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

Study Overview
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Brief Summary
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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
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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: 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. 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 To determine whether the APOL1 HR genotype is associated with worse longitudinal renal outcomes in Nigerians with prevalent albuminuria.

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

Conditions
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HIV/AIDS, Albuminuria, Kidney Diseases, Genetic Predisposition

Intervention / Treatment
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* Drug: Lisinopril
* Other: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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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.)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind, placebo-controlled RCT
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV/AIDS, sub-Saharan Africa, Kidney disease, Albuminuria, Genetic risk