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Differences in antiretroviral regimens do not impact safety or level of latency reversal in persons receiving romidepsin

Jørgensen, Sofiea,b; Leth, Steffena,b; Sommerfelt, Majac; Østergaard, Larsa,b; Tolstrup, Martina,b; Søgaard, Ole S.a,b

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doi: 10.1097/QAD.0000000000001904

The potent HIV-1 latency reversal agent (LRA) romidepsin (Istodax, Celgene) is primarily metabolized by cytochrome P450 3A4 (CYP3A4) [1,2]. As components in antiretroviral therapy (ART) such as ritonavir-boosted protease inhibitors (PI) and cobicistat-boosted integrase inhibitors (INI) inhibit CYP3A4, whereas nonnucleoside reverse-transcriptase inhibitors (NNRTI) induce CYP3A4 [3,4], there is a risk of drug–drug interactions (DDI) between ART and romidepsin in clinical HIV-1 eradication trials. The current report is a post-hoc investigation of potential DDIs between romidepsin and ART regimens in HIV-1 participants enrolled in the REDUC study [5,6].

In this two-step, single-arm, open-phase 1B/2A clinical HIV-1 eradication trial, participants received 5 mg/m2 romidepsin once a week for 3 weeks while maintaining ART. Blood was drawn 1 h prior to and 30 min after each infusion. The patients received two nucleoside reverse-transcriptase inhibitors (NRTI) as ART backbone components. In the current analysis, participants were stratified into three groups according to the third component in their ART regimen: PI-based, NNRTI/NRTI-based and INI-based groups.

As a pharmacokinetic outcome measure, the romidepsin concentrations were measured using liquid chromatography–mass spectrometry (performed at PPD Bioanalytical Laboratory, USA). As a pharmacodynamic outcome measure, lymphocyte histone H3 acetylation was measured using flow cytometry as described previously [5]. The latency reversal effect of romidepsin was determined by HIV-1 transcriptional activity using digital droplet PCR and as plasma HIV-1 RNA using the COBAS Taqman Assay (Roche). Adverse events were self-reported by questionnaire and graded according to Common Terminology Criteria for Adverse events, version 4.0 [7]. Comparison of baseline characteristics was performed using the Kruskal–Wallis test for continuous variables and Fisher's exact test for categorical variables. A Kruskal–Wallis test was performed to test for significant differences in outcomes measures between the groups.

All 23 participants in the REDUC study were included and divided into three groups according to ART regimen (PI-based n = 14; NNRTI/NRTI-based n = 7; INI-based n = 2). No significant differences in baseline characteristics between the groups were evident (Supplementary Table 1, https://links.lww.com/QAD/B302). Romidepsin concentrations, histone H3 acetylation levels and HIV-1 transcriptional activity after each romidepsin infusion were not significantly different between the ART groups (Fig. 1a–c). All three groups showed similar cyclic increases in plasma HIV-1 RNA following each romidepsin infusion (Fig. 1d). In total, 92 adverse events related to romidepsin were registered during the study. All were grade 1 with the most frequently being fatigued and nauseated (Supplementary Table 2, https://links.lww.com/QAD/B302). The number and type of adverse events did not differ significantly according to ART regimens (Supplementary Table 3, https://links.lww.com/QAD/B302).

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Fig. 1:
No difference in outcome measures between antiretroviral therapy regimens.Romidepsin drug concentration (a), mean fold change in histone H3 acetylation (b) and mean fold change in HIV-1 transcriptional activity (c) stratified according to antiretroviral therapy regimen at baseline and after repetitive romidepsin infusions; box-and-whisker plot with median, range. P values were determined by a Kruskal–Wallis test. Baseline samples were collected 1 h prior to the first romidepsin infusion (day 0). The postinfusion samples were collected 30 min after each repetitive infusion during the 3 weeks (days 0, 7 and 14). Cyclic pattern of median viral load measurements stratified according to antiretroviral therapy regime (d), the three arrows indicate romidepsin infusions during the 3 weeks (days 0, 7 and 14). Only patients from the first-step trial were included in the plasma HIV-1 RNA analysis to avoid potential bias from the therapeutic immunization phase, which occurred prior to the romidepsin infusions in the second-step of the trail. CA-US HIV-1 RNA, cell-associated unspliced HIV-1 RNA; HIV-1, human immune-deficiency virus type 1; INI, integrase inhibitor; NNRTI, non-nucleoside analog reverse-transcriptase inhibitor; NRTI, nucleoside reverse-transcriptase inhibitor; PI, protease inhibitor.

The current post-hoc analysis of a clinical trial found no significant differences in pharmacokinetic, pharmacodynamics, effect on virus reactivation or safety when comparing co-administration of romidepsin and different ART regimens. Consistent with our results, Iwamoto et al.[8] did not find any decrease in romidepsin exposure when coadministrated with a CYP3A4-inducing antiepileptic drug in cancer patients. In addition, only a modest increase in romidepsin exposure was observed when it was coadministrated with ketoconazole classified as a strong CYP3A4 inhibitor [9]. Interestingly, a single-nucleotide polymorphism in CYP3A4/5 did not affect the pharmacokinetics of romidepsin [10]. Thus, other CYP enzymes may contribute significantly to the in-vivo metabolism of romidepsin when the CYP3A4 pathway is inhibited.

Our analysis had some limitations. Within the NNRTI/NRTI-group, four out of seven participants received efavirenz (EFV) and one received nevirapine (NPV), with both drugs classified as CYP3A4 inducers [10]. One participant received rilpivirine, a substrate of CYP3A4, and the last participant in the group received an NRTI as third component, which do not interfere with CYP3A4 at all. This heterogeneity of interacting profiles within the NNRTI/NRTI-group could lead to an underestimation of the effect of EFV/NPV on CYP3A4 induction. Also, the participants were not sampled as intensively as in a true pharmacokinetic study. More frequent samplings would have contributed to a more detailed description of the pharmacokinetic profile of romidepsin and allowed calculations of AUC and Cmax. Lastly, this analysis was carried out on a small study population. Only patients from the first-step trial (n = 6) were included in the plasma HIV-1 RNA analysis to avoid potential bias from the therapeutic immunization phase, which occurred prior to the romidepsin infusions in the second-step of the trail.

Despite these caveats, our results have important implications for the HIV-1 eradication field and for novel trials utilizing romidepsin as a LRA. Our findings suggest that a romidepsin dose of 5 mg/m2 is well tolerated and effective in patients receiving different ART regimens regardless of ART-specific metabolic profile.

Acknowledgements

The current study was funded by The research Council of Norway, SkatteFUNN, Bionor Pharma.

Conflicts of interest

There are no conflicts of interest.

References

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