Clinical trial NCT03201939: Optimal Management of HIV Infected Adults At Risk for Kidney Complications in Nigeria
Official title: Optimal Management of HIV Infected Adults At Risk for Kidney Complications in Nigeria
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE2
Conditions: HIV/AIDS
Albuminuria
Kidney Diseases
Genetic Predisposition
Keywords: HIV/AIDS
sub-Saharan Africa
Kidney disease
Albuminuria
Genetic risk
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Aminu Kano Teaching Hospital
name: SAIC-Frederick, Inc.
name: Brigham and Women's Hospital
First posted: 2017-06-28
Enrollment: 280
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blind, placebo-controlled RCT
Primary purpose: TREATMENT

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.

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.)

Primary outcomes:
measure: Regression from microalbuminuria (uACR 30-300) to normoalbuminuria (uACR < 30 mg/g) by study arm
timeFrame: 2 years
measure: Progression from microalbuminuria (uACR 30-300) to macroalbuminuria (uACR > 300 mg/g) by study arm
timeFrame: 2 years
measure: Mean change in urinary albumin to creatinine ratio (uACR)
timeFrame: 2 years
Secondary outcomes:
measure: Doubling of serum creatinine from baseline
timeFrame: 2 years
measure: All-cause mortality
timeFrame: 2 years
measure: Proportion experiencing a 40% decline in eGFR
timeFrame: 2 years
measure: Mean change in eGFR over time
timeFrame: 2 years
measure: Change in clinical/performance status as ascertained via World Health Organization Quality of Life HIV (WHOQOL-HIV) scale
timeFrame: baseline, 1 year, 2 years
measure: Change in clinical/performance status as ascertained via Karnofsky Performance Score
timeFrame: baseline, 1 year, 2 years
Other outcomes:
Locations:
city: Kano
country: Nigeria
facility: Aminu Kano Teaching Hospital
Study officials:
affiliation: Vanderbilt University Medical Center
name: C. William Wester, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt University Medical Center
name: Muktar H. Aliyu, MD, DrPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.