Characterization and Management of Patients With HIV-1 Infection Who Experience Virologic Failure 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:

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.