CROI 2022: Risk factors for NAFLD and proteinuria in HIV positive people on ART
REPRIEVE is a large international clinical study of cardiovascular disease (CVD) risk factors in people with HIV (PWH). Participants were randomised to daily statins or placebo. A sub-study recently reported increased ECG abnormalities for 44% of participants. 
Two further REPRIEVE sub-studies that assessed non-alcoholic fatty liver disease (NAFLD) and proteinuria were presented at CROI 2022.
NAFLD was identified in 20% of sub-study participants. Risk factors for NAFLD were BMI >30 kg/m2, metabolic syndrome and being male. 
Relative risk of kidney disease was elevated in women, living in lower income countries, hypertension and TDF use. 
The double-blind REPRIEVE trial (NCT02344290) enrolled 7,770 people living with HIV on ART, aged between 40 to 75 years. Participants were randomised to daily pitavastatin (4 mg QD) or placebo.
Several sub-studies are embedded within the trial to evaluate CVD risk.
NAFLD reported for 1 in 5 participants in sub-study
NAFLD is common in people living with HIV and associated with increased CVD risk. Data from the mechanistic sub-study reported risk factors for NAFLD and inflammatory markers. 
Participants undergoing non-contrast CT scans were included in the study (n=655).
Clinical criteria for NAFLD were hepatic steatosis <40 HU or liver to spleen ratio <1.0. Steatosis was recorded in 21% of participants (139/655). Exclusion of participants that reported drinking >1 to 2 units per day, led to NAFLD diagnosis for 1 in 5 participants (97/477).
Participants in the NAFLD group were male (82%) and aged >40. Ethnicity was White (63%), Black or African American (20%), Hispanic or Latinx (34%).
BMI was 25 to 29.9 kg/m2 in 42% of participants and >30 kg/m2 in 45%; 51% had elevated waist circumference.
Average ASCVD risk scores in the NAFLD group were 5.8 (95% CI: 3.3 to 7.7, p=0.002). Scores indicated borderline or intermediate risk of atherosclerotic disease in 60% of participants.
The NAFLD group also had elevated liver enzymes (ALT; 45% vs 25%, p=0.001) and were more likely to have history of an AIDS-defining event.
NAFLD risk factors were BMI >30 kg/m2 (RR: 1.76; 95% CI: 1.21 to 2.57) and metabolic syndrome (RR: 1.56, 95% CI: 1.06 to 2.30), whilst females had reduced risk (RR: 0.47, 95% CI: 0.26 to 0.86).
Time since HIV diagnosis, CD4 count, CD4 nadir and viral load were not predictors of NAFLD risk.
Markers of arterial disease (LpPLA-2) and general inflammation (CRP) were modestly elevated in the NAFLD group but remained within the normal range.
NAFLD was not associated with ART or HIV-specific measures.
NAFLD or MAFLD?
Guaraldi and colleagues presented data from two cross-sectional studies showing a significant overlap of NAFLD and MAFLD (metabolic dysfunction-associated fatty liver disease) in HIV positive participants. 
MAFLD is emerging as a more sensitive criteria for liver disease than NAFLD. 
Uptake of MAFLD criteria may therefore lead to earlier detection of liver disease in the HIV population.
Women over 50 with previous TDF use have increased chance of proteinuria
People living with HIV have a greater chance of chronic kidney disease, compared to HIV negative people.
Risk factors for kidney disease (proteinuria and albuminuria) are being evaluated in the REPRIEVE kidney ancillary sub-study are assessing risk factors for kidney disease. 
Participants were split into three groups by proteinuria: normal to mildly increased (n=1963), moderately increased (n=655) or severely increased (n=74). Participants were women (38%) and median age was 49 years (IQR: 44 to 54). Ethnicity was Black (48%), White (31%) and Asian (17%). Viral load was <400 copies/mL (98%) and CD4 counts ranged from 443 to 629 cells/mm3.
Risk factors for kidney disease were being female (RR: 1.71, 95%CI: 1.42 to 2.05), aged over 50 (RR: 1.28, 95% CI: 1.06 to 1.78), current smoker (RR: 1.34, 95% CI: 1.12 to 1.61) and history of TDF use (RR: 1.90, 95% CI: 1.43 to 2.67).
Reduced risk of proteinuria was noted in Black participants and those with BMI <25 kg/m2.
Albuminuria was less common (9% of participants) and was associated with hypertension (RR: 1.56, 95% CI: 1.20 to 2.04). Participants on thymidine analogues had reduced risk (RR: 0.42, 95% CI: 0.19 to 0.97).
Kidney disease was more common in participants recruited from lower income regions (e.g., sub-Saharan Africa and East Asia). This difference may be due to reduced access to prevention services and other factors not covered by this study.
In summary, REPRIEVE sub-study data indicate associations between NAFLD and increased BMI, metabolic dysfunction, and male sex. Kidney disease was more common in women aged over 50 with history of TDF use.
These data highlight CVD risk factors but have not been adjusted for statin use. It will be important to determine whether these associations persist in the unblinded datasets.
Dr Overton answered questions from Drs Hunt, Mallon and Kallianpur during the poster discussion. Their exchanges highlighted that higher, but non-significant, rates of kidney disease reported from lower income countries may be related to reduced access to treatment and prevention services.
Associations between women and kidney disease may partly be explained by higher numbers of female participants from lower income countries.
Finally, reduced risk of albuminuria with thymidine analogues may be related to PWH that did not experience side effects and were not switched onto alternatives, such as TDF.
A patient leaflet on NAFLD and HIV is available from i-Base. 
- Collins S. ECG abnormalities reported by 44% of people older than 40 on ART: results from REPRIEVE study. (HTB 20 December 2021).
- Fichtenbaum CJ. NAFLD is common and associated with cardiovascular risk in REPRIEVE participants. CROI 2022. 12-16 February 2022, virtual. Poster 520.
- Overton ET. Proteinuria is common among people with HIV with controlled viremia. CROI 2022. 12-16 February 2022, virtual. Poster 607.
- Guaraldi G. From NAFLD to MAFLD: implications of change in terminology for people with HIV. CROI 2022. 12-16 February 2022, virtual. Poster 521
- Yamamura S. MAFLD identifies patients with significant hepatic fibrosis better than NAFLD. Liver International, Vol 40 (12) (3018-3030). DOI:10.1111/liv.14675 (30 September 2020).
- i-Base. NAFLD: HIV and fatty liver disease. (September 2019).
This report was first published on 17 March 2022.