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

Eric S. Daar, MD
Released: September 22, 2021

Emerging Therapies

P011 Metabolic and Bone Outcomes: Study Design

Emerging therapeutics still in development have the potential to impact HIV treatment in various settings. Any time a new drug is being developed, it is important to consider its unique tolerability issues.

One such agent is islatravir (ISL), a nucleoside reverse transcriptase translocation inhibitor. ISL is a very potent drug that can be given in small doses and is active against many viruses that harbor resistance to NRTIs. So, it has a potential role in first-line therapy, switch therapy, and perhaps in highly treatment–experienced patients who need new options. Indeed, it is being extensively evaluated in several trials.

At IAS 2021, we saw a follow-up analysis from the phase IIb Protocol 011 study, a 3-part dose-finding study in treatment-naive PWH with HIV-1 RNA ≥1000 copies/mL and CD4+ cell count ≥200 cells/mm3.9

This was a relatively small study enrolling patients who were randomized in part 1 to receive either DOR/3TC with ISL at different doses or DOR/3TC/TDF as a control. The goal of part 1 was to demonstrate the ability to achieve viral suppression, which they had previously reported.10

In part 2, the novel strategy was to switch those who had achieved viral suppression to a 2-drug regimen of ISL/DOR to evaluate whether they were able to maintain suppression, while keeping the control group on DOR/3TC/TDF.

P011 Metabolic and Bone Outcomes: Week 96 Changes in Weight and Bone Mineral Density

In keeping with the common theme of metabolic outcomes, I will review the data they reported on weight change across these relatively small (n ≤30) dosing groups at 96 weeks.

As anticipated, there was a small increase in weight over 96 weeks. Again, this is typically observed in any population initiating ART for the first time, but in these small groups, there was no obvious difference across treatment arms. In fact, previous data suggest that DOR/3TC/TDF is associated with limited weight changes,11 and now we see only modest increases with ISL and DOR out to 96 weeks without differences across study arms.

Bone mineral density is another important parameter, and in this study the regimen includes no other nucleosides except ISL with DOR. Among patients receiving any dose of ISL with DOR, there was a modest decrease in bone mineral density in the hip and spine, which is seen in virtually any patient starting therapy. However, there were greater decreases with DOR/3TC/TDF, especially in the hip, which is what we would anticipate in a TDF-based regimen. Hence, the investigational regimen appears to have more favorable bone safety relative to the TDF-based comparator.

P011 Metabolic and Bone Outcomes: Week 96 Changes in Body Fat

The investigators also assessed changes in peripheral and trunk fat and demonstrated little difference across the study arms.

P011 Metabolic and Bone Outcomes: Week 96 Changes in Metabolic Parameters

Of importance, they looked at fasting metabolic parameters, including glucose, cholesterol, HDL, LDL, and triglycerides.

The numbers are small, so their CIs are extremely wide, but in general the effect on lipids was more modest in the control arm vs the other arms. Although there were no major changes across any of the groups, the median percent change in most of these metabolic parameters was consistently higher in the ISL plus DOR groups. This is consistent with previous studies suggesting that TDF has independent lipid-lowering properties.

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