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Structured Treatment Interruptions Workshop Summary

January 31, 2001

Progress in STI Research:
The Outlook for Immune Response

The State of the Hypotheses for STI

Primary Infection

Hypothesis Evidence Next Step
Treat briefly to lower the viral setpoint and allow people to live longer with less drug exposure. We have anecdotal evidence that this is possible. Determine long-term benefit and safety.

Chronic Infection, Suppressed Virus

Hypothesis Evidence Next Step
Attain remission through HIV-1-specific immune control. There is evidence that this occurs in some patients. Identify responders and increase the proportion that responds.
Get acceptable clinical results with less drug exposure and prevent death and disease. There is evidence that abnormal lab values can recover during interruption; there is little evidence that drug-related symptoms recover, at least during the short interruption periods studied so far. Identify patients for whom this is safe.

Chronic Infection, Unsuppressed Virus

Hypothesis Evidence Next Step
Reduce toxicity by periodically stopping drug treatments. There is evidence that abnormal lab values can recover during interruption; there is evidence that fat redistribution does not improve. Practice careful medical management to minimize the risk of clinical events in patients with low and declining CD4+ cell counts.
Re-sensitize the virus to antiretroviral drugs so patients can avoid death and disease by returning to therapy and suppressing virus. The goal should be to maintain CD4+ cell counts and preserve immune repertoire. There is evidence that shift to WT virus can occur -- but drug susceptibility is eventually lost when therapy is reintroduced. Time required for shift to WT usually results in significant CD4+ cell count declines. These declines are greatest in those with higher CD4+ counts.

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Identify patients for whom this is safe.

Identify patients for whom this can be predicted.

Outstanding Immunology Issues

There is a crucial need to standardize:

  • Immune-related HIV assays [HIV strains, viral peptides, VIR]

  • Cell collection, storage and shipping protocols.

Correlate new assays with standard assays

  • Correlate new immune markers (other than CD4+) with clinical endpoints and with virology endpoints.

  • Fund immunology substudies of large clinical trials to standardize assays

  • Correlate assay results with clinical events

  • Correlate assay results in different populations

  • Take advantage of the DAIDS repository and immunology QA funding.

  • Use chip technology for multiple assay analysis.

  • Collect samples and save cells.

  • Obtain informed consent to save cells for future testing, including genetic analysis.

Expand the use of animal models

  • To investigate the ideal duration of STI in primary infection.

  • To correlate memory and naive cell numbers/ratios with disease progression or remission.

  • Are enough animals available and accessible?

Investigate

  • Host genomics

  • Humoral immunity

  • Cell collection, storage and shipping protocols.

  • Investigate how memory/effector cell ratio influences the outcome of STI.

  • Continue to look for ways to stimulate immune control during chronic infection.

  • Continue to investigate cytokines and therapeutic vaccines.

Outstanding Virology Issues

What are the virologic determinants for HIV-1-specific immune stimulation?

  • Amount (dose) of viral antigen

  • Duration of exposure to antigen

  • Viral genotypic and phenotypic variation during the interruption. What is the impact of viral evolution
    during STI?

  • What are the best doses and durations for ´prime-boost' approaches? While there may be a lower and higher level of antigen necessary for these responses, they remain undefined. 50,000 should be enough in PHI (Altfeld), there is less data for CHI.

  • Should durations be set by patient-oriented schedules, by fixed schedules or by fixed thresholds? Treat as viremia rises, allow VL to peak then go down, or treat when the CD4+ threshold is reached?

  • Ongoing trials and animal models may help pinpoint these numbers.

  • Could you predict the rebound magnitude based on pre-STI replication rates?

  • Do immune-suppressive viral proteins that accompany the viral rebound affect immune response functions and complicate existing models?

Virus rebound -- Immunogenic stimulus

  • What degree of viral control should be observed to accept the hypothesis that HIV-1-specific immunity can be stimulated? <50, <500, <5000 copies/mL? A relative drop? -1.0 log, -2.0 log? A lower setpoint than the pre-therapy setpoint? (Pre-therapy setpoints are difficult to determine.)

  • In PHI there is no pretreatment setpoint to compare with.

  • The risk thresholds for CD4+ or VL vary by opinions on "when to start" in CHI. How long does one wait to see VL rise then spontaneously fall? (Some suggest waiting 12 weeks off drug). Is there a viral threshold considered too risky to continue beyond? (Peak viremia is usually reached by week 7.)

  • Why would one use an arbitrary viral load copy number as a trigger to restart treatment rather than CD4+ cell counts? It may depend on the governing hypothesis - or on what one's IRB will allow.

Virus rebound -- Antigenic stimulus

  • What is the rebounding virus population?

  • Does the cellular source of the rebound virus matter in terms of "immunogenicity" and/or "antigenicity"? There is usually more heterogeneity in the viral populations during CHI than in PHI. Reservoirs are critical for reseeding the rebound. (ADARC and NIAID are looking at this.)

  • Is viral control on HAART associated with an SI-NSI switch? This could be measured.

  • Do chemokine receptor expression, activation markers, cytokines, or antibodies affect or reflect response?

  • Can there be an expansion of pre-existing drug-resistant minorities?

Drug exposed virus -- Drug pressure

  • Viral evolution continues if drug pressure is maintained

  • One benefit of STI is to stop the further accumulation of resistance mutations.

  • It is possible to allow the outgrowth of WT virus. But who shifts from drug resistant to WT virus and what are the predictors of this switch?

  • What is the impact on virus fitness, virulence, or pathogenicity? Are in vitro fitness or competitive outgrowth assays relevant?

  • Do so-called compensatory mutations actually compensate?

  • MDR HIV is highly impaired in replicative capacity but the virology is unclear. Should treatment be terminated? In which patients, for how long?

  • Yet MDR HIV can be transmitted and replicate to a high level.

  • What is the immunologic and clinical impact of a shift to WT as the dominant population?

  • What are the costs of this switch in terms of CD4+ cell loss and clinical endpoints?


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