Lenacapavir with Fostemsavir in a Multidrug-Resistant HIV-Infected Hemodialysis Patient

We report a hemodialysis MDR HIV-infected patient switched to fostemsavir with lenacapavir plus lamivudine for more than a year. She maintained a suppressed viral replication and did not present any clinical or biological drug-related side effects. The combination of lenacapavir plus fostemsavir looks promising in terms of safety and efficacy even in patients with end-stage renal disease awaiting renal transplant. Both drugs are first in class ARVs so that there is no cross resistance with previous drugs, maintaining their efficacy against MDR HIV.


Introduction
HIV-infected patients with end-stage renal disease (ESRD) have limited therapeutic options, even more if they harbor antiretroviral (ARV)-resistant HIV strains.Lenacapavir (LEN) [1] and fostemsavir (FTR) [2] are two recently approved ARVs combining activity against multidrug-resistant HIV, a possible administration in patients receiving hemodialysis or peritoneal dialysis, and a manageable drug-drug interactions (DDIs), for example, with antirejection medication in the case of renal transplantation.Tey have no cross-resistance with previous ARV classes and could be administered together, without anticipated mutual DDI.
Fostemsavir (FTR) is a frst-in-class prodrug metabolized to temsavir (TMR) by alkaline phosphatase on the luminal surface of the small intestine.It binds to the gp120 subunit of HIV-1, thus preventing viral attachment and cellular entry [3].Temsavir pharmacokinetics may be affected by drugs inducing or inhibiting P-glycoprotein, CYP3A enzymes, esterases, and/or breast cancer-resistant protein (BCRP) [4].However, pharmacokinetics (PKs) interaction studies with other ARVs (ritonavir, cobicistat, and NNRTI) showed no signifcant changes in TMR concentrations when coadministered with strong inhibitors or moderate inducers of CYP3A4, P-gp, or BCRP [4].On the contrary, TMR has no efect on CYP3A4 and anticipated weak DDI with other drugs including tacrolimus [5].TMR may increase the level of certain direct anti HCV drugs by organic anion transporting polypeptide (OATP)1B1/3 inhibition.TMR PK is not altered in ESDR patients including those on hemodialysis [6].
Lenacapavir (LEN), a frst-in-class drug, is an HIV capsid inhibitor.It interferes at multiple stages, thus disrupting the viral multiplication cycle with a prolonged duration of action [1].Lenacapavir is administered with an oral induction phase followed by a maintenance subcutaneous dose every 6 months.No dosage adjustment of lenacapavir is recommended in patients with mild, moderate, or severe renal impairment.Tere are no data in patients with ESRD.As LEN is highly protein bound, no      [7].Tere is a potential increase in several drugs' levels, including tacrolimus.
Tere is no report of the use of LEN in association with FTR in ESRD HIV-infected patients in terms of efcacy and safety.We report here the frst HIV-infected hemodialysis patient treated with LEN/FTR/lamivudine.

Ethical Aspects.
Te patient has given her written informed consent for publication.Lenacapavir is available through a compassionate access program by Gilead.

Discussion
We report an ESRD MDR HIV-infected patient switched to FTR with LEN plus lamivudine for more than a year.She maintained a suppressed viral replication and did not present any clinical or biological drug-related side efects (Table 2).
Tere is no switch study using FTR or LEN in virally suppressed HIV-infected patients or a study combining these two drugs yet.However, in our patient, the number of daily tablets dramatically dropped from 7 to 3 combined with biannual subcutaneous injections.Two drugs regimens are now common in order to avoid NRTIs or boosted-PI [10].LEN plus optimal backbone ARVs (OBR) has shown superior virological efcacy compared to other regimens, in particular FTR + OBR, in heavily treatment-experienced (HTE) patients failing their regimen [11].As experienced by our patient, the most prevalent side efect of LEN is injection site pain and induration.TMR is associated with metabolic abnormalities (glucose and lipid levels) in 4-5% of the patients.Decrease in GFR in some patients did not appear to be FTR related.Our patient did not experience signifcant changes in liver enzymes, glucose, or lipid levels.After subcutaneous administration, LEN has a half-life of 8-12 weeks, the frst real long-acting ARV.Search for companion drugs to coadminister with LEN is in progress, like the ultra-long-acting parenteral prodrug formulation of dolutegravir [12].A biannual subcutaneous two drugs' regimen could be a true game changer for adherence [13].Costs and drug's availability remain an issue.A preprint has previously been published [14].

Conclusion
Te combination of lenacapavir and fostemsavir is a viable treatment option for highly treatment-experienced patients either as a rescue regimen or as a switch regimen.It decreases the pill burden and the potential for drug-drug interactions.Lenacapavir and/or fostemsavir appear to be safe in end-stage renal disease patients including those on hemodialysis.Metabolic side efects and efect on weight have still to be evaluated.Prospective studies using this combination are required as rescue, switch, or even frst-line therapy.

Table 1 :
Evolution of the viral resistances according to time.

Table 2 :
Antiretroviral treatment and biological data history.HD) is expected.It is mainly cleared unchanged in the stools, with less than 1% excreted by the urine.It is a substrate of P-gp, UGT1A1, and CYP3A; hence, inducers or inhibitors of those enzymes seriously afect the PK of LEN.LEN itself is a moderate inhibitor of CYP3A afecting coadministered medication