Weight-gain risk for patients taking dolutegravir-TAF combination

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Dolutegravir (Tivicay) treatment paired with either of two tenofovir prodrugs showed non-inferior efficacy to a standard-of-care treatment regimen, MedPageToday research released at the International AIDS Society Conference on HIV Science (IAS 2019) found.

At week 48 in the South Africa-based ADVANCE trial, the percentage of patients with an HIV-1 RNA level of <50 copies/mL was 84% in patients receiving a regimen of dolutegravir, emtricitabine (Emtriva), and tenofovir alafenamide fumarate (TAF); 85% in the patients receiving dolutegravir, emtricitabine, and tenofovir disoproxil fumarate (TDF); and 79% among patients receiving standard-of-care efavirenz, tenofovir disoproxil, and emtricitabine, reported Dr Willem Daniel François Venter, of the Wits Reproductive Health and HIV Institute at the University of the Witwatersrand in Johannesburg.

The report quotes Venter as saying that the differences between the groups showed non-inferiority of the dolutegravir-based regimens compared with the efavirenz regimen. The statistical analysis also showed no superiority for one regimen over another.

“For these tests, an overall 1.7% significance level (P=0.017) was used, to adjust for the three pairwise treatment comparisons being made,” Venter and colleagues said. They added that the difference between the TAF-based group and the standard-care group was 5.1 percentage points (98.3% −1.9 to 12.2, P=0.08), while the difference between the TDF-based group and the standard-care group was 6.3 percentage points (98.3% CI −0.1 to 13.2, P=0.03), and the difference between the TAF-based group and the TDF-based group was -1.1 percentage points (98.3% CI −7.7 to 5.4, P=0.68).

However, patients taking the dolutegravir-TAF combination experienced more weight gain than with the standard-care regimen, the authors noted. Weight increase (both lean and fat mass) was greatest in the TAF-based group and among female patients (mean increase 6.4 kg in the TAF-based group; 3.2 kg in the TDF-based group; 1.7 kg in the standard-care group), they reported.

“These two new drugs are really important for our region — they will improve patients’ lives, decrease the use of more toxic second-line drugs, and save money. In summary, all regimens, the new ones studied [dolutegravir and TAF] and the one South Africa uses currently (efavirenz), rapidly and effectively suppressed HIV,” Venter said.
As for the weight gain and its long-term consequences, Venter said more follow-up was necessary.

In an accompanying editorial, Dr Diane V Havlir, of the University of California San Francisco, and Dr Meg C Doherty, of the World Health Organisation in Geneva, pointed out that there was no levelling off of the weight gain at 48 weeks, and 14% of the patients became newly obese.

The finding brings up complex “questions regarding metabolic complications associated with dolutegravir … What are the mechanisms and long-term outcomes … of excessive weight gain?” they wrote. “Is dolutegravir or dolutegravir plus TAF the true culprit? Can newly acquired obesity be reversed by switching to another treatment?”

The report says patients were eligible for ADVANCE if they were ages ≥12 years, had not received any antiretroviral therapy in the previous 6 months, had a creatinine clearance of >60 mL/minute (>80 ml per minute in patients age <19), and an HIV-1 RNA level of ≥500 copies/m.

The researchers randomised 1,053 patients from February 2017 through May 2018 to one of the treatment arms. More than 99% of the patients were black, and 59% were female. The mean age was 32, and the mean CD4 count was 337 cells per cubic millimetre.

In the per-protocol population, the standard-care regimen had equivalent potency to the other two regimens. The TAF-based regimen had less effect on bone density and renal function than the other regimens, the authors found.

While the number of patients who discontinued the trial regimen was higher in the standard-care group than in the other two groups (16% vs 12% for the TAF-based group vs 11% for the TDF-based group), “The patients did really, really well in all three regimens and the results were very similar to what we have seen in the registration studies in the richer countries of the world,” Venter said. “The virologic suppression rates were superb and the side effect profile was really, really good, bar one – the weight gain with TAF.”

Dr Anton Pozniak, International AIDS Society (IAS) president and international scientific chair, is quoted in the report as saying: “We have to work out now why is it that black African women who took dolutegravir and TAF put on a lot of weight? That has implication for further health concerns later on.”

But lack of data on weight gain should not hamper the use of dolutegravir, Havlir and Doherty stressed. “We need to accelerate (not slow) the transition to dolutegravir-based regimens for initial therapy, offer treatment as early as possible, make use of the best currently available treatment options, shore up pharmacovigilance, and continue research at the same time.”

Abstract
Background: Two drugs under consideration for inclusion in antiretroviral therapy (ART) regimens for human immunodeficiency virus (HIV) infection are dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF). There are limited data on their use in low- and middle-income countries.
Methods: We conducted a 96-week, phase 3, investigator-led, open-label, randomized trial in South Africa, in which we compared a triple-therapy combination of emtricitabine (FTC) and DTG plus either of two tenofovir prodrugs — TAF (TAF-based group) or tenofovir disoproxil fumarate (TDF) (TDF-based group) — against the local standard-of-care regimen of TDF–FTC–efavirenz (standard-care group). Inclusion criteria included an age of 12 years or older, no receipt of ART in the previous 6 months, a creatinine clearance of more than 60 ml per minute (>80 ml per minute in patients younger than 19 years of age), and an HIV type 1 (HIV-1) RNA level of 500 copies or more per milliliter. The primary end point was the percentage of patients with a 48-week HIV-1 RNA level of less than 50 copies per milliliter (as determined with the Snapshot algorithm from the Food and Drug Administration; noninferiority margin, −10 percentage points). We report the primary (48-week) efficacy and safety data.
Results: A total of 1053 patients underwent randomization from February 2017 through May 2018. More than 99% of the patients were black, and 59% were female. The mean age was 32 years, and the mean CD4 count was 337 cells per cubic millimeter. At week 48, the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter was 84% in the TAF-based group, 85% in the TDF-based group, and 79% in the standard-care group, findings that indicate that the DTG-containing regimens were noninferior to the standard-care regimen. The number of patients who discontinued the trial regimen was higher in the standard-care group than in the other two groups. In the per-protocol population, the standard-care regimen had equivalent potency to the other two regimens. The TAF-based regimen had less effect on bone density and renal function than the other regimens. Weight increase (both lean and fat mass) was greatest in the TAF-based group and among female patients (mean increase, 6.4 kg in the TAF-based group, 3.2 kg in the TDF-based group, and 1.7 kg in the standard-care group). No resistance to integrase inhibitors was identified in patients receiving the DTG-containing regimens.
Conclusions: Treatment with DTG combined with either of two tenofovir prodrugs (TAF and TDF) showed noninferior efficacy to treatment with the standard-care regimen. There was significantly more weight gain with the DTG-containing regimens, especially in combination with TAF, than with the standard-care regimen.

Authors
Willem DF Venter, Michelle Moorhouse, Simiso Sokhela,Lee Fairlie, Nkuli Mashabane, Masebole Masenya, Celicia Serenata, Godspower Akpomiemie, Ambar Qavi, Nomathemba Chandiwana, Shane Norris, Matthew Chersich, Polly Clayden, Elaine Abrams, Natasha Arulappan,Alinda Vos, Kaitlyn McCann, Bryony Simmons, Andrew Hill

 

With over 5m 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, write Dr Michelle Moorhouse and Dr Simiso Sokhela at the Wits Reproductive Health and HIV Institute in Spotlight, 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.

They write: “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, 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 Organisation (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.”

 

MedPageToday report
New England Journal of Medicine abstract
New England Journal of Medicine editorial
Spotlight report


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