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: -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.

Population

Community sample

Brief Title

Study of People With HIV Infection Who Have High Viral Loads Despite Combination Antiretroviral Therapy

Official Title

Characterization and Management of Patients With HIV-1 Infection Who Experience Virologic Failure Despite Combination Antiretroviral Therapy

Brief Summary

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

Outcome Measures

Outcome measures are the tests that investigators perform to prove whether or not a treatment being tested in a clinical trial is having any effect.