Successful switch to rilpivirine/tenofovir/emtricitabine inHIV-1-infected patients with an isolated K103N mutationacquired during prior nonnucleoside reverse transcriptaseinhibitor therapyC Rokx, A Verbon and BJA RijndersDepartment of Internal Medicine and Infectious Diseases, Erasmus University Medical Center, Rotterdam, theNetherlands

ObjectivesWhether treatment-experienced HIV-1-infected patients with an acquired K103N mutation afterfailing nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens can be treated withrilpivirine is unknown. The aim of this pilot study was to evaluate the efficacy of rilpivirine/tenofovir/emtricitabine in HIV-1-infected patients with an isolated K103N mutation.

MethodsA prospective study was carried out in HIV-1-infected adults who acquired the K103N mutationon failing NNRTI regimens. No other mutations in reverse transcriptase were allowed. Patientshad to be on second-line regimens with HIV-1 RNA < 200 copies/mL for ≥ 6 months. Exclusioncriteria were: use of acid-reducing agents, insufficient caloric intake and impaired renalfunction. Of primary interest was virological success (HIV-1 RNA < 200 copies/mL) at weeks 6,12, 24 and 48.

ResultsOf 1550 HIV-1-infected patients at the Erasmus Medical Center Rotterdam, we identified 10HIV-1-infected patients with an isolated K103N mutation acquired after NNRTI failure. Fivepatients were not eligible for inclusion in the study, and two patients refused participation. ThreeAfrican women (23–35 years of age) were included and were switched from boosted proteaseinhibitor-based second-line therapies to rilpvirine/tenofovir/emtricitabine. HIV-1 RNA was < 200copies/mL at weeks 6, 12, 24 and 48 for all patients. No adverse events were observed. Allpatients had HIV-1 RNA < 200 copies/mL for 6−50 months prior to the switch.

ConclusionsThis pilot study demonstrates the successful switch of HIV-1-infected patients who acquired anisolated K103N mutation during previous NNRTI therapy to rilpivirine/tenofovir/emtricitabine. Inselected patients, single-tablet regimens are also becoming a valid treatment option forsecond-line HIV-1 therapy.

Keywords: antiretroviral therapy, drug resistance, HIV-1, single tablet regimen

Accepted 7 March 2014

Introduction

Susceptibility to the first-generation nonnucleoside reversetranscriptase inhibitors (NNRTIs) efavirenz and nevirapine

is severely impaired in HIV-1 harbouring a transmitted oracquired K103N mutation. This mutation has no impacton the in vitro susceptibility of HIV-1 to the second-generation NNRTI rilpivirine [1]. In the case of a transmit-ted K103N-containing HIV-1 infection, rilpivirine mightstill be a first-line treatment option for therapy-naïvepatients. This was recently shown for patients with trans-mitted K103N mutated HIV-1 in the the Switching boosted

Correspondence: Dr Casper Rokx, Department of Internal Medicine andInfectious Diseases, Room Z-840, Erasmus University Medical Center, POBox 2040, 3000 CA Rotterdam, The Netherlands. Tel: +31 [0]6 813 36328; fax: +31 [0]10 703 3875; e-mail: c.rokx@erasmusmc.nl

DOI: 10.1111/hiv.12157© 2014 British HIV Association HIV Medicine (2014), 15, 611–614

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PI to Rilpvirine in combination with Truvada as single-tablet-regimen (SPIRIT) trial [2]. In this study, virologicallysuppressed HIV-1-infected patients on boosted proteaseinhibitor (PI) regimens switched to single-tablet rilpivirine/tenofovir/emtricitabine. All 18 patients with transmittedK103N mutated HIV-1 infections remained virologicallysuppressed 24 weeks after the switch.

However, whether treatment-experienced HIV-1-infectedpatients with acquired K103N-containing HIV-1 infectionsfollowing NNRTI failure can be effectively treated witha rilpivirine-containing regimen is currently unknown.Drug-resistant minority HIV-1 variants that remain unde-tected during standard genotyping may also impact thetreatment response in these patients. A phase II study onthe use of rilpivirine in treatment-experienced patientswho failed previous NNRTI-containing regimens showed asignificant decline in HIV-1 RNA after 7 days of treatment[3]. This observation suggests a potential role for rilpivirinein clinical settings as second-line therapy for HIV-1-infected patients with an acquired K103N mutation. In thispilot study, we prospectively evaluated the virological effi-cacy of a switch to the single-tablet regimen rilpivirine/tenofovir/emtricitabine as second-line therapy in HIV-1-infected patients with an acquired and isolated K103Nmutation who were virological suppressed first by othersecond-line regimens.

Methods

Eligible adult HIV-1-infected patients had to be on second-line boosted PI-containing regimens, to which thesepatients had been switched after failing their previousNNRTI regimens. Apart from the acquired K103N mutationfollowing their failing NNRTI-containing therapies, noother acquired mutations in reverse transcriptase associ-ated with intermediate or higher resistance levels (accord-ing to the Stanford HIV drug resistance database) wereallowed [4]. HIV-1 RNA < 200 copies/mL for at least 6months was required for eligibility prior to a potentialswitch to the single-tablet regimen rilpivirine/tenofovir/emtricitabine. Patients with an impaired renal function,defined as a baseline estimated glomerular filtration rate< 60 mL/min (according to the Modification of Diet inRenal Disease formula), were not eligible.

The treating physicians informed the patients of thenecessity of an adequate caloric intake and excludedpatients with concomitant use of antacids or other disal-lowed potentially interacting co-medications. It wasexplained to patients that it was as yet uncertain whether therilpivirine-based therapy would result in durable HIV-1suppression and that, in the case of subsequent virologicalfailure, patients would be switched back to their original

boosted PI-containing regimens. Treatment adherencewas assessed and documented by the treating physicians.All data were obtained from the electronic medicalcharts. Patients were prospectively evaluated after startingrilpivirine/tenofovir/emtricitabine at 6, 12, 24 and 48 weeksof follow-up on self-reported therapy adherence, clinicaland biochemical adverse events and HIV-1 RNA.

The primary outcome was virological success, defined ashaving HIV-1 RNA < 200 copies/mL at weeks 6, 12, 24 and48 after the switch. HIV-1 RNA > 200 copies/mL at weeks6, 12, 24 and 48 was considered virological failure, whichwould lead to discontinuation of rilpivirine/tenofovir/emtricitabine and restarting of the prior boosted PI-basedsecond-line regimen.

Results

Ten treatment-experienced HIV-1-infected patients (sixwomen) were identified with an isolated K103N mutation,from approximately 1550 HIV-1-infected patients receivingcare at the Erasmus University Medical Center Rotterdamin the Netherlands. The isolated K103N mutations in thesepatients were acquired following virological failure oneither efavirenz- or nevirapine-based regimens. All 10patients were on boosted PI-containing second-line regi-mens. One patient was not eligible for a switch to rilpivirinebecause of concomitant mandatory antacid treatment.Furthermore, two patients did not have HIV-1 RNA < 200copies/mL for at least 6 months and two patients were nolonger receiving their medical care at our site. Of the fiveeligible patients, two patients were not interested in chang-ing their antiretroviral regimens. Three eligible patientsgave informed consent and were included in the pilot study.

Three African women, 23 to 35 years of age, switchedtheir boosted PI regimens to the single-tablet regimenrilpivirine/tenofovir/emtricitabine (Table 1). This resultedin continued plasma HIV-1 RNA < 200 copies/mL atweeks 6, 12, 24 and 48 in all three patients. At the start ofrilpivirine therapy, two patients (patients 1 and 2) hadHIV-1 RNA < 50 copies/mL and one patient had HIV-1RNA of 64 copies/mL. Patients 1 and 2 continued to haveHIV-1 RNA < 50 copies/mL during 48 weeks of follow-up.The HIV-1 RNA of patient 3 was < 50 copies/mL at week 12and in the 50−200 copies/mL range at 24 and 48 weeks.The self-reported drug adherence of patient 3 was 95%during follow-up. No other adherence problems or adverseevents were reported during the 48 weeks of follow-up.

HIV-1 infections were diagnosed in 1997 (patient 1),2006 (patient 2) and 2002 (patient 3) and no resistance toHIV-1 reverse transcriptase was documented at diagnosis.At first presentation, patient 1 had HIV-1 RNA of 59 100copies/mL, patient 2 of > 100 000 copies/mL and patient 3

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© 2014 British HIV Association HIV Medicine (2014), 15, 611–614

of 4900 copies/mL. Nadir CD4 cell counts prior to initiationof the first antiretroviral regimens were 60, 120 and 250cells/μL, respectively. All patients were therapy-naïve whenthey started antiretroviral treatment with their NNRTI-based regimens and all acquired the isolated K103N muta-tion at the time of failure of these NNRTI-based regimens.Patient 1 acquired the K103N mutation following virologi-cal failure on efavirenz and lamivudine/zidovudine, patient2 acquired it after failure on nevirapine and tenofovir/emtricitabine and patient 3 acquired it after failure onefavirenz and tenofovir/emtricitabine. HIV-1 RNA at viro-logical failure on the NNRTI regimens was 34 300copies/mL in patient 1 and > 100 000 copies/mL in patients2 and 3. The total time on the boosted PI-containingsecond-line therapies prior to the switch to rilpivirine was154, 66 and 63 months, respectively. The treatment of theincluded patients with boosted PI regimens had resulted inHIV-1 RNA < 200 copies/mL for 50, 37 and 6 months inpatients 1, 2 and 3, respectively, and the patients had aminimum CD4 cell count at the initiation of rilpivirine of550 cells/μL.

Discussion

The observations in our pilot study suggest that adultHIV-1-infected patients with an isolated K103N mutation,acquired during a previously failing NNRTI-based therapy,can be safely switched to a single-tablet regimen contain-ing rilpivirine/tenofovir/emtricitabine after long-termHIV-1 RNA suppression has first been achieved on second-line PI-based regimens. This strategy might provide anefficacious NNRTI-based second-line antiretroviral therapythat has a favourable toxicity profile and is availableas a single-tablet regimen for a selected but considerablenumber of HIV-1-infected patients.

We realize that no definite conclusions can be drawnfrom the observations in this small study, as no comparatorarm was included and the follow-up time was limited to48 weeks. Of importance, and in contrast to a transmitted

K103N-harbouring HIV-1 infection, other resistance-associated mutations could have been selected which arenot yet detectable by standard genotyping. Failure to suc-cessfully suppress the HIV-1 infection with a suboptimalsecond-line therapy could rapidly induce the emergence ofa more resistant virus [5]. Furthermore, in vitro data suggestthat an isolated K103N mutation could facilitate the devel-opment of an E138K mutation following rilpivirine drugpressure [6]. Therefore, it seems imperative that the HIV-1infection is first controlled by a boosted PI-based regimenprior to starting rilpivirine. If patients are to be switched,frequent monitoring during the first 6 months of therapy isprobably necessary to allow for a prompt change in therapyif plasma HIV-1 RNA rebounds.

If confirmed in future studies, the applicability of ourapproach may be substantial. A recent study showedthat only 14.5% of HIV-1-infected patients who failedefavirenz-containing regimens and 25% of HIV-1-infectedpatients failing nevirapine-containing regimens acquiredrilpivirine resistance [7]. Specific major NRTI resistance toemtricitabine or tenofovir could occur after failing first-line therapy. However, the majority of patients treated witha non-thymidine analogue-containing NRTI backbone incombination with efavirenz or nevirapine lack majorresistance to tenofovir and emtricitabine [8,9]. Therefore,the possibility to treat patients with rilpivirine/tenofovir/emtricitabine as a single-tablet regimen could still be pre-served in a considerable number of HIV-1-infected patientswho acquired an isolated K103N mutation on previousantiretroviral therapies.

To our knowledge, this is the first study in which asingle-tablet regimen was used for second-line antire-troviral therapy after previous NNRTI failure. As othersingle-tablet regimens are being introduced in the nearfuture, the potential role of these co-formulated drugs assuitable second-line therapies is likely to increase substan-tially. A future prospective and preferably randomized studyis needed to confirm our findings and also to evaluate theimpact of minor resistance variants on treatment success.

Table 1 Characteristics of the HIV-1-infected patients who switched to rilpivirine/tenofovir/emtricitabine after acquiring an isolated K103Nmutation on previous efavirenz- or nevirapine-based antiretroviral regimens

Patient

Antiretroviral regimen* HIV-1 RNA (copies/mL)

Age(years)†

HIV-1diagnosis Subtype

HIV-1 RNA(copies/mL)

CD4 count(cells/μL)

At failure NNRTIregimen

At failure HIV-1RNA (copies/mL)

At switch toRPV/TDF/FTC

Week0

Week12

Week24

Week48

1 23 1997 CRF01_AE 59 100 60 EFV, 3TC/ZDV 34 300 LPV/r, ABC/3TC <50 <50 <50 <502 35 2006 CRF02_AG >100 000 120 NVP, TDF/FTC >100 000 ATV/r, TDF/FTC <50 <50 <50 <503 32 2002 CRF02_AG 4900 250 EFV, TDF/FTC >100 000 DRV/r, 3TC/ZDV 64 <50 70 76

*A ‘/’ symbol indicates fixed-dose co-formulations. †Age at the switch to rilpivirine/tenofovir/emtricitabine. 3TC, lamivudine; ABC, abacavir; ATV/r,atazanavir/ritonavir; DRV/r, darunavir/ritonavir; EFV, efavirenz; FTC, emtricitabine; LPV/r, lopinavir/ritonavir; NNRTI, nonnucleoside reverse transcriptaseinhibitor; NVP, nevirapine; RPV, rilpivirine; TDF, tenofovir; ZDV, zidovudine.

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© 2014 British HIV Association HIV Medicine (2014), 15, 611–614

In conclusion, our results indicate that a substantialsubgroup of HIV-1-infected patients with an isolatedK103N mutation, acquired on previous failing NNRTI regi-mens, could potentially benefit from rilpivirine in a single-tablet regimen after virological suppression has first beenachieved on other second-line regimens.

Acknowledgements

Contributions to authorship: All authors made sub-stantial contributions to the study design and the collec-tion, analysis and interpretation of the data. All authorscontributed to the manuscript and approved the finalversion.

Conflicts of interest: BJAR reports a research grant fromGilead Sciences outside the context of the submitted work.The other authors have no conflicts of interest to declare.

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