Optimal Management of HIV Infected Adults at Risk for Kidney Complications in Nigeria

In this study, the Investigators plan to determine the optimal means to prevent or slow the progression of kidney disease among genetically at-risk northern Nigerian HIV-infected adults. Based on data from studies of diabetic kidney disease that used medications that block the renin angiotensin aldosterone system (RAAS), we plan to evaluate whether or not RAAS inhibition (using a widely available medication that blocks RAAS) in HIV-infected adults produces similarly promising results.

Study Overview

• Status: Suspended
• Conditions: Kidney Diseases; HIV/AIDS; Albuminuria; Genetic Predisposition
• Intervention / Treatment: Drug: Lisinopril; Other: Placebo Oral Tablet

Detailed Description

Individuals of African descent have a much higher risk for glomerular diseases. Specifically, there are two risk variants in the chromosome 22 APOL1 gene (G1/G2) and persons possessing 2 copies of these risk variants (G1/G1, G1/G2, or G2/G2), referred to as the high-risk (HR) genotype, are at high risk for non-diabetic kidney disease. Kopp et al. have shown that the APOL1 high-risk genotype confers sizeable odds ratios (OR) for FSGS (OR = 17), HIVAN (OR = 29 in the US; 89 in S. Africa), and hypertension-attributed end stage kidney disease (OR = 7). The presence of these risk variants is highest in West Africa, and specifically in Nigeria among persons of Hausa, Fulani, and Igbo descent. In the setting of untreated HIV infection, we have estimated that ~50% of individuals carrying the APOL1 HR genotype will develop chronic kidney disease (CKD). However, there is limited availability of dialysis and kidney transplantation in Nigeria, and most individuals will die soon after developing ESKD. Markers of kidney disease include microalbuminuria, proteinuria, and/or reduced estimated glomerular filtration rate (eGFR). All 3 have been associated with increased mortality in HIV+ adults. Increased urinary albumin excretion has diagnostic and prognostic value in the identification and confirmation of renal disease, and changes in albuminuria can be useful in assessing treatment efficacy as well as disease progression. Microalbuminuria, i.e., urine albumin to creatinine ratio (uACR) in the 30-300 mg/g range, is likely the earliest stage of CKD, analogous to diabetic microalbuminuria. The renin-angiotensin aldosterone system (RAAS) is the central player in the pathophysiology of CKD and blocking RAAS with angiotensin converting enzyme inhibitors (ACEi) is a well-recognized strategy to slow or halt renal disease progression in diabetics with CKD. To determine whether the presence of APOL1 HR genotype alters or predicts responsiveness to conventional therapy and if the addition of an ACEi to standard antiretroviral therapy (ART) reduces the risk for renal complications among West African adults, we will screen 2,600 HIV+ ART-experienced adults; to conduct the following Specific Aims:

1. To determine the prevalence of APOL1 renal risk variants and assess whether APOL1 HR status correlates with prevalent albuminuria, eGFR, and/or prevalent CKD in a West African population.
2. To assess whether RAAS inhibition (with the ACEi lisinopril) in addition to ART, compared to the existing standard-of-care (SOC), will significantly reduce the incidence of additional kidney disease manifestations. We will randomize ART-experienced (6+ months) adults with prevalent microalbuminuria (uACR 30-300 mg/g) and an eGFR of > 30 ml/min/1.73m2 to lisinopril (n=140) vs. SOC (n=140); and
3. To determine whether the APOL1 HR genotype is associated with worse longitudinal renal outcomes in Nigerians with prevalent albuminuria.

• Study Type: Interventional
• Enrollment (Estimated): 280
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: C. William Wester, MD, MPH; Phone Number: +001-615-875-0145; Email: william.wester@vumc.org
• Study Contact Backup: Name: Usman J. Wudil, MPH; Phone Number: +001-615-875-8314; Email: usman.j.wudil@vumc.org

Study Locations

• Nigeria
  • Kano, Nigeria
    • Aminu Kano Teaching Hospital
    • Contact: Baba M Musa, MBBS, MPH; Phone Number: +234-803-347-2311; Email: babamaiyaki2000@yahoo.co.uk
    • Contact: Faisal S. Danikshiya, MBBS; Phone Number: 234-806-129-7871; Email: fdankishiya@yahoo.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion criteria:

• Participated in Study Aim 1
• 18-70 years of age
• HIV-positive (as documented by HIV-1 ELISA testing)
• On ART for a minimum of six (6) months AND having a suppressed plasma viral load result (< 20 copies/mL) within the past 6 months
• Average uACR between 30-300 mg/g (based on 2 uACRs [first morning voids], with the second obtained 4-8 weeks after the first specimen)(NOTE: All aim 1 screened patients having a uACR value > 300 mg/g will undergo urine dipstick analysis for aim 2 eligibility, and if their urine dipstick results reveals ≥ 2+ protein, then they will be considered ineligible (no additional uACR testing will be necessary to determine eligibility)
• eGFR = >60 ml/min/1.73m2 (using CKD-EPI-Cr-CyC equation) AND
• If female, non-pregnant (documentation of negative urine pregnancy test) and not breastfeeding/lactating

Exclusion criteria:

• Pregnant or currently breastfeeding
• eGFR of <60 ml/min/1.73m2 (using CKD-EPI-Cr-CyC equation)
• Average uACR > 300 mg/g (based on 2 uACRs [first morning voids], with the second obtained 4-8 weeks after the first specimen)
• K+ >5.0 meEq/L or reasons to be concerned about hyperkalemia
• Known history of Diabetes diabetes mellitus (would qualify for treatment with an ACEi/ARB)
• Poorly controlled hypertension (≥3 BP readings >160/110 in past 3 6 months)
• Known history of Congestive congestive heart failure (chronic)
• Average uACR (calculated on values obtained from 2 successive measures 4-8 weeks apart) of < 30 mg/g OR > 300 mg/g
• Relative symptomatic hypotension (BP <90/60)
• Currently receiving an ACEi and/or ARB; OR
• Lack of suitability as a study candidate (i.e. active substance use disorder, active use of potentially nephrotoxic medication(s) (i.e. traditional medicines, etc.) and/or consistent alcohol, drug, and/or traditional medication use, and/or history of poor compliance (i.e. multiple missed scheduled clinic appointments, etc.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active Medication (Intervention arm); ACE-inhibitor lisinopril	Drug: Lisinopril; ACE-inhibitor (lisinopril)(intervention arm; Other Names: Intervention arm
Placebo Comparator: Placebo comparator (Control arm); Matched placebo	Other: Placebo Oral Tablet; Comparator placebo (control arm); Other Names: Control arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Regression from microalbuminuria (uACR 30-300) to normoalbuminuria (uACR < 30 mg/g) by study arm	Reduction/improvement in degree/grade of albuminuria	2 years
Progression from microalbuminuria (uACR 30-300) to macroalbuminuria (uACR > 300 mg/g) by study arm	Progression/worsening in degree/grade of albuminuria	2 years
Mean change in urinary albumin to creatinine ratio (uACR)	Mean change in urinary albumin excretion	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Doubling of serum creatinine from baseline	Worsening renal function (as measured by serum creatinine)	2 years
All-cause mortality	Survival	2 years
Proportion experiencing a 40% decline in eGFR	Proportion with 40% decline in eGFR (measured using CKD-EPI-Cr-CyC equation)	2 years
Mean change in eGFR over time	Mean change in eGFR (measured using CKD-EPI-Cr-CyC equation)	2 years
Change in clinical/performance status as ascertained via World Health Organization Quality of Life HIV (WHOQOL-HIV) scale	WHOQOL-HIV scale evaluates quality of life based on physical, psychological, social, environmental, and spiritual domains, as well as level of independence. We will use the 31-question version, with each question rated on a 5-point Likert scale. Scores of questions within each domain are averaged to get domain score, and final score is mean of domain scores multiplied by 4. Final score ranges from 4 to 20, with 20 being optimal.	baseline, 1 year, 2 years
Change in clinical/performance status as ascertained via Karnofsky Performance Score	Karnofsky Performance Score measures change in clinical/performance status with values ranging from 0 to 100, where 100 is perfect health and 0 is death.	baseline, 1 year, 2 years

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Brigham and Women's Hospital; Aminu Kano Teaching Hospital; SAIC-Frederick, Inc.
• Investigators: Principal Investigator: C. William Wester, MD, MPH, Vanderbilt University Medical Center; Principal Investigator: Muktar H. Aliyu, MD, DrPH, Vanderbilt University Medical Center

Publications and helpful links

General Publications

• Wudil UJ, Aliyu MH, Prigmore HL, Ingles DJ, Ahonkhai AA, Musa BM, Muhammad H, Sani MU, Nalado AM, Abdu A, Abdussalam K, Shepherd BE, Dankishiya FS, Burgner AM, Ikizler TA, Wyatt CM, Kopp JB, Kimmel PL, Winkler CA, Wester CW. Apolipoprotein-1 risk variants and associated kidney phenotypes in an adult HIV cohort in Nigeria. Kidney Int. 2021 Jul;100(1):146-154. doi: 10.1016/j.kint.2021.03.038. Epub 2021 Apr 24.
• Aliyu MH, Wudil UJ, Ingles DJ, Shepherd BE, Gong W, Musa BM, Muhammad H, Sani MU, Abdu A, Nalado AM, Atanda A, Ahonkhai AA, Ikizler TA, Winkler CA, Kopp JB, Kimmel PL, Wester CW. Optimal management of HIV- positive adults at risk for kidney disease in Nigeria (Renal Risk Reduction "R3" Trial): protocol and study design. Trials. 2019 Jun 10;20(1):341. doi: 10.1186/s13063-019-3436-y.

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2024
• Primary Completion (Estimated): February 1, 2025
• Study Completion (Estimated): February 1, 2025

Study Registration Dates

• First Submitted: June 22, 2017
• First Submitted That Met QC Criteria: June 26, 2017
• First Posted (Actual): June 28, 2017

Study Record Updates

• Last Update Posted (Actual): April 16, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Albuminuria; HIV/AIDS; sub-Saharan Africa; Kidney disease; Genetic risk
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Urologic Diseases; Urological Manifestations; Disease Attributes; Urination Disorders; Slow Virus Diseases; Proteinuria; Disease Susceptibility; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases; HIV Infections; Kidney Diseases; Acquired Immunodeficiency Syndrome; Albuminuria; Genetic Predisposition to Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Protective Agents; Cardiotonic Agents; Angiotensin-Converting Enzyme Inhibitors; Lisinopril
• Other Study ID Numbers: Vanderbilt_University MC; U01DK112271 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Investigative team will work with study biostatisticians, DSMB members, and collaborators to release analysis scripts (with publications) and devise an IPD sharing plan at/near study completion.
• IPD Sharing Time Frame: Approximately 6 months after collection of the final patient data.
• IPD Sharing Access Criteria: Deidentified data will be available after the conclusion of the study for investigators who are approved by the trial leadership at VUMC, AKTH, and NIH.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No