Long-term safety and efficacy of rilpivirine in combination with nucleoside/nucleotide reverse transcriptase inhibitors in HIV-1 infected patients: 336-week rollover study of phase 2b and 3 clinical studies

Abstract

Background

To evaluate the long-term safety and efficacy of rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), in combination with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in human immunodeficiency virus (HIV)–infected patients.

Methods

RPV-treated HIV-infected patients from phase 2b or 3 studies rolled-over into this phase 3, open-label study and received RPV 25 mg once daily (QD) with choice of two NRTIs. Adverse events (AEs), plasma viral load, CD4⁺ cell count, and antiviral resistance were evaluated.

Results

Of the 482 patients treated, 437 (>90%) patients discontinued study treatment; 371 (77%) had switched to commercially available RPV, 14 (2.9%) discontinued due to AEs, and 6 (1.2%) had virologic failure. In this rollover study, patients were followed up to week 336, although data was limited beyond 288 weeks. Forty-five (9.3%) patients were still undergoing treatment at the time of data cut-off for the current analysis (8 February 2018). The most frequently reported AEs were pregnancy in 7 (1.5%) patients and syphilis in 5 (1.0%) patients. Grade 3–4 AEs were reported in 17 (3.5%) patients, and AEs possibly related to RPV in 23 (4.8%) patients. Over 288 weeks of treatment, 80.1% (95% CI: 74.9%; 84.3%) of patients maintained virologic suppression (HIV-1 RNA <50 copies/mL). The absolute CD4⁺ cell count increased over time until week 192 and remained constant thereafter.

Conclusions

RPV 25 mg QD in combination with an investigator-selected background regimen of two NRTIs demonstrated sustained long-term virologic suppression. The treatment was well-tolerated with no new safety findings.

Keywords

rilpivirine HIV-1 non-nucleoside reverse transcriptase inhibitor

Background

Approximately 36.9 million people were living with human immunodeficiency virus (HIV) worldwide in 2017, and up to 900 thousand HIV-related deaths were reported.¹ Antiretroviral therapy (ART), generally with a three-drug combination including two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), is recommended for all ART-naïve patients with chronic HIV infection.^2,3 Although there is currently no cure for HIV infection, patients with HIV have a near-normal life expectancy.⁴ For life-long treatment of this chronic disease, current advances in ART have aimed to improve tolerability and safety and to simplify dosing regimens in order to have a good adherence to treatment and low rates of resistance mutations.^3,5,6

Rilpivirine (RPV) is a next generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with in vitro activity against both wild type and NNRTI-resistant HIV type 1 (HIV-1). RPV was approved in the US and EU in 2011^7,8 and fixed-dose combinations of RPV with other antiretroviral agents (e.g., emtricitabine/tenofovir disoproxil,⁹ emtricitabine/tenofovir alafenamide,¹⁰ and dolutegravir¹¹ have been approved for the treatment of adult patients with HIV-1 infection. Given the chronic nature of HIV infection, most ART regimens are expected to be used long-term. In two phase 3 studies (C209 [ECHO] and C215 [THRIVE]) in treatment-naïve HIV-1-infected patient, 48-week ^12,13 and 96-week¹⁴ treatment with RPV 25 mg once daily (QD) versus efavirenz (EFV) both combined with a background regimen of 2 NRTIs demonstrated substantial efficacy that was non-inferior to EFV and was shown to be safe with good tolerability. However, safety and efficacy of RPV treatment for longer than 192 weeks¹⁵ has not been evaluated in a prospective study.

The primary objective of this study was to provide continued access to RPV (in countries where RPV was not commercially available or not reimbursed) for patients who were randomized to RPV in phase 2b (C204, NCT00110305)¹⁶ or phase 3 (ECHO, NCT00540449 and THRIVE, NCT00543725) studies ^12,13 and were benefiting from continuing RPV treatment. Secondary objectives of this 7-year rollover study were to evaluate the long-term safety and tolerability of RPV 25 mg QD in combination with a background regimen containing 2 NRTIs.

Methods

Patients

Adults with HIV-1 infection who were previously randomized to RPV treatment in phase 2b and 3 studies and were clinically assessed to benefit from continued treatment were rolled over to the present study. Patients were ART-naïve with no known NNRTI or NRTI resistance at the time of randomization in the parent studies. Patients who used a disallowed concomitant therapy, women of childbearing potential, and non-vasectomized heterosexually active men who did not comply to use an effective birth control method were excluded. This study reports results from the date that the first patient provided signed informed consent (25 February 2011) until the last contact with the last patient under Protocol Amendment 2 (8 February 2018). A total of 134 sites from 22 countries (Argentina, Australia, Austria, Belgium, Canada, Chile, China, Denmark, France, Germany, Great Britain, Italy, Puerto Rico, Romania, Russia, South Africa, Spain, Sweden, Taiwan, Thailand, The Netherlands, and the United States of America) were included in the present study. Patients were selected for enrollment at the investigator’s discretion. At the time of rollover, patients were assessed by the investigators whether they had shown benefit from RPV treatment, according to the efficacy and safety criteria of the parent study, and will continue to benefit from this treatment in the opinion of the investigator.

Study design

In this phase 3 multicenter, multinational, open-label, rollover study, patients continued treatment with RPV 25 mg QD until RPV became commercially available in the participant’s country or were switched to another treatment option per investigator’s decision or were withdrawn. From the rollover visit onward, patients could either continue the background regimen of 2 NRTIs that they were using or switch to another investigator-selected regimen according to local procedures as long as there was no evidence of resistance to the chosen NRTIs (e.g., abacavir was not administered to patients who were tested positive for human leukocyte antigen-HLA-B*5701). Treatment adherence was determined by tracking drug accountability for each patient.

The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. The Institutional Review Board reviewed and approved the protocol, informed consent form (ICF), and amendments. All patients provided written informed consent before enrollment. This trial was registered at ClinicalTrials.gov (NCT01266902).

Study evaluations

Safety was evaluated based on limited adverse event (AE) reporting and locally performed clinical laboratory tests (collected only in case of AEs considered at least possibly related to RPV, AEs leading to discontinuations, serious AEs [SAEs], or grade 3/4 events of rash regardless of causality). Adverse events leading to discontinuation, SAEs, AEs considered at least possibly related to RPV, pregnancies, any grade 3/4 events of rash (irrespective of causality), and HIV-related AEs were collected. Adverse events of special interest included neuropsychiatric events, hepatic laboratory events (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] elevation), and endocrinology events (pancreatic enzymes, and lipid analyses). Adverse events were reported using MedDRA version 14.1, version used at study start-up in 2011 and consistently throughout the study.

The viral load was measured every 24 weeks. Virologic failure was determined over the course of the study. Time (in days) from baseline to virologic rebound was defined as time to first occurrence of confirmed HIV-1 ribonucleic acid [RNA] ≥50 copies/mL or 200 copies/mL (or otherwise at the last on-treatment visit, excluding the rollover visit), and time to treatment failure defined as time to virologic rebound or discontinuation (due to any reason except discontinuation because RPV became commercially available). Baseline (day 1 rollover visit) viral load was not accounted for in the analysis, that is, time-to-event was derived beyond the rollover timepoint. Changes in background NRTIs while having undetectable HIV viral load were not considered as treatment failure. Actual CD4⁺ cell count and change in CD4⁺ cell count (absolute) from baseline were assessed. The participant was censored (i.e., no longer considered at risk of virologic rebound afterward) at the time of discontinuation (any reason). Genotypic resistance was evaluated according to local standard of care in case of virologic failure.

Statistical methods

No formal sample size determination was performed. For time to virologic rebound/treatment failure, Kaplan–Meier curves were constructed and estimates with 95% confidence intervals (CIs) were calculated. Cumulative number per 100 patient-years was summarized by 24-week interval and for the entire treatment period. Rate per 100 person-years was calculated as (the number of failures x 100) divided by (the total number of days summed over all patients)/(365.25). Exact 95% CIs for the number of events per 100 person-years were calculated.

Time to virologic rebound and time to treatment failure were also analyzed by age at baseline, gender, race, cumulative adherence based on drug accountability (≤95%, >95%), tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) as background regimen (yes/no), HIV-1 subtype, and HIV-1 viral load (≤100,000 copies/mL vs. >100,000 copies/mL) at baseline of the respective parent study.

Results

Patient disposition and baseline characteristics

A total of 482 patients were included in the study; 119 rolled over from the phase 2b study and 363 from the phase 3 studies. Median age at baseline was 40.0 (range: 22–69) years, most patients were younger than 50 years (412/482 [85.5%]), and most were men (357/482 [74.1%]) (Table 1). Majority of patients had no history of hepatitis B or C infection (470/480 [97.9%] and 450/469 [95.9%], respectively), and none had hepatitis B and C co-infection. The most frequently reported HIV-1 subtype was B (276/481 [57.4%] patients) (Table 1). The median baseline CD4⁺ cell count in study C204, for all patients was 203 cells/μL. In the ECHO study, mean absolute CD4⁺ cell count was 253.2 and 267.3 cells/μL in the RPV group and control group, respectively, and in the THRIVE study, mean absolute CD4⁺ cell count was 264.4 cells/μL in the RPV group and 274.1 cells/μL in the control group, at baseline. Median CD4⁺ cell count at baseline (at the time of rollover) was 563 (range 152–1680) cells/μL.

Table 1.

Patient baseline and baseline demographic characteristics (intent-to-treat population).

Characteristics	Rilpivirine
Characteristics	Phase 2b (C204)^b (N = 119)	Phase 3 (C209/C215)^b (N = 363)	All patients (N = 482)
Age (years), median (range)	40.0 (28; 66)	39.0 (22; 69)	40.0 (22; 69)
Men	78 (65.5)	279 (76.9)	357 (74.1)
Age category
<50 years	101 (84.9)	311 (85.7)	412 (85.5)
≥50–<65 years	17 (14.3)	50 (13.8)	67 (13.9)
≥65 years	1 (0.8)	2 (0.6)	3 (0.6)
Race/ethnicity
White	50 (42.0)	237 (65.3)	287 (59.5)
Asian	43 (36.1)	58 (16.0)	101 (21.0)
Black or African American	17 (14.3)	64 (17.6)	81 (16.8)
American Indian/Alaska Native	0	4 (1.1)	4 (0.8)
Other	9 (7.6)	0	9 (1.9)
History of hepatitis B, N	118	362	480
Yes	2 (1.7)	8 (2.2)	10 (2.1)
History of hepatitis C, N	113	356	469
Yes	8 (7.1)	11 (3.1)	19 (4.1)
History of hepatitis B/C Co-infection, N	118	362	480
No	118 (100.0)	362 (100.0)	480 (100.0)
Subtype, N	118	363	481
AE^a	33 (28.0)	0	33 (6.9)
B	51 (43.2)	225 (62.0)	276 (57.4)
C	15 (12.7)	47 (12.9)	62 (12.9)
CRF01_AE	0	64 (17.6)	64 (13.3)
Other	19 (16.1)	27 (7.4)	46 (9.6)

All values are expressed as n (%), unless mentioned otherwise. n: number of patients.

^a Subtype “CRF01_AE” was referred to as “AE” in study C204.

^b In the phase 2b study, C204 patients were on a RPV-based regimen for 240 weeks, and in the phase 3, studies C209/C215 patients were on a RPV-based regimen for at least 96 weeks.

A total of 1374.8 patient-years of RPV exposure were reported in this study; distribution of length of exposure/follow-up in the rollover study is presented in Figure 1. At the 336-week data cut-off, 437 patients (>90%) had discontinued the study as follows: 371 (77%) patients switched to commercially available RPV, 6 (1.2%) patients had virologic failure, 14 (2.9%) patients discontinued due to an AE. Forty-five (9.3%) patients were still undergoing treatment at the time of data cut-off (Table 2).

Figure 1.

Distribution of time on study after rollover by 48-week intervals—Intent-to-Treat. In the phase 2b study, C204 patients were on a RPV-based regimen for 240 weeks, and in the phase 3 studies, C209/C215 patients were on a RPV-based regimen for at least 96 weeks.

Table 2.

Patient disposition.

	Rilpivirine
	Phase 2b (C204)^d	Phase 3 (C209/C215)^d	All patients
Enrolled, N	119	363	482
Discontinuations, n (%)	108 (90.8)	329 (90.6)	437 (90.7)
Switched to commercially available RPV^a	89 (74.8)	282 (77.7)	371 (77.0)
Lost to follow-up	5 (4.2)	12 (3.3)	17 (3.5)
AE	3 (2.5)	11 (3.0)	14 (2.9)
Withdrew consent	2 (1.7)	12 (3.3)	14 (2.9)
Non-compliant	3 (2.5)	7 (1.9)	10 (2.1)
Virologic failure	4 (3.4)	2 (0.6)	6 (1.2)
Other^b	2 (1.7)	3 (0.8)	5 (1.0)
Ongoing ^c	11 (9.2)	34 (9.4)	45 (9.3)

AE, adverse event, RPV, rilpivirine.

^a Patients completed the study by switching to commercially available RPV, when RPV was available and reimbursed in their country.

^b Other reasons for discontinuation include: investigator’s decision (n = 2), patient wishes to fall pregnant (n = 1), patient switched to darunavir (n = 1), patient was imprisoned (n = 1).

^c These patients continue to have access to RPV in the study as RPV was not available in their country, but no data was collected.

^d In the phase 2b study, C204 patients were on a RPV-based regimen for 240 weeks, and in the phase 3, studies C209/C215 patients were on a RPV-based regimen for at least 96 weeks.

The most frequently used NRTIs were TDF (340 [70.5%]), FTC (325 [67.4%]), lamivudine (3TC; (155 [32.2%]), and zidovudine (AZT; (90 [18.7%]). During the study, 39 (8.1%) patients had switched one or more NRTIs, all but 1 (adherence improvement) for tolerability reasons of which 4 (<1%) patients switched from TDF to another NRTI. The study was initiated prior to tenofovir alafenamide (TAF) approval by FDA and EMA; hence, this study did not include TAF in the NRTI backbone.

Safety outcomes

Overall, AEs were reported in 102 (21.2%) patients, 18% (87/482) had AEs with grade 1 or 2 severity, and grade 3 or 4 AEs were reported in 3.5% (17/482) of patients including five patients with a grade 4 AE (Table 3). The most frequently reported AEs were pregnancy and syphilis. Adverse events most frequently belonged to the following system organ class (SOC): infections and infestations, gastrointestinal disorders, skin and subcutaneous tissue disorders and investigations (laboratory abnormalities reported as AEs) (Table 4).

Table 3.

Summary of adverse events.

n (%)	Rilpivirine
n (%)	Phase 2b (C204)^b (N = 119)	Phase 3 (C209/C215)^b (N = 363)	All patients (N = 482)
Patients with at least 1 AE	32 (26.9)	70 (19.3)	102 (21.2)
SAE	9 (7.6)	14 (3.9)	23 (4.8)
Fatal AE	0	2 (0.5)	2 (0.4)
Worst grade 1 or 2 AE	28 (23.5)	59 (16.2)	87 (18.0)
Worst grade 3 or 4 AE	8 (6.7)	9 (2.5)	17 (3.5)
Worst grade 4 AE	2 (1.7)	3 (0.8)	5 (1.0)
AEs leading to discontinuation of study drug^a	1 (0.8)	11 (3.0)	12 (2.5)
AE possibly related to study drug	7 (5.9)	16 (4.4)	23 (4.8)
SAE possibly related to study drug	0	1 (0.3)	1 (0.2)
Grade 3 or 4 AEs possibly related to study drug	1 (0.8)	2 (0.6)	3 (0.6)
Patients with ≥1 HIV-related AE	3 (2.5)	7 (1.9)	10 (2.1)

AE, adverse events; RPV, rilpivirine; SAE, serious adverse events.

^a 7 patients discontinued study treatment due to pregnancy.

^b In the phase 2b study, C204 patients were on a RPV-based regimen for at least 240 weeks, and in the phase 3 studies, C209/C215 patients were on a RPV-based regimen for at least 96 weeks.

Table 4.

Adverse events by system organ class.

	Rilpivirine
n (%)	Phase 2b (C204)^a (N = 119)	Phase 3 (C209/C215)^a (N = 363)	All patients (N = 482)
Summary of AEs by SOC in at least 3 patients
Infections and infestations	11 (9.2)	20 (5.5)	31 (6.4)
Syphilis	2 (1.7)	3 (0.8)	5 (1.0)
Herpes zoster	1 (0.8)	2 (0.6)	3 (0.6)
URTI	0	3 (0.8)	3 (0.6)
Gastrointestinal disorders	5 (4.2)	14 (3.9)	19 (3.9)
Abdominal pain upper	1 (0.8)	2 (0.6)	3 (0.6)
Skin and subcutaneous tissue disorders	6 (5.0)	9 (2.5)	15 (3.1)
Investigations	3 (2.5)	9 (2.5)	12 (2.5)
ALT increased	1 (0.8)	3 (0.8)	4 (0.8)
Blood triglycerides increased	0	3 (0.8)	3 (0.6)
Nervous system disorders	1 (0.8)	10 (2.8)	11 (2.3)
Headache	0	4 (1.1)	4 (0.8)
Psychiatric disorders	1 (0.8)	7 (1.9)	8 (1.7)
Anxiety	1 (0.8)	2 (0.6)	3 (0.6)
Insomnia	0	3 (0.8)	3 (0.6)
Respiratory, thoracic and mediastinal disorders	1 (0.8)	7 (1.9)	8 (1.7)
Oropharyngeal pain	0	3 (0.8)	3 (0.6)
Pregnancy, puerperium, and perinatal conditions	0	7 (1.9)	7 (1.5)
Pregnancy	0	7 (1.9)	7 (1.5)
Summary of grade 3–4 adverse events by system organ class
Nervous system disorders	1 (0.8)	3 (0.8)	4 (0.8)
Cerebrovascular accident	0	1 (0.3)	1 (0.2)
Cluster headache	0	1 (0.3)	1 (0.2)
Ischemic stroke	1 (0.8)	0	1 (0.2)
Sciatica	0	1 (0.3)	1 (0.2)
Injury, poisoning and procedural complications	3 (2.5)	0	3 (0.6)
Foot fracture	1 (0.8)	0	1 (0.2)
Hand fracture	1 (0.8)	0	1 (0.2)
Limb injury	1 (0.8)	0	1 (0.2)
Stab wound	1 (0.8)	0	1 (0.2)
Infections and infestations	1 (0.8)	1 (0.3)	2 (0.4)
Liver abscess	0	1 (0.3)	1 (0.2)
Pneumonia	1 (0.8)	0	1 (0.2)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	1 (0.8)	1 (0.3)	2 (0.4)
Colon cancer	1 (0.8)	0	1 (0.2)
Gastric cancer	0	1 (0.3)	1 (0.2)
Blood and lymphatic system disorders	0	1 (0.3)	1 (0.2)
Hemolytic anemia	0	1 (0.3)	1 (0.2)
Cardiac disorders	1 (0.8)	0	1 (0.2)
Coronary artery disease	1 (0.8)	0	1 (0.2)
Gastrointestinal disorders	0	1 (0.3)	1 (0.2)
Rectal hemorrhage	0	1 (0.3)	1 (0.2)
General disorders and administration site conditions	0	1 (0.3)	1 (0.2)
Death	0	1 (0.3)	1 (0.2)
Hepatobiliary disorders	0	1 (0.3)	1 (0.2)
Cholelithiasis	0	1 (0.3)	1 (0.2)
Metabolism and nutrition disorders	1 (0.8)	0	1 (0.2)
Hypercholesterolemia	1 (0.8)	0	1 (0.2)
Reproductive system and breast disorders	1 (0.8)	0	1 (0.2)
Benign prostatic hyperplasia	1 (0.8)	0	1 (0.2)
Skin and subcutaneous tissue disorders	1 (0.8)	0	1 (0.2)
Facial wasting	1 (0.8)	0	1 (0.2)
Adverse events at least possibly related to rilpivirine and reported in ≥2 patients
Investigations	0	6 (1.7)	6 (1.2)
Blood triglycerides increased	0	3 (0.8)	3 (0.6)
Blood cholesterol increased	0	2 (0.6)	2 (0.4)^b
Blood creatinine increased	0	2 (0.6)	2 (0.4)
Skin and subcutaneous tissue disorders	3 (2.5)	2 (0.6)	5 (1.0)
Lipodystrophy acquired	2 (1.7)	0	2 (0.4)
Metabolism and nutrition disorders	2 (1.7)	2 (0.6)	4 (0.8)
Hypercholesterolemia	1 (0.8)	1 (0.3)	2 (0.4)^b
Hyperglycemia	1 (0.8)	1 (0.3)	2 (0.4)

AEs, adverse events; ALT, alanine aminotransferase; SOC, system organ class; URTI, upper respiratory tract infection.

^a In the phase 2b study, C204 patients were on a RPV-based regimen for 240 weeks, and in the phase 3 studies, C209/C215 patients were on a RPV-based regimen for at least 96 weeks.

^b AEs of “blood cholesterol increased” and “hypercholesterolemia” comprise of 4 distinct patients.

In 12 patients (2.5%), RPV was discontinued due to an AE, of which 7 were due to pregnancy (Table 3). Other AEs leading to discontinuation were gastric cancer (grade 4, fatal SAE), death due to unknown reason (grade 4, fatal SAE), latent tuberculosis (grade 2, unrelated to RPV), lymph node tuberculosis (grade 2, unrelated to RPV), and allergic dermatitis (grade 2, possibly related to RPV), each reported in 1 (0.2%) patient. For two additional patients, AE was reported as the reason for study discontinuation at study termination; however, no AE leading to discontinuation of study drug was documented during the treatment phase. For one of these patients, pregnancy was reported during follow-up phase.

During the study, SAEs were observed in 23 (4.8%) patients, including cholelithiasis reported in 2 (0.4%) patients; all other SAEs were reported in 1 (0.2%) patient each. Two (0.4%) patients had fatal SAEs. One patient died of gastric cancer (grade 4 SAE), which was considered by the investigator to be unrelated to RPV or HIV and had been initially reported as a grade 3 AE during the parent study (ECHO). The cause of death for the second patient was unknown at the time of database lock but was considered by the investigator to be possibly related to RPV. However, based on information received after database lock, the investigator considered the death not related to RPV (patient was murdered). None of the SAEs were considered by the investigator to be at least possibly related to RPV.

Individual grade 3-4 AEs occurred in no more than one patient and most were considered unrelated to RPV. Three (0.6%) patients had a grade 3 or 4 AE. All were initially considered at least possibly related to RPV: hypercholesterolemia, cluster headache, and death. However, the death event was classified as unrelated to RPV based on information received after database lock. There were no grade 3 or 4 events of rash (Table 4).

Adverse events considered by the investigator to be at least possibly related to RPV occurred in 23 (4.8%) patients; most frequent was increased blood triglycerides reported in 3 (0.6%) patients. HIV-related AEs were reported in 10 (2.1%) patients. Adverse events of special interest were reported in 39 (8.1%) patients; the most frequently reported AEs of interest were neuropsychiatric events (14 [2.9%]), AEs leading to discontinuation (12 [12.5%]), and hepatic events (9 [1.9%]). The AEs of special interest that were considered at least possibly related to RPV were disturbance in attention, abnormal liver function test, abnormal dreams, cluster headache, ALT and AST increased, hepatitis C, and allergic dermatitis (all in 1 [0.2%] patient each). A grade 4 SAE hemolytic anemia was reported in one study participant at Day 104 of study entry, which was considered not related to RPV. The grade 4 AE was considered resolved on Day 111 (hemoglobin level increased to grade 3). One patient had a grade 4 increased AST level (475 U/L) on Day 1897 and a grade 3 increased ALT level (433 U/L) on Day 2017; of note, not all laboratory abnormalities were systematically reported as AEs in this study but collected only in case of AEs considered at least possibly related to RPV, AEs leading to discontinuations, SAEs, or grade 3/4 events of rash regardless of causality (see Methods above). No AEs were reported for this patient by the investigator. No other grade 3 or 4 laboratory abnormalities were recorded, and no grade 2 laboratory abnormalities were reported.

Efficacy outcomes

Using a cut-off of ≥50 copies/mL, Kaplan–Meier estimates (95% CI) for percentage of patients without virologic rebound at weeks 48, 96, and 288 in this study were 89.9% (86.6%; 92.5%), 85.7% (81.6%; 88.9%), and 80.1% (74.9%; 84.3%), respectively (Figure 2(a)). Using a cut-off of ≥200 copies/mL, the corresponding Kaplan–Meier estimates for percentage of patients without virologic rebound were 96.1% (93.7%; 97.6%), 95.0% (92.1%; 96.8%), and 91.0% (86.5%; 94.0%), at weeks 48, 96, and 288, respectively (Figure 2(b)). Thus, the majority of patients (80%) maintained virologic suppression, that is, experienced no virologic rebound through 288 weeks of treatment. Averaged over the total treatment duration, the rebound rate (95% CI) was 5.5 (4.4; 6.9) events per 100 patient-years. This corresponds to 68 (14.1%) patients having a virologic rebound, 39 of whom had a virologic rebound during the first 24 weeks after rollover. Of the 68 patients with virologic rebound (≥50 copies/mL), six discontinued treatment due to virologic failure at the discretion of the investigator, 23 experienced virologic rebound due to viral load ≥50 copies/mL at the last available visit, and 26 of the remaining 39 resuppressed with continued treatment.

Figure 2.

Time to virologic rebound and time to treatment failure at ≥50 copies/mL (A and C) and ≥200 copies/mL (B and D). ^a Baseline (day 1 rollover visit) viral load was not accounted for in the analysis, that is, time-to-event was derived beyond the rollover timepoint.

Kaplan–Meier estimates (95% CI) for time to treatment failure (i.e., virologic rebound or discontinuation for any reason other than switching to commercially available RPV) using a cut-off of ≥50 copies/mL at weeks 48, 96, and 288 were 85.9% (82.2%; 88.9%), 79.2% (74.7%; 82.9%), and 65.7% (59.8%; 70.9%), respectively (Figure 2(c)). Using a cut-off of ≥200 copies/mL, the corresponding Kaplan–Meier estimates were 91.2% (88.1%; 93.6%), 86.9% (83.0%; 90.0%), and 73.9% (68.1%; 78.9%), respectively (Figure 2(d)). Averaged over the total treatment duration, the treatment failure rate (95% CI) was 9.5 (8.0; 11.0) events per 100 patient-years. This corresponded to 117 (24.3%) patients with treatment failure, 56 of whom had treatment failure during the first 24 weeks (Supplementary Table S1).

The mean change from baseline in absolute CD4⁺ cell count increased over time until week 192 and thereafter a gradual decrease was observed based on the non-completer equals failure (NC=F) approach. However, the mean change from baseline remained constant based on the observed case approach (Supplementary Figure S1).

Subgroup analyses

Subgroup analyses were performed for time to virologic rebound and time to treatment failure (based on cut-off ≥50 copies/mL) by race, age at baseline (<50 years vs ≥50 years), gender, background regimen, baseline HIV-1 subtype, and cumulative adherence (>95% vs ≤95%) subgroups. A trend toward a higher response rate in the Asian race subgroup versus other races was observed, for example, Kaplan–Meier estimates (95% CI) at week 240 for time to virologic rebound (using a cut-off of ≥50 copies/mL) were 97.8% (91.4%; 99.4%) for Asian vs 73.5% (65.0%; 80.3%) for white patients and 80.0 (66.1; 88.6) for black or African American patients. No significant difference was observed among the other subgroups analyzed. The majority of patients had adherence of >95% as per drug accountability, and lack of adherence could not be necessarily linked to those with virologic rebound/failure.

An ad hoc subgroup analysis of viral rebound by baseline viral load in the parent study (i.e., ≤100,000 versus >100,000 copies/mL) did not show a difference (Kaplan–Meier estimate [95% CI] at week 240: 83.2 [76.9; 88.0] vs 80.4 [72.6; 86.3], respectively). Ad hoc analysis by baseline CD4⁺ in the parent study did not identify a difference in time to virologic rebound (HIV-1 RNA ≥50 copies/mL) by CD4⁺ count <200 cells/μL and CD4⁺ count ≥200 cells/μL (83.9 [75.5; 89.5] vs 81.1 [74.9; 85.9]).

Genotypic analyses

Post-baseline genotypic data were generated per local standard of care and were only available for 4 of 68 patients with virologic rebound (HIV-1 RNA ≥50 copies/mL); in 3 of these patients, RPV resistance-associated mutations (RAM) were observed at time of failure: Y181C (n=1), E138K + M230L (n=1), and Y181C + E138K + M230L (n=1). Two of these patients with RPV RAMs also had the NRTI RAM M184V at time of failure.

4. Discussion

In this long-term 336-week rollover study, once-daily RPV in combination with an investigator-selected background regimen containing two NRTIs was well-tolerated with few discontinuations due to treatment failure (6%) and no new safety findings in patients with HIV-1. Only 6 (1.2%) of the 482 patients that were treated discontinued due to virologic failure. 68 patients (14.1%) with virologic rebound (confirmed viral load ≥50 copies/mL) of whom 26/68 resuppressed.

The results of the present rollover study of RPV in combination with NRTIs are consistent with previous reports where combination therapy with NRTIs and RPV has been reported to be safe and efficacious for long-term management of adult patients with HIV-1 infection.^17–19 An analysis of the Swedish InfCare HIV database over a 5-year period showed that among patients initiating triple combination ART, patients using RPV were less likely to discontinue ARV treatment in comparison with EFV (adjusted HR 0.33; 95% CI 0.20–0.54, p<0.001).¹⁷ A retrospective cohort analysis conducted in the UK also demonstrated lower discontinuation rates with RPV administered as co-formulated RPV/tenofovir disoproxil fumarate/emtricitabine.¹⁸ In the present study, most of the patients who discontinued study treatment were switched to commercially available RPV and hence were continuing RPV use, although not within the confines of the study. Thus, the present study, together with previous reports, suggests that RPV as a third agent may be associated with longer treatment duration.

Our findings on first-line regimens containing RPV are in accordance with an observational cohort study on durability of first-line regimens that showed low incidence of viral rebound in individuals who initiated ART and achieved viral load suppression on a first-line regimen.¹⁹ Moreover, the authors found no evidence for limited sustainability of ART efficacy.¹⁹ It is known that temporal suboptimal adherence could be associated with virologic failure; however, in this study, treatment adherence measured by overall pill count was >95% and could not be linked to virologic rebound/failure. It is however acknowledged that pill count is a suboptimal instrument to measure adherence as actual pill intake was not directly observed. Additionally, other factors such as food intake could have played a role.

In the subgroup analysis by race, a trend toward higher response rates among Asians when compared to other races was observed. A similar trend in response rates was observed in the phase 3 (C209 and C215) and phase 2b (C204) studies.^12,13,20 Other subgroups analyzed such as age at baseline, gender, background regimen, and baseline HIV-1 subtype did not show any clinically significant differences. Statistical comparisons were not performed for the subgroup analyses considering the possible selection bias (this study included patients who had experienced benefit with long-term RPV therapy in the parent study) and that the subgroups were not randomized groups. Subgroup analyses by gender and race in pooled data from the phase 3 studies, ECHO and THRIVE, revealed higher RPV exposure in women versus men and in Asian patients compared to other races, which could be attributed to a lower average body weight.²⁰

In the present study, the response rate observed in patients with baseline viral load ≤100,000 copies/mL in the parent study compared to those with baseline viral load >100,000 copies/mL was comparable. However, it should be noted that this rollover study comprised patients who had clinical benefit with a RPV-based regimen over a long term (>2 years in the phase 3 studies, and >5 years in the phase 2b study), and thus, results may potentially be subject to selection bias and may have confounded subgroup analyses such as impact of race.

Limitations of this study were the low number of patients with virologic rebound and available resistance data; patient data of laboratory tests were only to be collected in case of AEs considered at least possibly related to RPV, AEs leading to discontinuations, SAEs, or grade 3–4 events of rash regardless of causality and thus not all AEs were collected. Additionally, the efficacy analysis is included only from rollover onward, and prior data from the parent studies phases 2b (240 weeks) and 3 (at least 96 weeks) was not taken into account. Patients were allowed to switch to commercially available RPV, and hence, total discontinuation rates were high (>90%), resulting in data interpretation difficulties.

Long-term treatment with once-daily RPV in combination with two NRTIs was well-tolerated with no new safety findings and with sustained virologic suppression in HIV-1-infected patients.

Supplemental Material

sj-pdf-1-avt-10.1177_13596535211062388 – Supplemental Material for Long-term safety and efficacy of rilpivirine in combination with nucleoside/nucleotide reverse transcriptase inhibitors in HIV-1 infected patients: 336-week rollover study of phase 2b and 3 clinical studies

Supplemental Material, sj-pdf-1-avt-10.1177_13596535211062388 for Long-term safety and efficacy of rilpivirine in combination with nucleoside/nucleotide reverse transcriptase inhibitors in HIV-1 infected patients: 336-week rollover study of phase 2b and 3 clinical studies by Jean Michel Molina, Luminita Ene, Pedro Cahn, Gerd Fätkenheuer, Eric Van Wijngaerden, Johan Lombaard, Natalia Zakharova, Veerle Van Eygen, Simon Vanveggel and Rodica Van Solingen-Ristea in Antiviral Therapy

Footnotes

Acknowledgments

Authors thank the study participants and their families without whom this study would not have been accomplished, and the investigational site staff for their contribution to this study. Ms Shweta Pitre, CMPP (SIRO Clinpharm Pvt. Ltd., India) provided writing assistance and Bradford Challis, PhD (Janssen Global Services, LLC, NJ, USA) provided editorial assistance, for this manuscript. The authors also thank Leen Gilles who as contract statistician in Janssen R&D performed the statistical analysis and helped tremendously drafting this manuscript.

Author contributions

J-MM, GF, EVW, PC, LE, and JL were the study investigators and contributed substantially to study planning, conduct, and data collection and interpretation. RVS-R (study responsible physician), VVE (study virologist), and SV (study statistician) had primary roles in the study design, study monitoring, and data analysis and interpretation. All authors met ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors had access to the study data and made the final decision about where to publish these data and approved the final version for submission to this journal.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by funding from Janssen Research & Development.

Disclosures

RVS-R, VVE, and SV are employees of Janssen Research & Development and may hold stock.

Supplemental material

Supplemental material for this article is available online.

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