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

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:

- 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

- 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 subjects enrolled in this protocol,
nonadherence, 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, inpatient,
selfguided directly observed therapy (DOT) on HIV RNA kinetics, when subjects will receive
their pre-enrollment ART regimens. During the DOT period, subjects will request their
antiretroviral 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. Adherence and psychosocial assessments will also be performed. Plasma concentrations
from at least one of the antiretroviral drugs in the regimen will be measured on the first
and last day of DOT 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 DOT (post-DOT 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 AEs, and psychosocial barriers). The team will then
design a new, individualized treatment plan for each subject. Subjects will either continue
on their pre-enrollment ART regimen, or they will receive a new, individually tailored
regimen. Only FDA-approved therapeutic agents will be offered on this protocol. Subjects may
be co-enrolled in an experimental protocol for optimal management of HIV disease, if one is
available and eligibility criteria are met. New regimens will be monitored during a second
7-day, inpatient, self-guided DOT. Subjects will be followed after the DOT at week 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 necessary. The same treatment plan may be
repeated if a subject 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 subjects. 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.

- INCLUSION CRITERIA:

1. Age, greater than or equal to 14 years.

2. Documented HIV-1 infection (prior written documentation such as positive standard
ELISA or rapid HIV-1/HIV-2 antibody test with confirmatory Western Blot, or
documentation of repeated HIV RNA of greater than 1,000 copies/mL)..

3. Established care with an HIV primary care provider.

4. Fulfilling one of the following criteria for virologic failure:

1. Documented virologic failure on at least 1 prior ART regimen and at least 2
consecutive HIV RNA plasma measurements of greater than 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 greater than 1,000 copies/mL for greater
than 6 months) despite multiple regimen changes, regardless of how long the
subject has been prescribed his or her current regimen.

5. Willingness to have samples stored for future research.

6. Willingness to undergo genetic testing.

7. Ability and willingness to provide informed consent and be hospitalized for the
inpatient DOT.

EXCLUSION CRITERIA:

1. HIV RNA levels at screening <1,000 copies/mL.

2. Receiving medical care for an acute medical illness stemming from a significant
comorbidity; enrollment may be deferred or postponed until the condition resolves or
stabilizes.

3. Pregnancy (if a subject becomes pregnant while enrolled in the protocol, she will
continue participation throughout her pregnancy).

4. Any illness or condition that, in the investigator s opinion, may substantially
increase the risk associated with the subject s participation in the study, or may
compromise the scientific objectives.