DSMB recommendations, laboratory quality control (QC) issues. All lab Q/C issues addressed; DSMB approved study re-opening, but due to length of time required to address lab QC issues, insufficient follow-up time was available to complete study.

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.

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.

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.)

Both males and females eligible

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.

Approximately 6 months after collection of the final patient data.

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.

AE data was collected over 7 months; NOTE: AE data planned to be collected among all study participants for the full 2 years of study follow-up, but study was suspended early due to identified laboratory quality issues (per DSMB) and once these lab QA/QC issues were rectified, there was insufficient time to follow all study participants for full, specified duration of follow-up; therefore the study was terminated.

The primary limitation of this study was laboratory quality control (QC) issues. While all QC concerns were addressed, the time required to resolve them led to a delay in the study. Although the Data and Safety Monitoring Board (DSMB) approved the study's re-opening, the extended resolution period resulted in insufficient follow-up time to complete the study as originally planned

Double-blind, placebo-controlled RCT