Meta-analysis proves value of fostemsavir in multidrug-resistant HIV-1

The first-in-class attachment inhibitor fostemsavir, when combined with optimized background therapy (OBT), provides an important treatment option for heavily treated HIV-1 patients with multidrug resistance and limited available antiretroviral (ARV) options, a matching adjusted indirect comparison (MAIC) analysis has shown.

In the pivotal phase III BRIGHTE trial, treatment with fostemsavir in addition to OBT resulted in sustained virologic and immunologic responses in heavily treatment experienced (HTE) patients throughout 96 weeks. [Lancet HIV 2020;7:e740-e751]

Relative to ibalizumab plus OBT (TMB-301; n=40), fostemsavir plus OBT (adjusted, n=236) was associated with a nonsignificant greater likelihood of virologic suppression (odds ratio [OR], 1.44, 95 percent confidence interval [CI], 0.74–2.80; p=0.284) and a comparable increase in CD4+ cell count of about 65 cells/mm³ from baseline through week 24 (mean difference, 7.05 cells/mm³; p=0.834). [Clin Ther 2022;doi:10.1016/j.clinthera.2022.04.007]

The comparison with OBT alone (VIKING-3; n=183) yielded similar results. Specifically, the odds of virologic suppression with fostemsavir plus OBT (adjusted, n=78) through week 48, while higher, were not significant (OR, 1.34, 95 percent CI, 0.78–2.30; p=0.297), with a modest CD4+ cell count increase (mean difference, 26.86 cells/mm³; p=0.162).

On the other hand, the results of another comparison with OBT (BENCHMRK-1/-2; n=237) indicated that fostemsavir plus OBT (adjusted, n=126) significantly improved the likelihood of achieving virologic suppression (OR, 3.26, 95 percent CI, 2.08–5.11; p<0.001) and increased CD4+ cell count (mean difference, 135.78 cells/mm³; p<0.001) at week 96.

All-cause discontinuations and safety comparisons varied across studies.

“These analyses support the use of fostemsavir plus OBT as a key treatment option in HTE people with multidrug-resistant HIV-1,” according to the investigators, adding that an indirect treatment comparison can help inform decision making in the absence of head-to-head evidence.

The challenge of conducting MAIC

“HTE individuals with multidrug-resistant HIV have few viable treatment options available. There are two comparators of interest for [this] population for whom fostemsavir is indicated: (1) a regimen of ibalizumab (administered intravenously every 14 days) plus OBT and (2) an optimized regimen in the absence of ibalizumab,” the investigators said.

“The [current] MAIC analyses are useful because of the absence of a long-term OBT-alone control group in the BRIGHTE trial and the need to compare outcomes with ibalizumab, another ARV indicated for the HTE population,” they added. [N Engl J Med 2018;379:645-654]

However, the investigators acknowledged that the suitability of the comparator data in the MAIC was not only complicated by highly heterogeneous existing optimized regimens and patient populations but also by the changing availability of OBT, which involve a wide range of ARV regimens. This might explain the finding of greater relative benefits with fostemsavir plus OBT vs OBT alone in the BENCHMRK comparison than in the VIKING-3 comparison.

“BENCHMRK started 9 years earlier than BRIGHTE, OBT regimens used at that time may not reflect the more contemporary regimens used in BRIGHTE (eg, dolutegravir was not available during BENCHMRK), and differences could exist in resistance measurement over time. Therefore, the efficacy of OBT in BENCHMRK may have been underestimated in the present analysis despite participants having comparable susceptibility scores to OBT,” the investigators said.

Nevertheless, as fostemsavir is indicated for HTE individuals with multidrug-resistant HIV-1 who are failing their current ARV regimen, it could be said that there is no suitable comparator for this patient group and that a comparator regimen is not available, they added.

“Interpretation of [the present] results and application to health technology assessment and economic evaluation require careful consideration of the therapies likely to be available to HTE people with multidrug-resistant HIV-1 and their resistance profiles to understand what the true comparator would be if fostemsavir were not available,” the researchers said.