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 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.

• INCLUSION CRITERIA:

• Age, greater than or equal to 18 years.
• 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)..
• Established care with an HIV primary care provider.
• Fulfilling one of the following criteria for virologic failure:

• 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

• 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.
• Willingness to have samples stored for future research.
• Willingness to undergo genetic testing.
• Ability and willingness to provide informed consent
• Willingness to be hospitalized for iDOT or record videos of themselves for eDOT.

Exclusion criteria

• HIV RNA levels at screening <1,000 copies/mL.
• 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.
• Pregnancy (if a subject becomes pregnant while enrolled in the protocol, she will continue participation throughout her pregnancy).
• 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.

NOTE: Participants will not be excluded based on stable laboratory abnormalities, hepatitis B virus (HBV) or hepatitis C virus (HCV) co-infection status, etc. Selection of a new ART regimen will account for any co-existing conditions, such as known risks of antiretroviral drugs to the fetus, dosage adjustment due to organ dysfunction, drug interaction potential with concomitant agents, and the need for treatment of HBV co-infection.