The efficacy of oral RPV as a component of combination antiretroviral therapy in antiretroviral-naïve patients with HIV infection was evaluated in a Phase II, randomized multinational, dose-ranging study23
and in the Phase III ECHO (Efficacy Comparison in Treatment-naïve HIV-infected Subjects of TMC278 and Efavirenz) (NCT00540449)24
and THRIVE (TMC278 against HIV in a once-daily regimen versus efavirenz) (NCT00543725)25
In the Phase II, dose-ranging study, patients received once-daily RPV 25 mg (n = 93), 75 mg (n = 95), or 150 mg (n = 91) or once-daily efavirenz 600 mg (n = 89). Patients and investigators were blinded to the RPV dosage, whereas the open design was used for efavirenz. Background regimens for this study were zidovudine/lamivudine or TDF/FTC.23
In the Phase II study, RPV reduced plasma HIV-RNA levels over the short term more than placebo.15
Patients with an HIV-RNA level of >5000 copies/mL and a CD4 cell count of 75–500 cells/mcL (n = 47) were randomized 3:1 to receive an oral solution of RPV (25, 75, or 150 mg) or placebo once daily as monotherapy for 7 days before commencement of standard antiretroviral therapy. There was a significantly greater reduction in HIV-RNA levels with all RPV dosages (median −1.199 log10
copies/mL in RPV groups combined) compared to placebo (+0.002 log10 copies/mL) (P < 0.01).15
ECHO and THRIVE were independent, randomized double-blind double-dummy, multinational trials of almost identical design.24
Included patients underwent a 6-week screening period after which they were randomized to 96 weeks of treatment with RPV 25 mg once daily or efavirenz 600 mg once daily, plus a fixed-dose background regimen.24
In the ECHO trial, the backbone was an FDC of TDF/FTC, while backbones in the THRIVE study were, at the physician’s discretion, TDF/FTC, zidovudine/lamivudine, and abacavir/lamivudine. Randomization was stratified by HIV-RNA level at screening (≤ 100,000, 100,000–500,000, or ≥500,000 copies/mL)24
and in the THRIVE trial, by backbone regimen as well.25
The primary analysis in both trials was a logistic regression analysis (adjusted for stratification factors) that predicted response rates at 48 weeks based on an intent-to-treat time-to-loss-of-virological-response (ITT-TLOVR) algorithm.24
Noninferiority of RPV to efavirenz was established if the lower limit of the two-sided 95% confidence interval (CI) for the difference in response rates was within a 12% margin. Patients who never achieved an HIV-RNA level of <50 copies/mL, had a level of ≥50 copies/mL at two consecutive assessments, or discontinued treatment prematurely were classified as nonresponders.24
At 48 weeks, ≥83% of RPV and efavirenz recipients in both trials achieved the goal of an HIV-RNA level of <50 copies/mL ().24
In the primary analyses, the predicted response rates in the RPV group met the noninferiority criterion versus efavirenz. There were no significant between-group difference in response rates in either trial.
Efficacy of oral rilpivirine as a component of combination therapy in antiretroviral-naïve patients with HIV infection.
In both trials, there was a virological response to treatment with RPV or efavirenz within 2–4 weeks from baseline and this increased steadily during the first 6 months of treatment, with no apparent between-treatment difference in the timing of response.24
Response rates were >80% by 24 weeks in all treatment groups.24
Similar results were obtained when the analyses were performed on the per-protocol populations.24
In descriptive subgroup analyses, response rates in RPV recipients were higher in those with a lower baseline HIV-RNA level (≤100,000 copies/mL) than in those with higher viral loads ().24
The proportion of virological failures (VFs) in Phase III trials was higher among patients treated with RPV (10%) compared with those who received efavirenz (6%).24
A subanalysis based on baseline viral load demonstrated that the proportion of VFs was the same for RPV and efavirenz (5%) recipients with baseline HIV-RNA ≤100,000 copies/mL, but was higher in RPV (17%) compared to efavirenz (7%) among those patients with a baseline HIV-RNA >100,000 copies/mL.
Among patients with VF who had evaluable post-baseline resistance data at week 48, 63% (39 of 62) and 54% (15 of 28) in the RPV and efavirenz groups, respectively, had treatment-emergent NNRTI resistance-associated mutations (RAMs). NRTI RAMs occurred at a significantly (P = 0.003; post hoc analysis) higher rate in RPV 68% (42 of 62) than efavirenz 32% (9 of 28) recipients.
In RPV recipients with ≤100,000 HIV-RNA copies/mL at baseline, eight of 16 (50%) patients had any NNRTI and/or NRTI RAM, compared with 36 of 46 (78%) patients with >100,000 HIV-RNA copies/mL at baseline.26
Specific NNRTI and NRTI RAMs occurring in ≥2 patients with VF at week 48 are shown in .
Resistance-associated mutations occurring in ≥2 patients at time of virological failure with (A) once-daily oral rilpivirine 25 mg plus a background regimen or (B) efavirenz 600 mg plus a background regimen.
Although the resistance profile for RPV has not been completely defined, the presence of a single NNRTI RAM seems to only marginally affect susceptibility to the drug. By far, E138 K was the most frequently selected (45%) mutation in antiretroviral-naïve patients that failed on RPV therapy in the ECHO24
studies. Interestingly, this substitution was generally associated with M184I mutation (34%), which confers lamivudine and FTC resistance.26
The combination E138K/M184I confers a 6.7-fold reduced phenotypic susceptibility to RPV compared with a 2.8-fold reduction for E138K alone. Mutation K103N, which is associated with clinical resistance to efavirenz and nevirapine, does not reduce susceptibility to RPV.
Drug-resistance interpretation systems (ie, Stanford [http://hivdb.stanford.edu/
], Agence Nationale de Recherhes sur le Sida [www.hivfrenchresistance.org
] [French National Agency for AIDS Research]) have recently incorporated predictions of virological response to RPV. The Drug Resistance Platform of the Spanish AIDS Research Network has weighted NNRTI RAMs27
so that, for considering resistance to RPV, at least two mutations must be present. Mutations with the greatest impact on RPV susceptibility are at four codons K101E/P/T, E138A/G/K/R, Y181C/I/V, and M230 L. Changes in the other nine positions display a lower impact (V90I, L100I, V106A/I, V108I, V179F/I/L, Y188I, G190E, H221Y, and F227C/L). However, in the presence of M184I, the selection of either E138K or K101E is sufficient to induce high-level RPV resistance.
Overall, the change in sensitivity to RPV ranges from 3.7- to 554-fold in the presence of a combination of two or three RAMs.10
VFs with RPV compared to efavirenz (EFV) were more likely to show cross-resistance with all NNRTIs.10
After VF with RPV, 89% of patients were resistant to etravirine and efavirenz and 63% were resistant to nevirapine, whereas none of the efavirenz recipients with VF were cross-resistant to etravirine.10
Response rates were higher in patients who were more adherent to RPV- or efavirenz-based regimens (86%–90% in those with >95% adherence versus 62%–73% in those with ≤95% adherence).24
RPV was associated with a positive immunological response. In both ECHO and THRIVE trials, the CD4 cell count steadily increased over time. At 48 weeks, the CD4 mean increment in RPV recipients was 190 cells/mcL (ECHO) and 189 cells/mcL (THRIVE), while in efavirenz-treated patients, the same values were 180 cells/mcL and 171 cells/mcL, respectively.
In generalized additive modeling, adherence to treatment, systemic exposure to the NNRTI, and lower baseline viral load were the most important predictors of virological response (persistence of an HIV-RNA level of <50 copies/mL) to both RPV and efavirenz at 48 weeks.28
In descending order of importance, the prognostic variables in the final RPV model were: adherence; plasma RPV Ctrough
; baseline viral load; baseline fold change in viral load with RPV; baseline CD4 cell count; undectable plasma level of RPV at any time point (a proxy of poor adherence); and trial (ECHO or THRIVE). For efavirenz, in descending order of importance, the variables in the final model were: undetectable plasma level of efavirenz at any time point; adherence; baseline viral load; plasma efavirenz Ctrough
; baseline fold change in viral load with efavirenz; and background regimen.28
The results of a post hoc pooled analysis of the ECHO and THRIVE trials restricted to the subset of patients receiving RPV or efavirenz plus FTC/TDF showed that RPV plus FTC/TDF was noninferior to efavirenz plus FTC/TDF at both 48 and 96 weeks.29
ITT-TLOVR response rates were high, both at 48 weeks (83.5% vs 82.4%) and at 96 weeks (77% in both groups). Response rates in RPV/FTC/TDF recipients were higher in those with a lower baseline HIV-RNA level (≤100,000 copies/mL) than in those with higher viral loads at 48 and 96 weeks ().30
Virological response in antiretroviral-naïve patients with HIV infection receiving oral rilpivirine plus emtricitabine/tenofovir.