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Expert Analysis: Insights for International Clinicians on New Data From CROI 2020

Josep M. Llibre, MD, PhD
Laura Waters, FRCP, MD
Released: April 21, 2020

Metabolic Outcomes With ART

ADVANCE: Study Design

Josep M. Llibre, MD, PhD:
We will now discuss metabolic outcomes from the ADVANCE trial, which is an ongoing, open-label phase III noninferiority trial conducted in Johannesburg, South Africa, evaluating differences between first-line DTG plus either FTC/TAF or FTC/TDF vs EFV/FTC/TDF (Capsule Summary).[8] Briefly, 1053 ART-naive patients with HIV-1 RNA ≥ 500 copies/mL were randomized across the 3 trial arms and evaluated for regimen efficacy and safety. At baseline, the overall population was 99% black and 59% female, mean age was 32 years, mean CD4+ cell count was approximately 340 cells/mm3, and approximately 80% of participants had HIV-1 RNA < 100,000 copies/mL.

ADVANCE: Weight Gain and Fat Changes Through 96 Weeks

Josep M. Llibre, MD, PhD:
It has been previously reported from this study that patients treated with DTG—particularly those also receiving TAF—experienced more weight gain, progressed to higher body mass index categories, and had higher rates of overweight and obesity.[9] In the current analysis, investigators examined the metabolic impact of this weight gain. One reason to study this question is because some have postulated that this weight gain may be a return-to-health phenomenon and not pathologic. Therefore, this study examined whether this weight gain leads to benign (nonmetabolic) obesity or to adverse metabolic outcomes.

ADVANCE: 96-Week Laboratory Value Changes and Metabolic Syndrome

Josep M. Llibre, MD, PhD:
Investigators found that patients treated with both DTG plus FTC/TAF and EFV/FTC/TDF had significantly worse lipid profiles at 96 weeks vs patients treated with DTG plus FTC/TDF. This is expected for EFV and its poor lipid profile has been reported previously.[10] In addition, increases in fasting glucose from baseline to Week 96 were significantly lower with DTG plus FTC/TAF or DTG plus FTC/TDF vs EFV/FTC/TDF. Change in systolic blood pressure was significantly less favorable with DTG plus FTC/TAF vs DTG plus FTC/TDF.

Next, the investigators looked at the proportion of patients who had metabolic syndrome, which is defined as clinical obesity (body mass index > 30) and any 2 of the following: increased triglycerides, reduced high-density lipoprotein cholesterol, increased blood pressure, and increased fasting glucose. They found that the proportion of patients who had metabolic syndrome was significantly higher at 2 years with DTG plus FTC/TAF vs EFV/FTC/TDF at 8% and 3%, respectively (P = .031).

ADVANCE: Predicted 10-Year Cardiovascular Disease Risk

Josep M. Llibre, MD, PhD:
Investigators also estimated the cardiovascular and diabetes risks associated with these regimens. Although the Framingham risk equation did not show a statistically significant difference in the 10-year estimated risk of myocardial infarction or coronary death between the regimens, the QRISK algorithm, which incorporates ethnicity, did show a statistically significant higher increase in risk with DTG plus FTC/TAF vs EFV/FTC/TDF (P = .027).

ADVANCE: Predicted 10-Year Diabetes Risk

Josep M. Llibre, MD, PhD:
Finally, investigators estimated the impact of these regimens on diabetes risk with the QDIABETES equation, which is available online. They found, again, that there were statistically significant differences in the scores between these regimens. Overall, patients had a higher increase in 10-year risk of developing diabetes with DTG plus FTC/TAF or EFV/FTC/TDF vs DTG plus FTC/TDF (P = .004 and .005, respectively, at Week 96).

Therefore, although greater weight increases and rates of obesity with DTG plus FTC/TAF have been previously observed,[9] the current analysis shows that DTG plus FTC/TAF was associated with a significantly higher increase in risk of heart attack or stroke vs EFV/FTC/TDF at Week 96 and a significantly higher increase in predicted 10-year diabetes risk vs DTG plus FTC/TDF.

ADVANCE: Clinical Implications

Laura Waters, MD:
These results were somewhat expected, given the weight signals from the original study. For me, this confirms that TAF with a second-generation INSTI may have a substantial metabolic impact. Since this study was conducted in a relatively young population, one concern could be whether this will be amplified in older individuals. Indeed, a single-arm retrospective study in the United States published in 2019 showed that switching from TDF to TAF in an older population (mean age: 50 years) significantly increased the cardiovascular risk.[11]

Given these collective results, I would try to avoid a second-generation INSTI in combination with TAF in older people. For example, in an older patient with no relevant baseline resistance who was hepatitis B immune, I would prefer DTG/lamivudine over DTG plus FTC/TAF because I think that regimen is more metabolically friendly.

Josep M. Llibre, MD, PhD:
Absolutely. I think this is a new piece in the jigsaw puzzle as we try to understand the relationship between weight gain and ARV exposure. Here, we see that weight gain is associated with adverse metabolic outcomes, which is important because some were attributing this result as a return-to-health effect due to better gastrointestinal tolerability, rather than an effect intrinsic to the treatment.

Laura Waters, MD:
While we are trying to learn more about the mechanism of weight gain and whether it is reversible, I think it is important to counsel patients about this adverse event because a prepared person may gain less weight than someone who is not warned about the effect. So, although we await the “why,” we should counsel about the “what.”

ADVANCE Substudy: CYP2B6 Genotype and Weight Gain

Josep M. Llibre, MD, PhD:
We also saw some data from ADVANCE on the influence of CYP2B6 genotype on EFV-related weight changes (Capsule Summary).[12] For some background on this study, recall that single-nucleotide polymorphisms (SNPs) in CYP2B6 have been reported to be associated with higher EFV plasma concentrations, presumably as a result of slowed drug metabolism.[13] Some data have shown that slow metabolizer CYP2B6 genotypes are present in approximately 20% to 40% of Africans.[13] In addition, higher weight gain has been observed with a switch from EFV to INSTI-based ART among CYP2B6 slow metabolizers, suggesting that impaired weight gain associated with higher EFV concentrations may contribute to the larger gains after switching from EFV.[15]

In this post hoc analysis of data from the ADVANCE trial in South Africa, investigators assessed whether CYP2B6 loss-of-function SNPs were associated with lower weight gain among the patients who initiated EFV-based ART. This is very important to understand because EFV has been the comparator in most studies analyzing weight gain differences between regimens.

Investigators categorized patients who received EFV into 3 categories, CYP2B6 extensive metabolizers (n = 51), CYP2B6 intermediate (or normal) metabolizers (n = 74), and CYP2B6 slow metabolizers (n = 46), and compared them with patients who received DTG plus FTC/TDF. A person who is a CYP2B6 slow or extensive metabolizer will have increased or decreased levels of EFV, respectively, vs patients who are normal metabolizers. Baseline characteristics were generally well matched between the groups, although not perfectly. Weight gain and limb fat were measured by dual-energy X-ray absorptiometry through Week 48.

ADVANCE Substudy: CYP2B6 Genotype and Weight Gain Differences Between DTG and EFV

Josep M. Llibre, MD, PhD:
The results showed that, among patients treated with EFV/FTC/TDF, the percent change in weight from baseline to Week 48 was significantly lower in slow vs extensive metabolizers (P = .004). Intermediate metabolizers remained at approximately the same weight and extensive metabolizers gained some weight, although not significantly more than intermediate metabolizers.

Investigators also analyzed any potential differences in limb fat change between CYP2B6 genotype groups and by sex. For women, the percent change in limb fat was significantly lower in slow metabolizers vs intermediate and extensive metabolizers (P = .012 and P = .008, respectively). No significant differences in the percent change in limb fat among slow, intermediate, and extensive metabolizers were observed for men.

ADVANCE Substudy: Clinical Implications

Josep M. Llibre, MD, PhD:
Based on these data, I think we have to be very careful when interpreting studies of weight gain that use EFV as the comparator because patients could be experiencing differential weight effects based on their CYP2B6 genotype and resulting EFV metabolism/exposure. It is also important to reiterate that the SNPs associated with slowed EFV metabolism are not uncommon and have been reported in between 20% and 40% of the population in regions of Africa.

Laura Waters, MD:
It is interesting to speculate about the potential mechanism. Is it because EFV can have an impact on fat cells and fat cell inflammation, as shown in previous studies?[16] Or could this be because people with higher EFV concentrations are eating less due to the adverse events?

Josep M. Llibre, MD, PhD:
We do know from an ACTG study that lipoatrophy was significantly more frequent with EFV vs lopinavir/ritonavir.[17] Therefore, it could be that EFV exhibits toxicity specifically within adipocytes, and normal or low EFV levels could result in a limited effect or even some weight gain, whereas at increased EFV levels, lipoatrophy occurs.

Laura Waters, MD:
I agree completely. We now need to determine whether a similar genotypic polymorphism could be driving the sex or race differences in DTG-related weight gain that we have seen in ADVANCE. That could be important in terms of predicting weight gain and perhaps stratifying the use of some of these drugs accordingly.

Josep M. Llibre, MD, PhD:
We have limited data, but there are some data in patients who experienced treatment failure with raltegravir or elvitegravir resistance and were then treated with a double dose of DTG 50 mg twice daily.[18] That trial did not report a pronounced signal for increased weight gain with the higher DTG dose, suggesting that the weight gain is not related to the dose or levels of DTG in the body.

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