Adverse Events During ART and Implications for Treatment: Key Data From Summer 2021

TANGO: Week 96 Post Hoc Analysis of Switch to DTG/3TC vs Continued 3-Drug or 4-Drug TAF-Based Regimen

There has been particular attention on weight changes with the use of second-generation INSTIs such as DTG and bictegravir (BIC), as well as evidence suggesting an association with TAF.

Two very important studies presented at IAS 2021 looked at patients switching from standard 3-drug regimens to the more novel 2-drug regimen of DTG/3TC.

When considering the impact of these switches on metabolic abnormalities and weight, it is important to understand the original study population.

In the open-label TANGO study, eligible participants were stably suppressed (HIV-1 RNA <50 copies/mL) for at least 6 months on a TAF-based regimen.⁴

Approximately 80% were receiving a TAF-based regimen that included an INSTI (primarily elvitegravir [EVG]), 13% were receiving nonnucleos(t)ide reverse transcriptase inhibitor (NNRTIs), and 8% were receiving boosted protease inhibitor (PIs). Hence, when they switched therapy, they were not only stopping TAF, but they also were switching that third drug to DTG. It is important to consider that any changes in metabolic markers and weight are driven by both of those changes.

TANGO met the primary endpoint of noninferiority of DTG/3TC in maintaining virologic suppression at 48 weeks, which was previously reported.⁵ The current analysis included follow-up out to 96 and 144 weeks.

TANGO: Week 144 Metabolic Outcomes

At Week 96, the virologic efficacy was comparable between study arms, but I want to focus on the safety data.

From a metabolic perspective, there was an overall trend toward a decline in lipids in those who switched vs those who continued the TAF-based therapy. Again, in considering the driving factors behind these changes, it is likely not just stopping TAF, but also switching the third drug to DTG, which we know is fairly lipid neutral.

Regarding other metabolic outcomes associated with the switch, they found little difference in mean changes in weight, glucose, the homeostasis model assessment of insulin resistance, and metabolic syndrome.

The conclusion is that the switch from a 3-drug TAF-based regimen to DTG/3TC was associated with some improvement in lipids without any significant change in other metabolic parameters, including weight gain and metabolic syndrome.

SALSA: Switch to DTG/3TC vs Continuing Any 3-Drug ART Regimen

SALSA was a related study that was presented for the first time at IAS 2021.⁶ Like TANGO, this open-label, noninferiority trial enrolled PWH who were stably suppressed on a 3-drug regimen and randomized some participants to the 2-drug regimen of DTG/3TC.

However, unlike TANGO, the starting regimens were not all TAF based. Participants received regimens with nucleoside backbones consisting of 2 nucleoside reverse-transcriptase inhibitors (NRTIs) plus an INSTI, NNRTI, or PI. Participants were randomized to continue their baseline 3-drug regimen or switch to DTG/3TC, and the primary endpoint was HIV-1 RNA ≥50 copies/mL at Week 48.

Again, the study population is important to consider when thinking about what changes occurred to parameters of safety and tolerability. The baseline regimens for these stably suppressed individuals included approximately 40% receiving integrase-based regimens, largely EVG/cobicistat (COBI), 50% NNRTIs, and 10% boosted PIs.

Unlike the TANGO study, where all patients received a TAF-based regimen, in SALSA only approximately one third of participants received a TAF-based regimen, and 45% received TDF.

SALSA: Safety and Tolerability at Week 48

Overall, SALSA met the primary endpoint, as viral rebound was rare in both arms, with virologic suppression at a high level in both arms. This is clearly an important measure, without which we would not be looking at this 2-drug strategy.

Regarding overall AEs, a larger percentage of patients experienced weight gain in the DTG/3TC group vs those who stayed on their current regimen.

The authors also looked at adjusted mean weight change and found that it was greater in the DTG/3TC group, as was BMI.

It is important to recognize that based on other studies TDF may act to suppress weight, so it would follow that switching off TDF may lead to weight gain. Indeed, many believe that the some of the AEs we see when PWH switch to TAF are attributable to removing TDF.

The rates of grade 2-5 AEs generally were comparable between groups, but insomnia and dizziness were slightly higher in the switch group (3% for both); both of which are well-known AEs associated with DTG.

Serious AEs were rare in both groups, and some AEs led to study withdrawal, including 3 psychiatric events and 1 weight increase in the DTG/3TC arm, as well as 1 psychiatric event, 1 gastrointestinal complication, and 1 postprocedural complication in the control arm.

Changes in markers of proximal renal tubular function and bone biomarkers favored DTG/3TC. Again—of importance—almost half of these patients were switching off TDF, which was probably the driving factor behind most of these differences.

Based on this study, we can conclude that—depending on which regimen patients start with—there may be distinct AE advantages to switching to DTC/3TC.

There also may be potential increases in certain AEs, such as increases in weight and BMI, as well as some neuropsychiatric AEs associated with stopping TDF and starting DTG.

Switch to BIC/FTC/TAF in Adults Aged 65 Years and Older

The next study was a multicenter, open-label, single-arm trial to look at the impact of switching stably suppressed PWH to BIC/FTC/TAF.⁷

As I keep mentioning, it is important to consider the patient population in any ART switch study.

Participants were aged 65 years and older, which is the population at substantial risk for adverse outcomes associated with metabolic changes such as lipids, weight, and insulin resistance. In this case, the median age was 69 years, and 87% of patients were men.

A large majority (92%) received EVG/COBI/FTC/TAF, and the remaining 8% received FTC/TDF plus a third agent. Thus, in most participants, the study entailed a switch from a first-generation boosted INSTI to a second-generation INSTI without a booster.

Participants were often receiving at baseline additional medications for comorbid conditions, as you might expect in an older population. For example, 64% received medications for cardiovascular disease.

Switch to BIC/FTC/TAF in Adults Aged 65 Years and Older: Week 96 Weight and Lipid Changes

Most participants were receiving TAF-based therapy before the switch, and—perhaps because TAF also was in the new regimen—no renal, bone, or hepatic AEs were associated with the switch.

What’s more interesting to explore is the effect on weight with the switch to BIC in this population—and, as it turns out, there was very little, if any.

The changes in fasting lipids were favorable, with a reduction in total cholesterol, LDL, and triglycerides, and a reduction in total cholesterol to HDL ratio. Most of these differences are likely driven by the switch from a boosted to a nonboosted INSTI.

They also looked at the number of patients receiving lipid-modifying medications, which was 42% at baseline, with an additional 7% started during the study.