People in South Africa who fall ill with tuberculosis (TB) often also have other health issues. HIV, which drives much of the TB epidemic in South Africa, is the most obvious co-infection, but people who fall ill with TB are also more likely to have diabetes and mental health problems than the general public.
Another issue that is often mentioned at conferences and in journal articles, but that doesn't often make the headlines, is the complex set of links between TB and liver problems. With the World Health Organization estimating that in the region of 300 000 people fall ill with TB in South Africa every year, the scale of the issue is likely to be substantial, although we do not have particularly good data on liver problems in South Africa, and even less so on people experiencing TB and liver problems together.
Complex interactions
Broadly speaking, the link between TB and the liver can be divided into two categories. First, there are the liver-related side effects of some TB treatments, and second, there is the interaction between TB and liver conditions such as viral hepatitis. In some cases, TB itself can also cause liver problems directly.
Start with hepatitis. Dr Louisa Dunn, Think TB Provincial TB Technical Lead in KwaZulu-Natal, explains that hepatitis is a general term meaning inflammation of the liver. She says that there are many causes of hepatitis, such as infections, alcohol, or an overdose of certain medications. There is also autoimmune hepatitis, where a person's own immune system is attacking the liver. "Even lifestyle can cause inflammation in the liver from a build-up of fatty tissue, which is more common in people who are overweight and obese," she says.
Infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) are thought to cause significant illness and death in South Africa. According to a study published in 2022, over 1.9 million people in South Africa are living with chronic HBV infection - earlier research put the number at 3.5 million. HBV can be treated and there is an effective childhood vaccine for it that has been used in South Africa since 1995.
Estimates for HCV are less certain than for HBV - an estimate of 400 000 chronic infections was quoted in an HBV and HCV investment case for South Africa. Highly effective cures for HCV infection have been developed over the last decade, although access to these cures remains limited. The Department of Health published viral hepatitis treatment guidelines in December 2019.
Given these numbers, some people in South Africa would simply, by chance, get both TB and hepatitis. But since there are common risk factors, co-infection will be higher than what one would expect purely through chance. HIV infection, for example, increases both a person's risk of TB and HCV.
"There is no data from South Africa about viral hepatitis and TB co-infection that I am aware of," says Dr Andrew Scheibe, a Technical Advisor for TB HIV Care and an infectious disease specialist at the University of Pretoria. He points out that people who use drugs and other groups of people who are marginalised, including people experiencing homelessness or people in prison, are at increased risk for these co-infections. The risk of HCV transmission is particularly high when people who inject drugs share needles.
In addition, as Dunn points out, TB itself can also cause hepatitis.
Hepatotoxicity
The picture is further complicated by the fact that several of the medicines used to cure TB have liver-related side effects. Drug-sensitive TB is treated with a combination of four different medicines, while drug-resistant TB is treated with anything from three to eight different medicines.
"Medications used to treat both drug-sensitive and drug-resistant TB can cause hepatitis through drug-induced liver toxicity (hepatotoxicity)," says Dunn. "The presence of other risk factors may further increase the risk of hepatitis in TB patients. These risk factors could be alcohol use, older age, malnutrition, co-infection with HIV or viral Hepatitis B, and taking other potentially hepatotoxic drugs with TB treatment."
Wieda Human, project coordinator and communications officer at TB advocacy group TB Proof says 3 to 28% of people with TB may experience hepatotoxicity and other side effects. "Those who are already infected with the hepatitis B infection are at an increased risk for hepatotoxicity," she says.
She refers to a study done in Ethiopia that found having hepatitis B and hepatitis C infection made having TB disease more severe. "This study also found that people with TB who have hazardous alcohol use have a 1.5 times increased risk of developing hepatitis C," says Human.
What it means for treatment
Dunn says although it is less straightforward to treat a person with TB and hepatitis than a person with just TB, it is important to understand treatment is still available. "It involves establishing the cause for hepatitis and treating this where possible, for instance, treating a viral hepatitis [and TB] co-infection at the same time or [providing] support to reduce alcohol intake. It may involve closer monitoring and follow-up, changes to medications, including stopping treatments either permanently or temporarily, and using alternative more 'liver-friendly' treatment regimens," she says.
"If the hepatitis is stable, then TB can be treated," Scheibe says. He explains hepatitis B requires long-term treatment (there is no cure), while hepatitis C can be cured with direct-acting antivirals (recently registered in SA, but not yet on the Government Essential Medicines List, so not easily available in the public sector). He says HCV treatment may be delayed until the TB is cured.
No routine screening
South Africa's National Strategic Plan for HIV, TB, and STIs 2023-2028 under Goal 2 sets out to reduce viral hepatitis morbidity through scale-up of prevention, diagnostic testing, and treatment. However, according to Dunn, screening for viral hepatitis infections, such as HBV, is not part of the current drug-sensitive or drug-resistant TB guidelines.
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But she says everyone should be assessed for symptoms and risk factors for liver disease at the start of TB treatment - a sentiment Scheibe shares. According to them, these screenings are however performed at diagnosis of HIV infection before a person is commenced on antiretroviral treatment for HIV, as chronic hepatitis B infection has specific implications for HIV treatment.
"During [TB] treatment, it is critical that clinicians assess people for signs and symptoms that may suggest hepatitis at each visit and educate them on recognising these side effects as well," says Dunn. "This includes loss of appetite, feeling tired and unwell, nausea, vomiting, abdominal pains, yellowing of the eyes and skin, and darkening of urine."
Treatment guidelines for drug-induced liver injury are available here. The guidelines focus on the management of suspected drug-induced rash, kidney injury, and liver injury for patients on TB treatment and or antiretroviral treatment.
Scheibe adds that people at high risk for HCV should receive TB screening regularly due to potential exposure to TB (e.g. if living in closed settings with many people in contexts of high TB prevalence and /or with HIV co-infection).
