and both have a place in the therapeutic armamentarium against chronic hepatitis B. Long-term therapy with nucleoside analogs, however, raises a number of practical concerns that have not been fully addressed as of yet. I will present evidence in support of the recommendation that antiviral therapy should ideally be directed toward achieving the highest rate of viral clearance with the shortest interval of treatment.

Adult↗

PubMed2002

Persistent HIV-1-specific cellular responses despite prolonged therapeutic viral suppression.

DESIGN: Antiretroviral therapy (ART) currently represents the best way to avert the lethal consequences of chronic persistent HIV-1 infection. It leads to significant reductions of plasma viremia, often to undetectable levels, but it can also be linked with the reduction and disappearance of detectable HIV-specific CD8 T-cell responses. RESULTS: Here we describe a group of patients in whom ongoing replication of HIV, particularly transcription of Nef mRNA species, was detected despite prolonged and clinically successful antiretroviral treatment. Modest, but significant, numbers of HIV-specific CD8 T cells and CD4 T-cell responses were found in these subjects, with the strongest responses directed towards Nef epitopes. Detailed phenotypic analysis of the HIV-specific CD8 cells demonstrated low perforin levels and persistent expression of CD27, a phenotype associated with incomplete differentiation of cytotoxic T lymphocytes (CTL). CONCLUSION: This immature CTL phenotype has been described previously in association with chronic HIV disease, but its continued persistence is surprising in the setting of prolonged viral suppression on therapy and the presence of HIV-specific CD4 cell activity.

Anti-HIV Agents↗

PubMed2006

Maintenance of viral suppression in HIV-1-infected HLA-B*57+ elite suppressors despite CTL escape mutations.

Rare human immunodeficiency virus 1-infected individuals, termed elite suppressors (ES), maintain plasma virus levels of <50 copies/ml and normal CD4 counts without therapy. The major histocompatibility complex class I allele group human histocompatibility leukocyte antigen (HLA)-B*57 is overrepresented in this population. Mutations in HLA-B*57-restricted epitopes have been observed in ES, but their significance has remained unclear. Here we investigate the extent and impact of cytotoxic T lymphocyte (CTL) escape mutations in HLA-B*57+ ES. We provide the first direct evidence that most ES experience chronic low level viremia. Sequencing revealed a striking discordance between the genotypes of plasma virus and archived provirus in resting CD4+ T cells. Mutations in HLA-B*57-restricted Gag epitopes were present in all viruses from plasma but were rare in proviruses, suggesting powerful selective pressure acting at these epitopes. Surprisingly, strong CD8+ T cell interferon-gamma responses were detected against some mutant epitopes found in plasma virus, suggesting the development of de novo responses to viral variants. In some individuals, relative CD8+ T cell interleukin-2 responses showed better correlation with the selection observed in vivo. Thus, analysis of low level viremia reveals an unexpectedly high level of CTL escape mutations reflecting selective pressure acting at HLA-B*57-restricted epitopes in ES. Continued viral suppression probably reflects CTL responses against unmutated epitopes and residual or de novo responses against epitopes with escape mutations.

CD4 Lymphocyte Count↗