What are we to make of the ADVANCE trial results?

By Dr Michelle Moorhouse and Dr Simiso Sokhela

With over 5 million South Africans on life-saving antiretroviral therapy, making treatment safer, more potent and cheaper is a priority, especially in the context of rising drug resistance across the country. However, antiretrovirals are developed largely in richer countries, while Southern African populations, with high levels of TB, hepatitis B, and a large proportion of women desiring pregnancy, are not represented in the studies.

The 48-week results of ADVANCE, a ground-breaking HIV treatment study conducted by Ezintsha, a division of the Wits Reproductive Health and HIV Institute, was presented at the prestigious IAS conference in Mexico on 24 July 2019, and published in a top medical journal, the New England Journal of Medicine.

ADVANCE assessed two newer antiretrovirals, dolutegravir and tenofovir alafenamide fumarate (TAF), that are now used in richer countries, in people with HIV starting antiretroviral therapy (ART), against what we currently use in South Africa. These two new drugs (TAF is not even registered in South Africa, awaiting a much-delayed licence from the South African Health Products Regulatory Authority (SAHPRA)) both have toxicity benefits over the drugs they replace. They are cheaper to make and give us a smaller tablet size, which has other cost benefits beyond the cost of production. Dolutegravir appears almost unbreakable, in terms of resistance.

The following three regimens were compared in ADVANCE:

• Dolutegravir, TAF, FTC
• Dolutegravir, TDF, FTC (A regimen being introduced in South Africa.)
• Efavirenz, TDF, FTC (Currently the most commonly used regimen in South Africa.)

All three regimens investigated in ADVANCE performed extremely well, with high rates of viral suppression, very little resistance, and few people stopping their study regimen as a result of side effects. In fact, participants stopped their study medication more as a result of personal or social factors, rather than side effects – older people and those employed had the best outcomes. Almost everyone “failing” their treatment, that is where their viral load starts going up, were able to control their virus again with a simple adherence intervention, whatever drug regimen they took.

Even so, there were some differences in side effects across the study arms. We saw an increase in weight in the dolutegravir-containing arms of the study, consistent with recent reports of weight gain associated with this class of drug. The weight gain in ADVANCE was worse in women; those also receiving TAF; and those with more advanced HIV (lower CD4 counts and higher viral loads).

At this stage, the potential mechanisms for the weight gain are poorly understood. In ADVANCE, weight gain did not appear to be associated with the things that worry us with people being overweight, such as changes in blood pressure, cholesterol or blood sugar, but it may be too early to see these effects, as they have only been followed for 48 weeks. We will follow the patients further, hopefully for the next few years, to see if the weight gain causes metabolic problems. It is complex to understand the implications of these findings, especially as we are facing an epidemic of obesity in South Africa, irrespective of HIV status.

The ADVANCE study and its results are important for a number of reasons. When newer antiretrovirals (ARVs) such as dolutegravir and TAF are developed, most of the research is conducted in richer countries, with studies that recruit mainly white middle-aged men – this is not representative of the majority of people with HIV who will ultimately be treated with these drugs. The ADVANCE population was 99% black, almost 60% women and the average age was 32 years, which reflects the demographics in Southern Africa more accurately, and so the results are very relevant to large HIV treatment programmes such as ours.

Once new ARVs are approved, little is known about their safety in pregnancy; whether they can be used with drugs used to treat TB; effectiveness in everyday people with HIV – all of which we consider to be the “real world” effectiveness of ARVs. ADVANCE did not exclude people with advanced HIV or other common illnesses; participants who developed TB or became pregnant were allowed to stay in the study and so the data gleaned from ADVANCE helps us understand more fully the utility of newer ARVs such as dolutegravir and TAF in these groups. In ADVANCE, most participants were given isoniazid to prevent TB, and as a result we saw hardly any new TB in the study, confirming the effectiveness of TB preventive therapy.

Because of concerns about neural tube defects, a severe birth defect that is often severely disabling or fatal, that were seen with women conceiving on dolutegravir in Botswana, we have been monitoring women who become pregnant and their infants very carefully in ADVANCE. The number of pregnancies is too small to be meaningful but to date, there have been no neural tube defects in ADVANCE.

Although ADVANCE took place in inner-city Johannesburg only, we recruited a very diverse African population, with 60% of study participants being from across South Africa and the remaining 40% from other African countries, mainly Zimbabwe. This makes the results of ADVANCE applicable to other countries in sub-Saharan Africa, where dolutegravir is already being rolled out or where rollout is imminent, as in South Africa. This is important, as there is a paucity of data from randomised studies of the regimens investigated in ADVANCE in African populations. On account of this, the results of ADVANCE have been shared with global bodies including SAHPRA, World Health Organization (WHO), the US Food and Drug Agency (FDA) and guideline committees to inform their processes are guided by data relevant to populations being treated.

Another unique feature of ADVANCE is the fact that it was designed by a consortium of leading international HIV clinicians and researchers, with input from global bodies such as the WHO, Clinton Health Access Initiative, as well as treatment advocates and activist groups including HIV i-Base, AfroCAB, the Treatment Action Campaign, and the South African government. It was funded by USAID, Unitaid, the South African Medical Research Council, and study drugs were donated by Gilead Sciences and ViiV Healthcare.

 

For us, the key message is that South African patients and healthcare workers can achieve amazing results simply by following Department of Health guidelines – sort out the adherence when the viral load goes up, and use TB prevention. Weight gain is an issue with more data needed, but the guidelines recommend lifestyle changes, something all of us, whatever our HIV status, should be doing.

Both Dr Moorhouse and Dr Sokhela are from Ezintsha, a division of the Wits Reproductive Health and HIV institute.