Why a major finding on HIV and statins may not be that relevant in SA

Why a major finding on HIV and statins may not be that relevant in SAPeople living with HIV have a twofold increased risk of developing cardiovascular disease. (Photo: Stefan Heunis/MSF)
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One of the biggest stories in HIV in the last year was that a class of medicines called statins could help reduce cardiovascular disease in people living with the virus. In response, treatment guidelines in the United States were quickly updated, but the picture is more complicated in South Africa. Spotlight’s Elri Voigt explores why the case for widespread use of statins by people living with HIV is less compelling in South Africa than in some other countries.

People living with HIV, provided they are stable on antiretroviral therapy, are affected by the same diseases as those who don’t have HIV, including cardiovascular disease, says Professor Mpiko Ntsekhe, head of Cardiology at Groote Schuur Hospital in Cape Town.

The key difference, he says, is that although both groups of people get the same spectrum of diseases, people living with HIV get those diseases more frequently and earlier. One way to think about this, he explains, is to imagine twins who are identical in every way except one is living with HIV. The twin living with HIV is more likely to get cardiovascular disease than the other twin.

And these differences can be substantial. Current evidence shows that people living with HIV have a twofold increased risk of developing cardiovascular disease compared to people not living with HIV, says Professor Hans Strijdom. He is the Head of the Division of Medical Physiology and Deputy Director of the Centre for Cardio-Metabolic Research in Africa (CARMA) at Stellenbosch University.  The cardiovascular risk attributable to HIV, Strijdom adds, is now believed to be equivalent to that posed by traditional risk factors such as smoking. This prompted an editorial in 2018 in one of the top cardiovascular journals, Circulation, advocating for HIV to be recognised as a major cardiovascular risk factor.

He explains that people living with HIV who are stable on treatment are living longer, making them susceptible to the normal risk posed by older age. They also have “modifiable risk factors, in other words lifestyle risk factors”, like a higher smoking and alcohol use incidence, as well as increasing rates of being overweight and obesity. Strijdom says that living with HIV, even when someone is stable on treatment, causes low-grade inflammation, which over time increases a person’s risk for cardiovascular disease. “That all in combination are the current theories [of] why we think that they have a bigger risk of cardiovascular disease,” he says.

Important study findings

Arguably, the biggest news from last year’s International AIDS Society (IAS) Conference in Australia was findings from a study on heart disease in people living with HIV. The trial, called REPRIEVE, showed that a class of cholesterol-busting drugs called statins can prevent a lot of cardiovascular disease events in people living with HIV whose cardiovascular disease (CVD) risk score meets a certain threshold. Spotlight previously reported on these findings, which showed that compared to placebo, daily treatment with 4mg oral pitavastatin – a specific statin – led to a 35% reduction in major adverse cardiovascular events (MACE) in people living with HIV classified to be at risk of cardiovascular disease.

When the findings were presented at the IAS conference, the study’s principal investigator, Dr Steven Grinspoon, said that while the researchers still have to assess more of the data collected to get a clearer picture of things, like the mechanisms driving cardiovascular disease across regions and conduct additional sub-group analyses, the study has already shown that using pitavastatin can save lives.

These sub-group analyses were discussed in greater detail at the Conference on Retroviruses and Opportunistic Infections (CROI) held in Denver in March this year. For the most part, the use of pitavastatin in the manner prescribed by REPRIEVE was considered a huge success, and the United States has since changed its guidelines to include the use of statins in the primary prevention of atherosclerotic cardiovascular disease.

Why it is different in South Africa

However, for low-and-middle-income countries like South Africa, the case for pitavastatin might not be as clear-cut. In fact, a panel discussion at CROI was dedicated to exploring the implications of the REPRIEVE findings for such countries.

Ntsekhe, who was a speaker on the CROI panel, tells Spotlight that data from REPRIEVE’s sub-group analyses reveal there was a striking difference in event rates – which in the case of the study are MACE in those who were getting the placebo – by country income status. He explains that as predicted in high-income countries, the event rates were high, while in low-and-middle income countries – particularly in Sub-Saharan Africa – event rates were very low.

He says one of the reasons for the difference in event rates was that the screening tool used in REPRIEVE worked well to identify those people living with HIV who might benefit from pitavastatin in high-income countries like the United States, but it did not work well in Sub-Saharan Africa.

This means using pitavastatin as part of a primary prevention strategy is a much more effective intervention in high-income countries than in low-and-middle income countries like in Sub-Saharan Africa because the cardiovascular disease profile is so different.

Ntsekhe explains the term cardiovascular disease itself is broad and all-encompassing and there are many forms, including valve disease, heart muscle disease, and vascular disease. The dominant form of cardiovascular disease in the high-income countries (which he refers to as the Global North) is known as atherosclerotic cardiovascular disease, which is characterised by a build-up of fatty deposits and plaque in the arteries.

In Sub-Saharan Africa though, Ntsekhe says “atherosclerotic cardiovascular disease is but one of many forms of cardiovascular disease”, taking the fourth or fifth place in the ranking of types of major heart disease.

Research conducted in high-income countries don’t always take differences in disease burden into account, according to Ntsekhe. This means that interventions researched in high-income countries and shown to be effective in that context won’t necessarily work as well in low-and-middle income countries like South Africa.

Strijdom concurs that while results from REPRIEVE in the global context were a game-changer, the findings are not easily transferable to South Africa’s context because pitavastatin is mainly aimed at reducing “bad cholesterol” and coronary artery disease (also called atherosclerosis).

‘Taking money away’

During the panel discussion at CROI, Ntsekhe asked whether Sub-Saharan Africa could justify taking money away from other health programmes that work in order to invest in pitavastatin.

“I said basically what should be a priority for us is a) finding tools that can better identify those at risk and b) continuing to focus on what our local data suggests are the priority areas,” Ntsekhe says.

“If your entire prevention strategy is aimed at atherosclerotic cardiovascular disease, but it isn’t the dominant cause of disease [in your country], you’re going to be treating a whole host of people to try and tackle this thing that affects very few in a sense,” he says.

“It was not anything about REPRIEVE, it was a wonderful study, the hypothesis was tested, and it was shown to be correct, the intervention we know works,” Ntsekhe says. “It really then comes down to regional areas to think very carefully about how best they’re going to get their biggest bang for their buck,” he says. “We have to carefully consider the local context, local burden, we have set local health priorities, and weigh benefit and cost before we adopt new interventions or recommendations.”

SA’s cardiovascular disease burden

While Strijdom says we don’t have great data, he points to a large systematic review and meta-analysis published in 2018 in Circulation, which estimates that around 15% of the total cardiovascular disease burden in South Africa is attributable to HIV. “It’s probably higher than that. I would say that probably about one in five people with heart disease have heart disease because of HIV in South Africa,” he says, adding “that figure is probably only going to increase”.

Because of this, he says, there is a need for proper and clear primary healthcare guidelines specifically aimed at managing cardiovascular disease in people living with HIV, which we don’t currently have.

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Strijdom says what we have at the moment since the rollout of the 2019 National ART Clinical Guidelines is very basic guidelines. This involves screening someone who has just been diagnosed with HIV by taking their blood pressure, and testing urine for glucose and proteins, and an assessment of their general cardiovascular disease risk by taking their medical and family history. These guidelines, according to Strijdom, only make provision for routine screening at baseline, but screening guidelines at follow-up visits are insufficient.

“I am, however, aware of the fact that there is progress especially from the integrated chronic disease management model which is currently being piloted in South Africa – and hopefully with that will come much more definitive and universal guidelines,” he says. “The bottom line is that South Africa, in its public health [sector] especially, really very quickly needs to come up with very clear and more comprehensive guidelines to actively manage cardiovascular disease risk in people with HIV.”

Need for annual screening

Strijdom suggest that to improve screening for cardiovascular disease risk in people living with HIV, there needs to be annual screening of people’s weight, their measure of body fat based on height and weight, waist circumference, blood pressure, cholesterol and triglyceride levels as well as testing urine samples for kidney function. There also needs to be a thorough family and medical history conducted for each patient.

“It’s not really a very expensive or very exhaustive list of stuff that you have to do. Unless of course they have specific symptoms and signs that leads you in a specific direction that you then have to perhaps do an ECG [a test used to evaluate the functioning of the heart] or cardiac imaging but that is usually determined by what you get from their history and clinical examination,” he says.

Ntsekhe says public health strategies to combat the growing burden of non-communicable diseases (NCDs), including cardiovascular disease, in South Africa must be strengthened. These include screening and prevention tools like checking a patient’s blood pressure and blood glucose, advising against smoking and alcohol as well as promoting health lifestyle choices like exercise and weight loss. These interventions should be offered to everyone, regardless of whether they are living with HIV or not, he says.

“The thing about NCDs and cardiovascular disease, for the most part, they are diseases of lifestyle and behaviour. So, when you talk prevention, it’s not always about drug prevention,” he says. “It’s more about intensification of those [interventions] that are already in the public domain, are very effective, and cost very little. Many of the public health and primary healthcare guidelines do advise local ministries, local health authorities on what should be happening.”

In terms of public education, Stritjdom says people need to be aware that there is something like high blood pressure. “If people are aware they will come to the clinic and will say please measure my blood pressure,” he says.

“Our health system is understandably focused on infectious diseases, but if we are not careful, we will then be totally unprepared to tackle the epidemic that will have replaced it. Namely, cancer, heart disease, stroke, obesity, diabetes, and it will totally overwhelm our public healthcare system,” he says.

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