In a prospective cohort study of adults cured of chronic hepatitis C virus infection with direct-acting antivirals, investigators observed no significant 18-month changes in bone microarchitecture by HR-pQCT versus uninfected controls, while IL-18 and TNF-α declined in the cured group. The dissociation between inflammatory improvement and bone structure suggests longer follow-up may be needed before structural gains are detectable, underscoring the importance of continued bone risk assessment after cure.
Contagion spoke with study investigator Vincent Lo Re, MD, MSCE, FISPE, in the following email Q&A, and he discusses the dissociation between declines in IL-18 and TNF-α and unchanged HR-pQCT at 18 months, subgroup signals including the impact of HIV coinfection and implications for DXA screening, and next steps such as longer follow-up and additional mechanistic assessments.
Contagion: You found declines in IL-18 and TNF-α after HCV cure without HR-pQCT changes at 18 months. How do you interpret this dissociation, and what time horizon might be needed to see bone effects?
Lo Re: “We speculated that the lack of observed changes at 18 months after DAA initiation may have been due to too short an observation time following cure. The optimal time to examine changes in bone quality after HCV cure is unknown. We examined bone measurements at Month 18 (at least 12 months after cure) because one study evaluating pQCT measures after initiation of Crohn’s disease therapy found that changes in trabecular volumetric BMD and endocortical bone were evident 12 months after treatment initiation (see Thuya M et al. Improvement in biomarkers of bone formation during infliximab therapy in pediatric Crohn's disease: results of the REACH study. Clin Gastroenterol Hepatol 2008; 6(12): 1378-84). However, longer follow-up after HCV cure may be necessary to observe changes in bone microarchitecture and strength and should be pursued in future studies.”
Contagion: Were there subgroup signals (age, sex, cirrhosis, body composition, smoking), and how should clinicians think about DXA/FRAX or other bone health strategies post-cure?
Lo Re: “Our analyses adjusted for age, sex, change in ALMI, change in visceral fat area, and smoking, so we could not stratify on variables we adjusted for."
"However, when evaluating results stratified by HIV status, we observed that participants with cured HCV and no HIV had some improvements in bone microarchitecture, including decrease in radius cortical porosity and increases in radius stiffness and failure load, compared to controls. The radius bone is less subject to mechanical forces of weight-bearing and might be more sensitive to changes in microarchitecture following HCV cure, which may explain why we observed improvements in measurements at the radius but not tibia. These patients also had improvements in cytokines levels, including significant decreases in mean levels of IL-18 and TNF-a over the 18-month observation period. No consistent patterns of improvement in HR-pQCT measurements across the radius and tibia were observed for participants with cured HCV plus HIV infection, and no significant decreases in IL-6, IL-18, or TNF-a were found in this group. It is possible that HIV coinfection might interfere with improvements in bone microarchitecture and mechanical properties following HCV cure. However, these results should be interpreted with caution given the small sample of participants with HIV (n=12)."
"Since BMD by DXA has been shown to be lower in people with chronic HCV than those without HCV infection and because chronic HCV infection is also associated with increased rates of bone fractures, people with chronic HCV, especially those with other risk factors for osteoporosis, may possibly benefit from BMD screening by DXA to identify bone loss.”
Contagion: Could HR-pQCT site choice or study power have limited detection of change, and what are your planned next steps (longer follow-up, bone turnover markers, mediation analyses)?
Lo Re: “We did not believe the site of evaluation could have limited our detetion of changes. Assessment of bone microarchitecture by HR-pQCT provides more accurate quantification of trabecular and cortical structure than DXA or conventional pQCT, and we examined two sites (radius [a non-weight-bearing bone], tibia [a weight-bearing bone]). We also measured bone mechanical properties, including axial stiffness and failure load using micro-finite element analysis, at both bone sites.
Regarding the sample size, we aimed to include 100 participants (50 per group) to have sufficient power to detect group differences in Month 0-18 changes in bone measurements and cytokines, but we experienced larger than anticipated withdrawals from each group due to the reasons specified in Figure 1 of the manuscript."
What You Need To Know
After DAA cure, IL-18 and TNF-α decreased, but HR-pQCT did not show structural bone changes at 18 months compared with controls.
Signals of improvement at the radius were observed among cured HCV participants without HIV, while no consistent HR-pQCT or cytokine improvements were seen among those with HIV coinfection.
Clinicians should continue standard bone risk assessment and consider DXA in patients with chronic HCV, particularly when other osteoporosis risk factors are present.
"We are discussing additional observational studies of longer duration to evaluate for possible changes in bone microarchitecture following HCV cure with DAAs.”
The prospective cohort of 40 adults who initiated DAAs and achieved a cure and 48 uninfected controls. Assessments at baseline and 18 months included HR-pQCT of radius and tibia for volumetric bone mineral density, cortical dimensions, and mechanical properties; whole-body DXA for visceral fat area and appendicular lean mass; and serum TNF-α, IL-6, and IL-18. Multivariable linear regression estimated between-group differences in mean changes, adjusting for age, sex, appendicular lean mass index, visceral fat area, and smoking.
Limitations include a modest sample size and withdrawals, reducing the power to detect change. The 18-month horizon may be insufficient to capture the structural bone improvements that occur after HCV cure. Observational design and residual confounding are possible. Peripheral HR-pQCT sites may not reflect axial skeleton changes.
DAA cure was associated with declines in IL-18 and TNF-α without measurable HR-pQCT gains at 18 months. A longer follow-up is warranted to determine whether inflammatory improvements translate into structural bone benefits, and bone health surveillance should continue after treatment.
Reference
Lo Re V III, Carbonari DM, Newcomb CW, et al. Changes in Bone Microarchitecture and Inflammatory Cytokines after Cure of Chronic Hepatitis C Infection With Direct-Acting Antiviral Therapy. Open Forum Infect Dis. 2025; ofaf571. doi:10.1093/ofid/ofaf571
