Menopause is associated with accelerated liver fibrosis in women with HIV and hepatitis C virus (HCV) co-infection, investigators from the United States report in the online edition of Clinical Infectious Diseases. The study showed that liver damage due to fibrosis – the build-up of scar tissue after cell death caused by HCV-related inflammation – begins to speed up as the menopause takes place.
The researchers say that the findings have important clinical significance, suggesting that peri- and post-menopausal women should be prioritised as candidates for HCV therapy using direct-acting antiviral agents (DAAs) to avoid further liver damage.
“We found that liver fibrosis rates…increased as women transitioned through menopause,” comment the authors. “Importantly, we employed a robust statistical approach to account for potential confounding effects of chronological aging, and evaluated reproductive stages by hormonal confirmation of ovarian reserve. Acceleration of hepatic fibrosis also began during peri-menopausal years, suggesting that women may be at increased risk of liver scarring earlier than suggested by prior data relying on self-reported menopausal age.”
Up to 15% of people with HIV in the United States have co-infection with HCV, at least three times the HCV infection rate seen in the general population. Untreated HIV infection is associated with accelerated HCV-related liver fibrosis. Sex is also a risk factor for fibrosis progression, with men having higher rates than women. This is thought to be because of the protective effects of oestrogen in women, and higher rates of fibrosis have been observed in post-menopausal women.
However, previous research exploring the impact of reproductive ageing on fibrosis progression has been limited by lack of adjustment for chronological ageing and an absence of longitudinal follow-up. Moreover, the relationship between oestrogen and fibrosis progression has not been assessed in HIV-positive women.
Investigators from the Women Interagency HIV Study (WIHS) designed a study involving 405 women with HIV/HCV co-infection who were pre-menopausal at baseline. Progression of menopause and liver fibrosis were monitored longitudinally. To enable the investigators to robustly assess the relationship between reproductive ageing and the progression of liver fibrosis, data were also collected on chronological age, race, alcohol use, metabolic syndrome, HCV viral load and HIV-related factors (CD4 cell count, use of antiretroviral therapy [ART], viral load).
Menopausal status was assessed using serial measures of anti-Müllerian hormone (AMH). The level of AMH indicates the reserve of eggs left in the ovaries. Pre-menopause was defined as the presence of detectable AMH; peri-menopause was defined as the period within five years of AMH becoming undetectable; post-menopause was more than five years after AMH loss.
Fibrosis was assessed using two measures: APRI and FIB-4.The APRI and FIB-4 scales use levels of liver enzymes and platelets to calculate the extent of liver damage.
Median age at baseline was 37 years, and average age at the onset of menopause was 49 years. The majority of women were Hispanic (58%). At the start of the study, 6% had fibrosis stage 3 or above, which increased during follow-up to 32% when assessed using FIB-4 and 20% using APRI. Only 6% of participants reported heavy alcohol use. Most were taking ART (88%), but only 23% received any kind of HCV therapy with just 2% treated with DAAs. Approximately a quarter of participants had a history of diabetes and 11% had ever been diagnosed with metabolic syndrome.
Median follow-up was 9.1 years, and a fifth of women took some form of hormone replacement therapy during this period.
After taking into account chronological age, the investigators found that fibrosis was accelerated during peri-menopause compared to pre-menopause using FIB-4 (0.12 units/year faster; 95% CI, 0.02-0.21; p = 0.001) and APRI (0.05- units/year after; 95% CI 0.002-0.09; p = 0.06). Faster fibrosis progression was also present post-menopause compared to pre-menopause, though the difference was short of statistical significance for both FIB-4 (p = 0.07) and APRI (p = 0.06).
After adjustment for other potential confounders including Hispanic ethnicity, ART use and alcohol consumption, peri-menopause continued to be associated with accelerated fibrosis (0.10 FIB-4 units/year after vs pre-menopause; 95% CI, 0.008-0.20; p = 0.034).
“The current study represents an important advance in our understanding of the effects of reproductive ageing on liver fibrosis by highlighting the accelerated fibrosis that begins as early as pre-menopausal years,” comment the researchers. “Using AMH as a gold standard measurement of ovarian reserve we were able to evaluate each woman’s fibrosis rate as she transitioned across reproductive stage.”
The authors conclude that fibrosis progression in women with HIV/HCV co-infection accelerates with reproductive age, independent of chronological age. “Accelerated fibrosis began in peri-menopausal years, highlighting a previously unrecognized group of women at increased risk of progressive fibrosis and associated complications,” they note. “Similar analyses using serial measures of fibrosis should be conducted in non-HCV related liver diseases, including women without HIV infection, given potential implications of ovarian reserve on fibrosis progression in women with a broad spectrum of liver diseases.”
Sarkar M et al. Reproductive aging and hepatic fibrosis progression in HIV/hepatitis C virus co-infected women. Clin Infect Dis, online edition, 2017.