Study of People With HIV Infection Who Have High Viral Loads Despite Combination Antiretroviral Therapy
Condition: Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; AIDS Virus; Human Immunodeficiency Virus; Human Immunodeficiency Viruses
MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections; Immunologic Deficiency Syndromes; Syndrome
Study type: Observational

Summary: 
      Background:

      - The human immunodeficiency virus (HIV) causes acquired immune deficiency syndrome (AIDS).
      Combination antiretroviral therapy (ART) drugs treat HIV infection. They generally decrease
      the amount of HIV virus in the blood (called viral load) to very low levels. This happens
      only if the drugs still fight HIV and if taken every day exactly as prescribed. When not
      taken as directed, or if the ART drugs are not strong enough, the virus can become resistant
      to them, and the ART will not work to control the virus. Researchers want to know how to
      control HIV in people who can t lower their viral load with their current ART drugs.

      Objective:

      -<TAB>To better control HIV in people who can t get a lower viral load even with ART drugs
      and to learn more about why the HIV is not under control.

      Eligibility:

        -  People at least 18 years old and with HIV.

        -  People who have been on at least two combinations of ART drugs (including current ART).

        -  People whose last two viral loads were greater than 1,000 copies/mL.

      Design:

        -  Participants will be screened with medical history, physical exam, and blood tests.

        -  Participants will then have a baseline visit. They will have another physical exam,
           blood tests, plus answer questions about what they know about HIV and ART, and how they
           take their ART.

        -  Participants will arrange to stay in the NIH hospital for 7 8 days.

        -  They will take their medications as usual. At the time to take the ART drugs, they will
           have to ask a nurse to bring them. If they forget, the nurse will bring them.

        -  Participants will meet with a doctor, pharmacist, social worker and nurse to discuss
           ways to help participants remember to take their drugs.

        -  Participants will have blood drawn about every other day.

        -  Researchers will study the test results. Some participants will be put on different ART
           drugs. If that happens, participants will have another NIH hospital stay for 7-8 days.

        -  Participants will have 4 follow-up visits over 12 weeks, then every 3 months for 2 years
           or more.
    

Detailed description: 
      Combination antiretroviral therapy (ART) has dramatically improved survival in individuals
      with human immunodeficiency virus type1 (HIV-1) infection. Despite recent development of more
      potent regimens with fewer toxicities and lower pill burden, there remains a subpopulation of
      subjects who fail to achieve and maintain viral suppression while on treatment. Factors known
      to contribute to virologic failure include suboptimal adherence, drug resistance, suboptimal
      regimen potency, sequential introduction of single drugs to a failing regimen, and reduced
      ART exposure due to impaired drug absorption or pharmacokinetic drug-drug interactions.

      This is a natural history protocol with intensive observation intended to characterize and
      manage HIV-infected subjects who have documented virologic failure on their current regimen
      and who have experienced virologic failure in meeting one of the following criteria:

        1. Documented virologic failure on at least 1 prior ART regimen and at least 2 consecutive
           HIV RNA plasma measurements of >1,000 copies/mL, including the last documented value,
           while on the current prescribed ART regimen for at least 6 months; or

        2. Documented extensive resistance to at least 3 ARV drug classes, and has persistent
           plasma viremia (HIV RNA > 1,000 copies/mL for > 6 months) despite multiple regimen
           changes, regardless of how long the subject has been prescribed his or her current
           regimen.

      We anticipate that, for a large proportion of the participants enrolled in this protocol,
      non-adherence, with or without drug resistance, is the most common reason for the virologic
      failure. Another objective for the study is to assess the impact of a 7-day, self-guided,
      inpatient directly observed therapy (iDOT) or a 7-day outpatient, self-guided electronic
      directly observed therapy (eDOT) on HIV RNA kinetics, when participants will receive their
      pre-enrollment ART regimens. During the iDOT period, participants will request their ARV
      drugs at a pre-arranged time reflecting their home medication schedule. Failure to do so will
      be recorded and the medications will then be provided by the nursing staff. Blood draw will
      be done on days 1, 3, 5, and 8. Participants will be discharged on Day 8 after morning blood
      draw. During the eDOT period, participants will submit video recordings of themselves taking
      their medications at the scheduled time for 7 days. Reminders (eg, short message service
      [SMS], push notifications) will be sent to participants if they have not submitted their
      video recordings 2 hours past the scheduled time . Participants who use eDOT will present to
      the NIH Clinical Center on Day 1 and return on Day 8 to have blood draw for HIV RNA and
      safety labs as per protocol. Adherence and psychosocial assessments will also be performed.
      Plasma concentrations from at least one of the ARV drugs in the regimen will be measured on
      the first and last day of iDOT/eDOT to determine if suboptimal drug plasma concentration was
      a contributing factor to virologic failure.

      Within approximately 2 weeks, but no later than 4 weeks, after iDOT/eDOT (post-iDOT/eDOT
      phase), the research team will review the results from the HIV-1 viral load kinetics, current
      and cumulative genotypic and/or phenotypic resistance tests, ART history and responses, and
      other identified factors that could have contributed to the treatment failure (such as
      concomitant medications, history of antiretroviral adverse events, and psychosocial
      barriers). The team will then design a new, individualized treatment plan for each
      participant. Participants will either continue on their pre-enrollment ART regimen, or they
      will receive a new, individually tailored regimen that consists of FDA-approved ARVs.

      Alternatively, participants may co-enroll on a clinical trial for investigational ARVs, or
      may receive expanded access treatment, if either option is available.

      New regimens initiated due to virologic failure will be monitored during a subsequent 7-day,
      self-guided iDOT or 7-day self-guided eDOT. Participants will be followed after the iDOT/eDOT
      at weeks 2 (plus/minus 3 working days), 4 (plus/minus 3 working days), 8 (plus/minus 7 days),
      and 12 (plus/minus 7 days), and then every 3 months (plus/minus 2 weeks) for up to 2 years,
      with the option of extending participation longer if there is continued research interest as
      identified by the study team. The same treatment plan may be repeated if a participant fails
      to respond to a new regimen.

      In a select group of subjects who fail to achieve viral suppression, advanced HIV-1 variant
      analysis may be used to attempt to identify the presence of minority drug resistant variants.
      This analysis will be used as supplemental information to construct new regimens for this
      group of participants. Samples of plasma, serum, and peripheral blood mononuclear cells will
      be stored for further evaluation of virologic evolution and other factors that may be
      contributing to treatment failure in this population.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Community sample
      
Keywords: HIV; Treatment Failure; Drug Resistance; Natural History