Early HIV Therapy in Patients With High CD4 Cell Counts (EARLI)

Early Antiretroviral Therapy in Resource Limited Settings in Patients With High CD4+ Cell Counts (EARLI)

A study of antiretroviral therapy (ART) initiation under a "streamlined model of care" in HIV-positive patients with CD4+ cell counts greater ≥ 250 cells/uL

Study Overview

• Status: Completed
• Conditions: HIV
• Intervention / Treatment: Drug: Standard ART; Drug: Study-Provided ART

Detailed Description

After dramatic progress in recent years, HIV care for patients in resource limited settings is rapidly evolving to newer models of care delivery. Governments, non-governmental organizations and charitable foundations are placing increasing scrutiny on the programmatic costs associated with delivering antiretroviral therapy (ART). Given these realities, if the global ART roll-out is to continue successfully, we must develop innovative new ways of providing HIV care and ART that are more efficient, more cost-effective, and tightly integrated within country-level health systems. We must treat more patients with fewer resources, and we need sustainable simple models for ART delivery.

These goals can be accomplished building on several existing knowledge points. First, initiating ART at earlier disease stages and at higher CD4+ cell counts may prevent irreversible immunologic damage, prevent opportunistic infections and non-AIDS-associated morbidities, and may prevent death. International and national HIV policy bodies have increasingly recognized this and adjusted recommendations in this direction. Second, ART initiation at higher CD4+ cell counts is less complex, triggers fewer complications, and is less costly to healthcare systems. Third, patients responding to therapy and doing well require fewer physician-administered follow-up visits. This can allow for "task-shifting" to non-MD providers, and the establishment of tiered healthcare delivery down the spectrum of medical acuity. Fourth, the lack of viral load monitoring is responsible for major structural problems in how we deliver ART, causing delays in recognizing ART failure, preventing clinicians from diagnosing HIV drug resistance, and making the decision to switch a patient to a new ART regimen very error-prone.

The EARLI study is a pilot study that will address and investigate all of the above critical issues. This study will focus exclusively on asymptomatic patients with CD4 cell counts ≥250 cells/uL. These relatively healthier individuals are well suited to a more streamlined approach to ART delivery and healthcare provision.

Primary Objectives:

A. To evaluate the 48 week efficacy of ART initiated in asymptomatic individuals with high CD4+ cell counts (CD4+ > 250 cells/uL) and provided in a "streamlined" mode of care.

B. To evaluate the programmatic costs of streamlined ART delivery to asymptomatic high CD4+ count individuals.

Secondary Objectives:

A. To evaluate the 96 week efficacy of ART initiated in high CD4+ cell count individuals.

B. To identify predictors of retention in care among high CD4+ cell count ART initiators.

C. To assess adverse events among high CD4+ cell count ART initiators.

D. To assess medication adherence among high CD4+ cell count ART initiators.

• Study Type: Interventional
• Enrollment (Actual): 279
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Uganda
  • Mbarara district
    • Bwizibwera, Mbarara district, Uganda
      • Bwizibwera Level IV Health Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• HIV-1 infection diagnosed by a rapid HIV test or any licensed ELISA test kit and documented in the participant's medical chart and re-verified at the time of study screening (hereafter: "screen date").
• Most recent CD4+ cell count ≥ 250 cells/uL:

Arm A: CD4+ cell count 250-350 cells/uL Arm B: CD4+ cell count >350 cells/uL

• Age ≥ 18 years.
• Residence within a 30 kilometer radius of the Bwizibwera HC-IV.
• Willing to initiate ART if the CD4+ cell count is ≥ 350 cells/uL.

• The following laboratory values obtained at the screening visit:

  • Absolute neutrophil count (ANC) ≥ 500 cells/uL
  • Hemoglobin ≥ 7.0 g/dL
  • Platelet count ≥ 50,000/uL
  • ALT (SGPT) ≤ 5 times greater than the upper limit of normal
  • Estimated glomerular filtration rate (eGFR) of ≥ 60 mL/minute by the Modification of Diet in Renal Disease (MDRD) formula:

eGFR = 186 * Serum creatinine-1.154 * Age-0.203 * [1.21 if African] * [0.742 if female]

• Ability to swallow oral medications.
• Ability and willingness of participant to give informed written consent.

Exclusion Criteria:

• Receipt at any time prior to study entry of > 7 days cumulative treatment with any ARV or combination of ARVs, except ARVs taken for any length of time during pregnancy for the prevention of mother to child transmission (pMTCT) or ARVs taken for occupational exposure.
• For Arm B participants only: allergy/sensitivity to TDF, FTC, EFV, RTV, LPV or formulations of any of these three medications, or to co-formulated Truvada®.
• Active World Health Organization (WHO) HIV stage 3 or 4 illness
• Pregnancy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Arm A; Treatment for HIV in participants with CD4+ cell counts 250-350 cells/uL	Drug: Standard ART; Standard Ugandan 3-drug antiretroviral therapy regimen consistent with current practices
ACTIVE_COMPARATOR: Arm B; Treatment for HIV in participants with CD4+ cell counts >350 cells/uL	Drug: Study-Provided ART; Study provided drugs: Truvada® (one tablet PO daily of fixed dose combination consisting of tenofovir disoproxyl fumarate [TDF] and emtricitabine [FTC]) PLUS; Efavirenz [EFV]; Other Names: 1) FTC/TDF; 2) Sustiva®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
48-Week Efficacy	Proportion of patients with virologic suppression (HIV-1 plasma RNA ≤400 copies/cc) at 48 weeks, stratified by study arm.	When all participants reach 48 weeks on study
Programmatic Costs	Total estimated costs of provider time, medications, diagnostic testing, and healthcare facility infrastructure per patient treated with ART for one year, stratified by study arm	When all participants reach 48 weeks on study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
96-Week and 144-Week Efficacy	Proportion of patients with virologic suppression (HIV-1 plasma RNA ≤400 copies/cc) at 96 and 144 weeks, stratified by study arm.	When all particiants reach 96 and 144 weeks on study, respectively
Predictors of Retention in Care	Factors statistically significantly associated with attendance at all scheduled clinical visits throughout the first 48 weeks of ART, and throughout the full 144 week study period, stratified by study arm.	When all participants reach 48 weeks on study, then again 144 weeks on study
Adverse Event Rates	Describe grade 3 or 4 toxicities (defined by NIH DAIDS scale) that occur throughout the first 48 weeks of ART, and throughout the full 144 week study period, stratified by study arm. These will be assessed by active and passive ascertainment and clinical verification, stratified by study arm.	When all participants reach 48 weeks on study, then again at 144 weeks
Medication Adherence	Proportion of total medication doses taken by patients at 48 weeks, assessed by pharmacy refill records, stratified by study arm.	When all participants reach 48 weeks on study

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Makerere University; Infectious Diseases Research Collaboration, Uganda; Makerere University Joint AIDS Program
• Investigators: Study Chair: Diane Havlir, MD, University of California, San Francisco, San Francisco, CA, USA; Principal Investigator: Vivek Jain, MD, University of California, San Francisco, San Francisco, CA, USA; Principal Investigator: Moses Kamya, MBChB, MMed, PhD, Makerere University School of Medicine, Kampala, Uganda

Publications and helpful links

General Publications

• Jain V, Byonanebye DM, Amanyire G, Kwarisiima D, Black D, Kabami J, Chamie G, Clark TD, Rooney JF, Charlebois ED, Kamya MR, Havlir DV; SEARCH Collaboration. Successful antiretroviral therapy delivery and retention in care among asymptomatic individuals with high CD4+ T-cell counts above 350 cells/mul in rural Uganda. AIDS. 2014 Sep 24;28(15):2241-9. doi: 10.1097/QAD.0000000000000401.
• Jain V, Chang W, Byonanebye DM, Owaraganise A, Twinomuhwezi E, Amanyire G, Black D, Marseille E, Kamya MR, Havlir DV, Kahn JG. Estimated Costs for Delivery of HIV Antiretroviral Therapy to Individuals with CD4+ T-Cell Counts >350 cells/uL in Rural Uganda. PLoS One. 2015 Dec 3;10(12):e0143433. doi: 10.1371/journal.pone.0143433. eCollection 2015.

Helpful Links

• MU-UCSF Research Collaboration website

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (ACTUAL): June 1, 2015
• Study Completion (ACTUAL): June 1, 2015

Study Registration Dates

• First Submitted: November 22, 2011
• First Submitted That Met QC Criteria: November 22, 2011
• First Posted (ESTIMATE): November 24, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): March 4, 2016
• Last Update Submitted That Met QC Criteria: March 3, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: HIV; ART
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Efavirenz
• Other Study ID Numbers: EARLI