Mathematical Analysis of Antiretroviral Therapy Aimed at HIV-1 Eradication or Maintenance of Low Viral Loads

Abstract Background The gold standard for HIV-1 treatment is to administer triple antiretroviral therapy, but a shift to simplified regimens is being explored. Boosted darunavir monotherapy can be considered for patients who are for specific reasons not good candidates for dual or triple therapy. Still, a number of patients fail virologically or need to switch treatment. Objectives To identify predictive markers for those patients that are more likely to sustain virological control under monotherapy, virological and immunological markers were explored in HIV-1-positive patients that experienced virological failure on ritonavir-boosted darunavir monotherapy in the PROTEA trial. Methods As a retrospective nested study of the PROTEA study (NCT01448707), we analysed 77 HIV-1-infected patients who were on darunavir/ritonavir 800/100 mg monotherapy up to 96 weeks. Patients were appointed to three distinct cohorts based on viral loads (VLs): (i) undetectable VL after 96 weeks; (ii) very-low-level viraemia (5–39 copies/mL); and (iii) failing treatment. Total HIV-1 DNA, integrated HIV-1 DNA and 2-long terminal repeat circular HIV-1 DNA (2LTR circles) were measured in PBMCs at baseline, week 48 and week 96. Results Total HIV-1 DNA and integrated HIV-1 DNA at baseline differed significantly between patients who experienced virological failure on monotherapy (P < 0.01 and P < 0.001). Although a higher level of HIV-1 DNA was measured in failures, this marker by itself does not provide enough predictive value to prospectively predict virological failure in patients on monotherapy. Conclusions HIV-1 reservoir markers correlate with therapy failure in ritonavir-boosted darunavir monotherapy. However, their role as a predictive marker combined with other markers in a routine clinical setting should be further explored.

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2249. Insulin Resistance Is Associated with Higher Viral Loads Among HIV-1-Infected Patients Initiated on 12 Months of First-Line Antiretroviral Therapy

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy210.1902 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S665-S665

Author(s):

Lloyd Mulenga ◽

Patrick Musonda ◽

Lameck Chirwa ◽

Mpanji Siwingwa ◽

Henry Phiri

Keyword(s):

Insulin Resistance ◽

Antiretroviral Therapy ◽

First Line ◽

Viral Loads ◽

Hiv 1

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Management of HIV-2 resistance to antiretroviral therapy in a HIV-1/HIV-2/HBV co-infected patient

AIDS Research and Therapy ◽

10.1186/s12981-021-00394-4 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Margarida Cardoso ◽

Joana Vasconcelos ◽

Teresa Baptista ◽

Isabel Diogo ◽

Fátima Gonçalves ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Virologic Failure ◽

Standard Of Care ◽

Resistance Testing ◽

Current Standard ◽

Viral Loads ◽

B Virus ◽

Tenofovir Alafenamide ◽

Viral Load Determination ◽

Hiv 1

Abstract Background The current standard of care is to start antiretroviral therapy in all patients diagnosed with HIV-1, as for HIV-2 current DHHS guideline suggests ART for HIV-2 as soon as diagnosis is established, although this practice is not universal, for instance, in Portugal there are specific criteria to start treatment. Case presentation We present a case of a man, chronically infected with HIV-1, HIV-2 and hepatitis B virus who developed resistance to HIV-2 while maintaining HIV-1 under control. 6 years after starting antiretroviral therapy he had his first virologic failure. We performed HIV-2 resistance tests that revealed high-grade resistance to all nucleoside reverse-transcriptase inhibitors except tenofovir and to all protease inhibitors except darunavir. After a decade of permanent poor adherence to therapy he developed resistance to both tenofovir and darunavir. We put together a new regiment with tenofovir alafenamide + emtricitabine + dolutegravir + maraviroc and nowadays he is with undetectable HIV-1 and HIV-2 viral loads. Conclusions This shows the importance of having access to HIV-2 viral load determination and HIV-2 resistance testing.

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Re-evaluating evolution in the HIV reservoir

10.1101/140731 ◽

2017 ◽

Author(s):

Daniel I. S. Rosenbloom ◽

Alison L. Hill ◽

Sarah B. Laskey ◽

Robert F. Siliciano

Keyword(s):

T Cells ◽

Antiretroviral Therapy ◽

Viral Replication ◽

Latent Reservoir ◽

Sequence Evolution ◽

Evolutionary Patterns ◽

Hiv Reservoir ◽

Viral Loads ◽

Additional Barrier ◽

Hiv 1

Despite antiretroviral therapy (ART), a latent reservoir of replication-competent HIV-1 persists in resting memory CD4+ T-cells and precludes cure1-6. Lorenzo-Redondo et al.7 analyzed HIV-1 sequences collected from three individuals during the first six months of ART, discovered specific patterns of sequence evolution, and concluded that viral replication persists during therapy. We believe these evolutionary patterns are artifacts of rapidly decaying viral subpopulations present during the first months of therapy and are not characteristic of the long-lived reservoir. The study therefore provides no evidence that ongoing replication is an additional barrier to cure for treated individuals who consistently maintain low viral loads.

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Profile of Patients With Kaposi's Sarcoma in the Era of Highly Active Antiretroviral Therapy

Journal of Clinical Oncology ◽

10.1200/jco.2005.04.156 ◽

2005 ◽

Vol 23 (6) ◽

pp. 1253-1260 ◽

Cited By ~ 51

Author(s):

James H. Gallafent ◽

Susan E. Buskin ◽

Peter B. De Turk ◽

David M. Aboulafia

Keyword(s):

Antiretroviral Therapy ◽

Drug Use ◽

Highly Active Antiretroviral Therapy ◽

Kaposi's Sarcoma ◽

Kaposi’S Sarcoma ◽

Alcohol Problems ◽

King County ◽

Viral Loads ◽

Highly Active ◽

Hiv 1

Purpose Since the advent of highly active antiretroviral therapy (HAART), the incidence of Kaposi's sarcoma (KS) among AIDS patients has declined both nationwide and in King County, Washington. We sought to compare clinical parameters of patients diagnosed with KS in the pre-HAART (1990 to 1996) and HAART (1997 to 2002) eras. Methods We used patient data abstracted from the Adult/Adolescent Spectrum of HIV-Related Diseases study of Public Health—Seattle and King County. Results Patients diagnosed with KS in the HAART era (n = 40) were significantly more likely (P < .05) than pre–HAART-era KS patients (n = 366) to be diagnosed with alcohol problems (43% v 18%), noninjection drug use (45% v 18%), injection drug use (25% v 10%), psychosis (25% v 13%), and hypertension (13% v 2%). Although median CD4+ count and HIV-1 viral load at the time of KS diagnosis were not significantly different between the two groups, significantly fewer (P < .01) HAART-era KS patients developed opportunistic illnesses (OIs) during their follow-up. The risk of dying among KS patients diagnosed in the HAART era is significantly lower (P < .01) than for KS patients diagnosed in the pre-HAART era (hazard ratio, 0.24). Conclusion Although HAART-era KS patients in King County were as likely to have a depleted CD4+ cell count and high HIV-1 viral loads at the time of KS diagnosis as pre-HAART KS patients, they survived longer and fewer of them were diagnosed with other OIs. They also had an increased prevalence of substance abuse and mental illness, contributing to a dynamic and changing KS clinical profile.

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CD8+ T-Cell Mediated Control of HIV-1 in a Unique Cohort With Low Viral Loads

Frontiers in Microbiology ◽

10.3389/fmicb.2021.670016 ◽

2021 ◽

Vol 12 ◽

Author(s):

Amber D. Jones ◽

Svetlana Khakhina ◽

Tara Jaison ◽

Erin Santos ◽

Stephen Smith ◽

...

Keyword(s):

Viral Load ◽

T Cell ◽

Antiretroviral Therapy ◽

Undetectable Viral Load ◽

Underlying Mechanism ◽

T Cell Response ◽

Dependent Manner ◽

Viral Loads ◽

Hiv 1

A unique population of HIV-1 infected individuals can control infection without antiretroviral therapy. These individuals fall into a myriad of categories based on the degree of control (low or undetectable viral load), the durability of control over time and the underlying mechanism (i.e., possession of protective HLA alleles or the absence of critical cell surface receptors). In this study, we examine a cohort of HIV-1 infected individuals with a documented history of sustained low viral loads in the absence of therapy. Through in vitro analyses of cells from these individuals, we have determined that infected individuals with naturally low viral loads are capable of controlling spreading infection in vitro in a CD8+ T-cell dependent manner. This control is lost when viral load is suppressed by antiretroviral therapy and correlates with a clinical CD4:CD8 ratio of <1. Our results support the conclusion that HIV-1 controllers with low, but detectable viral loads may be controlling the virus due to an effective CD8+ T-cell response. Understanding the mechanisms of control in these subjects may provide valuable understanding that could be applied to induce a functional cure in standard progressors.

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CRISPR/Cas9-Induced Mutagenesis Corroborates the Role of Transportin-SR2 in HIV-1 Nuclear Import

Microbiology Spectrum ◽

10.1128/spectrum.01336-21 ◽

2021 ◽

Author(s):

Julie Janssens ◽

Jolien Blokken ◽

Yulia Lampi ◽

Flore De Wit ◽

Irena Zurnic Bonisch ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Nuclear Import ◽

Viral Suppression ◽

Combination Antiretroviral Therapy ◽

Viral Loads ◽

Sustained Viral Suppression ◽

Induced Mutagenesis ◽

Hiv 1

Combination antiretroviral therapy (cART) effectively controls HIV-1 by reducing viral loads, but it does not cure the infection. Lifelong treatment with cART is a prerequisite for sustained viral suppression.

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Replicate Aptima Assay for Quantifying Residual Plasma Viremia in Individuals on Antiretroviral Therapy

Journal of Clinical Microbiology ◽

10.1128/jcm.01400-20 ◽

2020 ◽

Vol 58 (12) ◽

Cited By ~ 2

Author(s):

Sonia Bakkour ◽

Xutao Deng ◽

Peter Bacchetti ◽

Eduard Grebe ◽

Leilani Montalvo ◽

...

Keyword(s):

Viral Load ◽

Antiretroviral Therapy ◽

False Negative ◽

Study Cohort ◽

Plasma Samples ◽

Plasma Viremia ◽

Viral Loads ◽

The Impact ◽

Hiv 1 ◽

Residual Plasma Viremia

ABSTRACT Detection of residual plasma viremia in antiretroviral therapy (ART)-suppressed HIV-infected individuals is critical for characterizing the latent reservoir and evaluating the impact of cure interventions. Ultracentrifugation-based single-copy assays are sensitive but labor intensive. Fully automated replicate testing using a standard clinical viral load assay was evaluated as a high-throughput alternative for the quantification of low-level viremia. Four plasma samples from blood donors with acute HIV-1 infection and one viral culture supernatant were serially diluted into 25-ml samples to nominal viral loads ranging from 39 to <0.5 copies (cp)/ml. Each dilution was tested with 45 replicates (reps) using 0.5 ml/rep with the Aptima HIV-1 Quant assay. The nominal and estimated viral loads based on the single-hit Poisson model were compared, and a hybrid Poisson digital model for calibrated viral load estimation was derived. Testing performed using 45 reps on longitudinal plasma samples from 50 ART-suppressed individuals in the Reservoir Assay Validation and Evaluation Network (RAVEN) study cohort (range of 1 to 19 years of continuous ART suppression) showed a median viral load of 0.54 cp/ml (interquartile range [IQR], 0.22 to 1.46 cp/ml) and a 14% (95% confidence interval [CI], 9% to 19%) decline in viral load for each additional year in duration suppressed. Within the RAVEN cohort, the expected false-negative rate for detection at lower rep numbers using 9 and 18 reps was 26% and 14%, respectively. Residual plasma viremia levels positively correlated with cell-associated HIV RNA and DNA. The performance characteristics of the replicate Aptima assay support its use for quantifying residual plasma viremia to study the latent HIV reservoir and cure interventions.

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