Successful switch to rilpivirine/tenofovir/emtricitabine in HIV-1-infected patients with an isolated K103N mutation acquired during prior nonnucleoside reverse transcriptase inhibitor therapy


  • C Rokx,

    Corresponding author
    1. Department of Internal Medicine and Infectious Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands
    • Correspondence: Dr Casper Rokx, Department of Internal Medicine and Infectious Diseases, Room Z-840, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Tel: +31 [0]6 813 363 28; fax: +31 [0]10 703 3875; e-mail:

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  • A Verbon,

    1. Department of Internal Medicine and Infectious Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands
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  • BJA Rijnders

    1. Department of Internal Medicine and Infectious Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands
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Whether treatment-experienced HIV-1-infected patients with an acquired K103N mutation after failing nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens can be treated with rilpivirine 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.


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


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


This pilot study demonstrates the successful switch of HIV-1-infected patients who acquired an isolated K103N mutation during previous NNRTI therapy to rilpivirine/tenofovir/emtricitabine. In selected patients, single-tablet regimens are also becoming a valid treatment option for second-line HIV-1 therapy.


Susceptibility to the first-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine is severely impaired in HIV-1 harbouring a transmitted or acquired K103N mutation. This mutation has no impact on the in vitro susceptibility of HIV-1 to the second-generation NNRTI rilpivirine [1]. In the case of a transmitted K103N-containing HIV-1 infection, rilpivirine might still be a first-line treatment option for therapy-naïve patients. This was recently shown for patients with transmitted K103N mutated HIV-1 in the the Switching boosted PI to Rilpvirine in combination with Truvada as single-tablet-regimen (SPIRIT) trial [2]. In this study, virologically suppressed HIV-1-infected patients on boosted protease inhibitor (PI) regimens switched to single-tablet rilpivirine/tenofovir/emtricitabine. All 18 patients with transmitted K103N mutated HIV-1 infections remained virologically suppressed 24 weeks after the switch.

However, whether treatment-experienced HIV-1-infected patients with acquired K103N-containing HIV-1 infections following NNRTI failure can be effectively treated with a rilpivirine-containing regimen is currently unknown. Drug-resistant minority HIV-1 variants that remain undetected during standard genotyping may also impact the treatment response in these patients. A phase II study on the use of rilpivirine in treatment-experienced patients who failed previous NNRTI-containing regimens showed a significant decline in HIV-1 RNA after 7 days of treatment [3]. This observation suggests a potential role for rilpivirine in clinical settings as second-line therapy for HIV-1-infected patients with an acquired K103N mutation. In this pilot study, we prospectively evaluated the virological efficacy 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 K103N mutation who were virological suppressed first by other second-line regimens.


Eligible adult HIV-1-infected patients had to be on second-line boosted PI-containing regimens, to which these patients had been switched after failing their previous NNRTI regimens. Apart from the acquired K103N mutation following their failing NNRTI-containing therapies, no other acquired mutations in reverse transcriptase associated with intermediate or higher resistance levels (according to the Stanford HIV drug resistance database) were allowed [4]. HIV-1 RNA < 200 copies/mL for at least 6 months was required for eligibility prior to a potential switch 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 in Renal Disease formula), were not eligible.

The treating physicians informed the patients of the necessity of an adequate caloric intake and excluded patients with concomitant use of antacids or other disallowed potentially interacting co-medications. It was explained to patients that it was as yet uncertain whether the rilpivirine-based therapy would result in durable HIV-1 suppression and that, in the case of subsequent virological failure, patients would be switched back to their original boosted PI-containing regimens. Treatment adherence was assessed and documented by the treating physicians. All data were obtained from the electronic medical charts. Patients were prospectively evaluated after starting rilpivirine/tenofovir/emtricitabine at 6, 12, 24 and 48 weeks of follow-up on self-reported therapy adherence, clinical and biochemical adverse events and HIV-1 RNA.

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


Ten treatment-experienced HIV-1-infected patients (six women) were identified with an isolated K103N mutation, from approximately 1550 HIV-1-infected patients receiving care at the Erasmus University Medical Center Rotterdam in the Netherlands. The isolated K103N mutations in these patients were acquired following virological failure on either efavirenz- or nevirapine-based regimens. All 10 patients were on boosted PI-containing second-line regimens. One patient was not eligible for a switch to rilpivirine because of concomitant mandatory antacid treatment. Furthermore, two patients did not have HIV-1 RNA < 200 copies/mL for at least 6 months and two patients were no longer receiving their medical care at our site. Of the five eligible patients, two patients were not interested in changing their antiretroviral regimens. Three eligible patients gave informed consent and were included in the pilot study.

Three African women, 23 to 35 years of age, switched their boosted PI regimens to the single-tablet regimen rilpivirine/tenofovir/emtricitabine (Table 1). This resulted in continued plasma HIV-1 RNA < 200 copies/mL at weeks 6, 12, 24 and 48 in all three patients. At the start of rilpivirine therapy, two patients (patients 1 and 2) had HIV-1 RNA < 50 copies/mL and one patient had HIV-1 RNA of 64 copies/mL. Patients 1 and 2 continued to have HIV-1 RNA < 50 copies/mL during 48 weeks of follow-up. The HIV-1 RNA of patient 3 was < 50 copies/mL at week 12 and 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 adverse events were reported during the 48 weeks of follow-up.

Table 1. Characteristics of the HIV-1-infected patients who switched to rilpivirine/tenofovir/emtricitabine after acquiring an isolated K103N mutation on previous efavirenz- or nevirapine-based antiretroviral regimens
Patient Antiretroviral regimen*HIV-1 RNA (copies/mL)
Age (years)HIV-1 diagnosisSubtypeHIV-1 RNA (copies/mL)CD4 count (cells/μL)At failure NNRTI regimenAt failure HIV-1 RNA (copies/mL)At switch to RPV/TDF/FTCWeek 0Week 12Week 24Week 48
  1. *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 transcriptase inhibitor; NVP, nevirapine; RPV, rilpivirine; TDF, tenofovir; ZDV, zidovudine.
1231997CRF01_AE59 10060EFV, 3TC/ZDV34 300LPV/r, ABC/3TC<50<50<50<50
2352006CRF02_AG>100 000120NVP, TDF/FTC>100 000ATV/r, TDF/FTC<50<50<50<50
3322002CRF02_AG4900250EFV, TDF/FTC>100 000DRV/r, 3TC/ZDV64<507076

HIV-1 infections were diagnosed in 1997 (patient 1), 2006 (patient 2) and 2002 (patient 3) and no resistance to HIV-1 reverse transcriptase was documented at diagnosis. At first presentation, patient 1 had HIV-1 RNA of 59 100 copies/mL, patient 2 of > 100 000 copies/mL and patient 3 of 4900 copies/mL. Nadir CD4 cell counts prior to initiation of the first antiretroviral regimens were 60, 120 and 250 cells/μL, respectively. All patients were therapy-naïve when they started antiretroviral treatment with their NNRTI-based regimens and all acquired the isolated K103N mutation at the time of failure of these NNRTI-based regimens. Patient 1 acquired the K103N mutation following virological failure on efavirenz and lamivudine/zidovudine, patient 2 acquired it after failure on nevirapine and tenofovir/emtricitabine and patient 3 acquired it after failure on efavirenz and tenofovir/emtricitabine. HIV-1 RNA at virological failure on the NNRTI regimens was 34 300 copies/mL in patient 1 and > 100 000 copies/mL in patients 2 and 3. The total time on the boosted PI-containing second-line therapies prior to the switch to rilpivirine was 154, 66 and 63 months, respectively. The treatment of the included patients with boosted PI regimens had resulted in HIV-1 RNA < 200 copies/mL for 50, 37 and 6 months in patients 1, 2 and 3, respectively, and the patients had a minimum CD4 cell count at the initiation of rilpivirine of 550 cells/μL.


The observations in our pilot study suggest that adult HIV-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 containing rilpivirine/tenofovir/emtricitabine after long-term HIV-1 RNA suppression has first been achieved on second-line PI-based regimens. This strategy might provide an efficacious NNRTI-based second-line antiretroviral therapy that has a favourable toxicity profile and is available as a single-tablet regimen for a selected but considerable number of HIV-1-infected patients.

We realize that no definite conclusions can be drawn from the observations in this small study, as no comparator arm was included and the follow-up time was limited to 48 weeks. Of importance, and in contrast to a transmitted K103N-harbouring HIV-1 infection, other resistance-associated mutations could have been selected which are not yet detectable by standard genotyping. Failure to successfully suppress the HIV-1 infection with a suboptimal second-line therapy could rapidly induce the emergence of a more resistant virus [5]. Furthermore, in vitro data suggest that an isolated K103N mutation could facilitate the development of an E138K mutation following rilpivirine drug pressure [6]. Therefore, it seems imperative that the HIV-1 infection is first controlled by a boosted PI-based regimen prior to starting rilpivirine. If patients are to be switched, frequent monitoring during the first 6 months of therapy is probably necessary to allow for a prompt change in therapy if plasma HIV-1 RNA rebounds.

If confirmed in future studies, the applicability of our approach may be substantial. A recent study showed that only 14.5% of HIV-1-infected patients who failed efavirenz-containing regimens and 25% of HIV-1-infected patients failing nevirapine-containing regimens acquired rilpivirine resistance [7]. Specific major NRTI resistance to emtricitabine or tenofovir could occur after failing first-line therapy. However, the majority of patients treated with a non-thymidine analogue-containing NRTI backbone in combination with efavirenz or nevirapine lack major resistance to tenofovir and emtricitabine [8, 9]. Therefore, the possibility to treat patients with rilpivirine/tenofovir/emtricitabine as a single-tablet regimen could still be preserved in a considerable number of HIV-1-infected patients who acquired an isolated K103N mutation on previous antiretroviral therapies.

To our knowledge, this is the first study in which a single-tablet regimen was used for second-line antiretroviral therapy after previous NNRTI failure. As other single-tablet regimens are being introduced in the near future, the potential role of these co-formulated drugs as suitable second-line therapies is likely to increase substantially. A future prospective and preferably randomized study is needed to confirm our findings and also to evaluate the impact of minor resistance variants on treatment success.

In conclusion, our results indicate that a substantial subgroup of HIV-1-infected patients with an isolated K103N mutation, acquired on previous failing NNRTI regimens, could potentially benefit from rilpivirine in a single-tablet regimen after virological suppression has first been achieved on other second-line regimens.


Contributions to authorship: 

All authors made substantial contributions to the study design and the collection, analysis and interpretation of the data. All authors contributed to the manuscript and approved the final version.

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