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Background Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in persons with HIV and can lead to hepatic fibrosis. Integrase strand-transfer inhibitors (INSTIs), first-line agents in antiretroviral therapy (ART), are associated with increased body mass index (BMI), particularly in women living with HIV (WLWH). We evaluated change in hepatic fibrosis risk following INSTI initiation in WLWH. Table 1.Change over time in hepatic fibrosis scores among group switching to INSTI-regimens versus group staying on non-INSTI regimens INSTI=integrase strand-transfer inhibitor; SD=standard deviation; FIB-4=Fibrosis-4 Score (calculated by Age*AST/[platelet count*ALT1/2]; APRI=AST to Platelet Ratio Index (calculated by [AST/AST upper limit of normal]/platelet count); NFS = Non Alcoholic Fatty Liver Disease Fibrosis Score (calculated by -1.675+(0.037*age) + (0.094*body mass index)+(1.13*hyperglycemia or diabetes [yes=1, no=0])+ (0.99*AST/ALT)-(0.013*platelet count)-(0.66*albumin)); CI=Confidence Interval. Linear regression model with unstructured covariance matrix for repeated observations with a person. Adjusted models for all outcomes included the following covariates: age, race/ethnicity, education, baseline CD4 lymphocyte count, baseline antiretroviral anchor drug, and abacavir, tenofovir disoproxil fumarate, and tenofovir alafenamide use. Body mass index was included in models for FIB-4 and APRI only. Age was included for APRI only. Methods Data from 2007-2020 were analyzed from virologically-suppressed WLWH enrolled in the Women’s Interagency HIV Study (WIHS). We excluded WLWH with untreated viral hepatitis, heavy alcohol use and autoimmune or metabolic chronic liver disease. WLWH who switched to or added an INSTI to ART were compared to women who remained on non-INSTI ART. Outcomes included change in noninvasive markers of hepatic fibrosis: Fibrosis-4 (FIB4), AST to Platelet Ratio Index (APRI), and NAFLD fibrosis score (NFS), measured 4-12 months before and 4-19 months post INSTI switch/add. Longitudinal linear regression models compared change over time in each outcome by group, adjusted for covariates. Results 872 WIHS participants (323 INSTI, 549 non-INSTI) were followed for a median 3.0 years (Q1 2.0, Q3 4.5). Mean age was 47.2 years (SD 9.0), 61% were Non-Hispanic Black, and mean BMI was 31.4 (8.8) kg/m2. Absolute mean changes in FIB4, APRI, and NFS scores were +0.021, -0.005, +0.194, respectively, in the INSTI group compared to +0.003, -0.011, +0.016, respectively, in the non-INSTI group (Table 1). No significant differences in mean AST and ALT change between the INSTI and non-INSTI groups were noted. There was a significant increase in NFS score in the INSTI group (p< 0.0001) and this difference remained in adjusted models (p=0.0135). Compared to the non-INSTI group, a larger proportion of participants in the INSTI group changed to a higher NFS risk category: 15.7% vs 9.0%, p=0.014. Conclusion Starting INSTIs was associated with minimal change in FIB4 and APRI scores but increased NFS score in WLWH. The increase in NFS score likely reflects BMI gain with INSTI use, as BMI is not factored into FIB4 or APRI calculators and AST and ALT did not change significantly. Nonetheless, patients starting INSTIs need close monitoring of metabolic changes and low thresholds for additional noninvasive liver fibrosis testing. Disclosures Michael A. Yu, MD, Ligera: Advisor/Consultant Maria L L. Alcaide, MD, Gilead: Advisor/Consultant Adaora A. Adimora, MD, MPH, Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support Jennifer C. Price, MD, PhD, Abbvie: Grant/Research Support|Gilead: Grant/Research Support|Merck: Grant/Research Support Phyllis C. Tien, MD, MSc, Gilead: Grant/Research Support|Merck: Grant/Research Support Cecile D. Lahiri, MD, MS, Theratechnologies: Advisor/Consultant.

BackgroundHuman immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) are associated with bone loss leading to increased fracture rate among persons with HIV (PWH). We previously showed long-acting antiresorptive zoledronic acid (ZOL) prevented ART-induced bone loss through 48 weeks of therapy and here investigate whether protection persisted.MethodsWe randomized 63 nonosteoporotic, treatment-naive adult PWH initiating ART to ZOL (5 mg) versus placebo in a double-blinded, placebo-controlled, phase IIb trial. Here we analyzed the long-term outcome data (144 weeks). Plasma bone turnover markers and bone mineral density (BMD) were quantified at weeks 0, 12, 24, 48, 96, and 144. Primary outcome was change in bone resorption marker C-terminal telopeptide of collagen (CTx). Repeated-measures analyses using mixed linear models were used to estimate and compare study endpoints.ResultsAt 96 weeks, mean CTx was 62% lower with ZOL relative to placebo (n = 46; CTx = 0.123 vs 0.324 ng/mL; P < .001); at 144 weeks a 25% difference between arms was not statistically significant. At 48 weeks, lumbar spine BMD with ZOL was 11% higher than placebo (n = 60; P < .001) and remained 9–11% higher at 96 (n = 46) and 144 (n = 41; P < .001) weeks. 144 weeks after ZOL infusion, BMD did not change at the lumbar spine (P = .22) but declined at the hip (P = .04) and femoral neck (P = .02).ConclusionsA single dose of ZOL administered at ART initiation blunts bone resorption and BMD loss at key fracture-prone anatomical sites in treatment-naive PWH for 3 years. A multicenter randomized phase III clinical trial validating these results in a larger population is needed.Clinical Trials RegistrationNCT01228318.

BACKGROUND Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) are associated with bone loss leading to increased fracture rate among HIV-infected individuals. ART-induced bone loss is most intense within the first 48 weeks of therapy, providing a window for prophylaxis with long-acting antiresorptives. METHODS In a phase 2, double-blind, placebo-controlled trial, we randomized 63 nonosteoporotic, ART-naive adults with HIV initiating ART with atazanavir/ritonavir + tenofovir/emtricitabine to a single zoledronic acid (ZOL) infusion (5 mg) vs placebo to determine the efficacy of ZOL in mitigating ART-induced bone loss. Plasma bone turnover markers and bone mineral density (BMD) were performed at weeks 0, 12, 24, and 48 weeks. Primary outcome was change in C-terminal telopeptide of collagen at 24 weeks. Repeated-measures analyses using mixed linear models were used to estimate and compare study endpoints. RESULTS The ZOL arm had a 65% reduction in bone resorption relative to the placebo arm at 24 weeks (0.117 ng/mL vs 0.338 ng/mL; P < .001). This effect of ZOL occurred as early as 12 weeks (73% reduction; P < .001) and persisted through week 48 (57% reduction; P < .001). The ZOL arm had an 8% higher lumbar spine BMD at 12 weeks relative to the placebo arm (P = .003), and remained 11% higher at 24 and 48 weeks. Similar trends were observed in the hip and femoral neck. CONCLUSIONS A single dose of ZOL administered at ART initiation prevented ART-induced bone loss through the first 48 weeks of ART, the period when ART-induced bone loss is most pronounced. Validation of these results in larger multicenter randomized clinical trials is warranted. CLINICAL TRIALS REGISTRATION NCT01228318.