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

NCT ID: NCT03201939

Last Updated: 2025-06-26

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 66 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-04-01
• Study Completion Date: 2025-02-01

Brief Summary

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.

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.

Conditions

HIV/AIDS; Albuminuria; Kidney Diseases; Genetic Predisposition

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Active Medication (Intervention arm)

ACE-inhibitor lisinopril

Group Type: ACTIVE_COMPARATOR

Lisinopril

Intervention Type: DRUG

ACE-inhibitor (lisinopril)(intervention arm

Placebo comparator (Control arm)

Matched placebo

Group Type: PLACEBO_COMPARATOR

Placebo Oral Tablet

Intervention Type: OTHER

Comparator placebo (control arm)

Interventions

Lisinopril

ACE-inhibitor (lisinopril)(intervention arm

Intervention Type: DRUG

Placebo Oral Tablet

Comparator placebo (control arm)

Intervention Type: OTHER

Other Intervention Names

Intervention arm; Control arm

Eligibility Criteria

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.)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Aminu Kano Teaching Hospital

OTHER

Sponsor Role: collaborator

SAIC-Frederick, Inc.

INDUSTRY

Sponsor Role: collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

C. William Wester

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

C. William Wester, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Muktar H. Aliyu, MD, DrPH

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

Aminu Kano Teaching Hospital

Kano, , Nigeria

Countries

Nigeria

References

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.

Reference Type: BACKGROUND

PMID: 33901548 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 31182139 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

U01DK112271

Identifier Type: NIH

Identifier Source: secondary_id

View Link

Vanderbilt_University MC

Identifier Type: -

Identifier Source: org_study_id