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Islatravir Dose Optimization and Data on LA CAB + RPV in the Real World: Perspectives From Latin America

Brenda E. Crabtree Ramírez, MD

Assistant Professor, HIV Program
Department of Infectious Diseases
Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán
Mexico City, Mexico


Brenda E. Crabtree Ramírez, MD: consultant/advisor/speaker: GlaxoSmithKline, MSD.


View ClinicalThoughts from this Author

Released: November 22, 2022

Key Takeaways

  • A modeling analysis of islatravir doses predicted that at 0.25 mg daily, lymphocyte changes would be similar to other antiretroviral therapy regimens and effective concentrations would be reached.
  • In the real-world US OPERA Cohort, long-acting cabotegravir plus rilpivirine was highly effective, including in a small number of individuals who were not virologically suppressed at initiation.

Several studies presented at the fall 2022 conferences will inform the future use of newer antiretroviral options in Latin America. Here are my thoughts on 2 such studies.

Modeling and Simulation of Optimal Islatravir Dose
Islatravir (ISL) is the first nucleoside reverse-transcriptase translocation inhibitor that has approached clinical phase trials for the treatment and prevention of HIV. The FDA put trials of ISL on a clinical hold in December 2021 because of concern about decreases in total lymphocytes and absolute CD4 cell counts. According to investigators, the mechanism for this decrease in lymphocytes is that the active form, ISL triphosphate, accumulates in lymphocytes and causes apoptosis. It is not due to mitochondrial toxicity, which can occur with other antiretrovirals. 

At HIV Glasgow 2022, Vargo and colleagues presented modeling data for the selection of the optimal ISL daily dose. Through modeling and simulations, they assessed the changes in total lymphocyte and CD4 cell counts for virologically suppressed individuals participating in clinical trials on ISL who were exposed to effective concentrations for both wild-type and M184V/I HIV strains.

Through the model, the investigators demonstrated that ISL 0.25 mg daily reached the desired effective concentrations of active drug in peripheral blood mononuclear cells for both wild-type and M184V/I variants.

Moreover, from a database of 64 publications from 2015-2020, which represented 19,847 people with HIV (PWH) from 50 studies in 103 different antiretroviral therapy (ART) study arms, they calculated the mean change in CD4 cell counts of people virologically suppressed while receiving ART. With this mean change as reference, they predicted that ISL 0.25 mg daily will have a similar impact on the mean changes of CD4 cell counts when compared with other ART regimens in this data set.

Based on this data, investigators plan to use ISL 0.25 mg daily in combination with doravirine in future phase III studies for ART-naive and virologically suppressed patient populations.

We will have to wait to see what happens with lymphocyte changes in the planned clinical trials ahead. Nevertheless, it is exciting to see a new antiretroviral agent as part of dual treatment of HIV that could be a simple option for patients in Latin America in the future.

Real-world Effectiveness of LA CAB Plus RPV in First Year in US OPERA Cohort
Long-acting (LA) cabotegravir (CAB) plus rilpivirine (RPV) has proven to be noninferior to standard of care regimens in PWH who are stable while receiving ART in the ATLAS, FLAIR, and ATLAS-2M studies and has been approved for use as a complete ART regimen for virologically suppressed individuals in the United States since January 2021.

At IDWeek 2022, investigators presented data from individuals in the OPERA cohort who received LA CAB plus RPV from January 2021 to February 2022. The OPERA cohort consists of 145,398 PWH across 96 clinics and includes approximately 14% of PWH in the United States. Using this cohort, investigators aimed to describe the real-world virologic effectiveness of LA CAB plus RPV through the following outcomes: frequency of virologic failure defined as 2 consecutive HIV-1 RNA values of ≥200 copies/mL or a single value ≥200 copies/mL that led to discontinuation of the regimen. Discontinuation also was considered when 2 or more doses were missed.

In total, 383 patients were included in the analysis; 84% (n = 321) had HIV-1 RNA <50 copies/mL at LA CAB plus RPV initiation, 7% (n = 27) had HIV-1 RNA 50-200 copies/mL, and 7% (n = 28) had HIV-1 RNA ≥200 copies/mL at initiation. Most patients had monthly dosing frequency (79%).

Of those with HIV-1 RNA <50 copies/mL at initiation, 95% maintained HIV-1 RNA <50 copies/mL throughout follow-up, and 99% maintained HIV-1 RNA <200 copies/mL. There was similar effectiveness in those with HIV-1 RNA 50-200 copies/mL at initiation.

Although 7% had HIV-1 RNA >200 copies/mL at initiation, 89% were still receiving the LA regimen at the end of follow-up, and 91% of those who were not virologically suppressed at initiation achieved HIV-1 RNA <200 copies/mL. Investigators reported that there were multiple types of oral bridging strategies across sites; this was poorly documented in the electronic clinical records, which could have implications on the study results and clinical outcomes. Nevertheless, LA CAB plus RPV in the real-world setting was shown through this study to be highly effective, including in a small number of patients who were not virologically suppressed at the time of initiation.

This study shows promising data for the use of LA CAB plus RPV in the real world. However, access to such treatments is still unequal throughout the world, and questions regarding implementation effectiveness and challenges within resource-constrained settings—such as the Latin American region—remain unanswered.

Your Thoughts?
How do you think the data on lymphocyte changes will impact the future development of ISL for HIV treatment? How are you considering the latest real-world data on LA CAB plus RPV for your patients? Join the discussion and share your experiences by posting a comment.

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