Most liver disease in people with HIV in low and middle-income countries is caused by metabolic disorders

Metabolic disorders – including excess weight, obesity and diabetes – are significant causes of liver disease among people with HIV in lower and middle-income countries, while hepatitis B and C play a minimal role, a study published in the Journal of the International AIDS Society has revealed. As liver disease is a leading cause of morbidity and mortality in people living with HIV, these results raise concerns.

It is now established that while the expansion of antiretroviral therapy has increased the life expectancy of people living with HIV worldwide, it has also resulted in a growing burden of non-AIDS-related comorbidities such as cardiovascular and liver disease.

Liver steatosis, or fatty liver disease, is the build-up of excess fat in the liver. Not too problematic at first, it can worsen slowly over time, causing liver inflammation and eventually leading to scarring (fibrosis) and liver failure. It may also lead to cirrhosis (deeper scarring) or liver cancer.

In high-income countries, the prevalence of liver steatosis has increased significantly among people with HIV.  This is due to well-identified risk factors such as hepatitis B, hepatitis C, alcohol use, metabolic disorders and the use of first-generation antiretrovirals. In lower and middle-income countries (LMICs), hepatitis B and C are generally considered to be significant risk factors for liver disease. However, there have been recent contextual changes in these countries. On one hand, HIV medications such as tenofovir that also control hepatitis B and curative hepatitis C treatments are increasingly available. On the other hand, the prevalence of metabolic diseases is increasing in the general population, due to unhealthy changes in diet and less physical activity.

These recent considerations brought Dr Marie Kerbie Plaisy and her colleagues from the IeDEA (International epidemiology Databases to Evaluate AIDS) to estimate the prevalence of liver fibrosis and steatosis, and to look at the contributing role of metabolic disorders on these liver outcomes, among adults living with HIV in LMICs.  

The IeDEA is an international research consortium established in 2006 by the US National Institutes of Health to collect data from over two million people with and at risk for HIV around the world. It recently established the Sentinel Research cohort of people with HIV aged 40 years or older, on antiretroviral therapy for at least six months, and attending one of eight HIV clinics in six predefined IeDEA regions:

• Asia-Pacific (India)
• Central/South America (Brazil, Mexico)
• Central Africa (Rwanda)
• East Africa (Kenya)
• Southern Africa (Zambia)
• West Africa (Côte d’Ivoire, Togo).

Data from participants’ first study visit in 2020 to 2022 were used for this analysis. The researchers collected demographic information (sex, age, etc.), treatment history (nadir CD4 cell count, current and past antiretrovirals), an alcohol use disorder assessment, anthropometry (measures of Body Mass Index, waist and hip circumference), blood pressure measurement and laboratory tests. A Vibration-Controlled Transient Elastography (VCTE) assessment was also performed with Fibroscan – an imagery technique that tells how stiff (fibrosis) and fatty (steatosis) the liver is.  

Overall, 2120 people with HIV were included in the study. The majority were female (56%) with important differences between participating countries: for example, the proportion of women was as high as 71% among participants in Kenya, while it was as low as 29% in Brazil/Mexico.

Median age in the study was 50. Over half of participants were overweight or obese (32% and 19%, respectively). Other main characteristics of participants were as follows:

• A little over half (53%) had dyslipidaemia (abnormal levels of lipids, including cholesterol and triglycerides, in the blood).

• 12% had diabetes, with regional differences (22% in India vs 6% in Kenya).
• 29% had hypertension (as high as 36% in Brazil/Mexico vs 20% in Rwanda).
• 96 participants (5% of the whole cohort) had hepatitis B, ranging from 9% in Côte d’Ivoire to 1% in India.
• 37 participants (2%) had hepatitis C antibodies, indicating current or past infection: 46% of this group had received hepatitis C treatment. Figures ranged from 7% in Brazil/Mexico to 0.5% in India.
• Alcohol use considered as hazardous was found in 255 (12%) participants, with important regional differences, ranging from 26% in Zambia to 2.5% in India.
• Most participants were on effective antiretroviral therapy, although 7% had an unsuppressed viral load, with significant regional differences: 22% in East Africa vs 0.5% in Southern Africa.

Exploration of HIV treatment history revealed that 26% of participants had been on stavudine for a median of 40 months, while 4% had taken didanosine for a median of 25 months. These older antiretrovirals are known to contribute to liver fibrosis and steatosis.

The overall prevalence of liver fibrosis and steatosis was 8% and 28%, respectively, with quite significant regional differences. For instance, in Mexico, the liver fibrosis rate approached 20%, while it was less than 5% in Togo and Kenya. In the meantime, the prevalence of liver steatosis reached almost 60% in Mexico, but around 15% in Togo.

These regional differences do not, however, mitigate the high overall prevalence of both conditions in a cohort representing eight LMICs from six global regions.

The following variables were independently associated with significant liver fibrosis:

• Male sex at birth (OR 1.62, 95% confidence interval 1.10-2.40).
• Excess weight/obesity (OR 2.50, 95% CI 1.46-3.47).
• Elevated liver enzyme AST (OR 1.11, 95% CI 2.54-6.01).
• Past didanosine use for over one year (OR 3.13, 95% CI 1.46-6.49), despite a median time of 20 years since discontinuation.

Hazardous alcohol use, hepatitis B and hepatitis C were not associated with liver fibrosis. Using the population attributable fraction illustrates this well (this is the proportion of cases of a disease in a population that is attributable to a specific risk factor). In this population, 42% of cases of liver fibrosis were attributable to excess weight/obesity and 11% to diabetes, but only 3% of cases were attributable to hepatitis B, 1% to hepatitis C and 1% to hazardous alcohol use.

Factors associated with liver steatosis included excess weight/obesity (OR 4.25, 95% CI 3.29-5.51), diabetes (OR 2.06, 95% CI 1.47-2.88), elevated liver enzyme ALT (OR 1.95, 95% CI 1.39−2.71), prolonged use of stavudine despite a median time of twelve years since discontinuation (OR 1.69, 95% CI 1.27-2.26) and dyslipidaemia (OR 1.68, 95% CI 1.31-2.16).

Discussing the results, the investigators highlight that obesity and diabetes accounted for most of the burden of liver fibrosis, with a minor contribution of hepatitis B and C. According to them, beyond the burden of metabolic disorders in the general population in LMICs, HIV and antiretroviral therapy-related risk factors – diabetes, abnormal lipids, drug liver toxicity – should be considered as contributing to liver steatosis and liver fibrosis.

The significant association between male sex and liver fibrosis is also highlighted. It may be explained by a probable protective effect of oestrogen release in pre-menopausal women against fibrosis, observed in previous research.

The associations between prolonged use of antiretroviral regimens containing didanosine and stavudine with liver fibrosis and steatosis respectively have also been previously reported by studies in high-income countries. Basically, this demonstrates that the liver damage induced by these drugs’ mitochondrial toxicity may persist long after discontinuation.

Finally, the surprising marginal association of viral hepatitis with liver fibrosis and steatosis could be due to the use of tenofovir and lamivudine against hepatitis B, and of hepatitis C treatments, which are nowadays available in most countries included in this cohort.

Plaisy and colleagues advocate for the integration of prevention and care of metabolic risk factors, and the monitoring of liver disease, in people with HIV in resource-limited settings.