Abstract
Background:
Despite the benefit of maintaining inactive Nucleotide/side reverse transcriptase inhibitors (NRTIs) in salvage regimens, they are associated with increased toxicity and treatment costs. Current evidence suggests that NRTI-sparing regimens in patients failing ART are non-inferior to NRTI-including regimens. This study aimed to evaluate the impact of removing at least one inactive NRTI on virologic, safety, and financial outcomes.
Methods:
Drug-resistant, virologically suppressed patients with CD4 >250 cells/ml on a stable regimen of four or more antiretrovirals (ARVs) were enrolled in a 48-week prospective, open-label pilot trial. One inactive NRTI was removed at baseline. Patients taking over five ARVs had a second inactive NRTI removed at 24 weeks. Viral load, CD4 count, and adverse events were assessed at baseline, 24, and 48 weeks.
Results:
Thirty-one male patients participated. Twenty-nine (94%) patients had lamivudine (3TC) or emtricitabine (FTC) removed and four patients had an additional NRTI removed. One patient was excluded at week 26 for discontinuing an active NRTI. All patients maintained undetectable viral loads at weeks 24 (100%) and 48 [PP = 100%; Intent-to-treat (ITT) = 97%]. At 48 weeks, patients had a median gain of 20 CD4 (IQR: − 50, +133; mean +39) compared to baseline. Three patients exhibited Grade III bilirubin elevation (two Grade II and one Grade III at baseline), which returned to baseline levels. No serious adverse events were observed. Removal of one or two ARVs equated to a mean annual savings of $3319 CDN (11%) and $8630 CDN (24%), respectively.
Conclusion:
Removing inactive NRTIs in patients with a controlled viral load appears to be safe, maintains virological suppression, and reduces treatment costs.
Introduction
Nucleotide/side reverse transcriptase inhibitors (NRTIs) are an integral component of antiretroviral therapy. Their use is recommended in all first-line treatment regimens in conjunction with a third agent. Keeping inactive NRTIs in failing regimens has also become common practice, yet there are no definitive recommendations in treatment guidelines with regards to their use or discontinuation.Citation1–Citation3 Nonetheless, the therapeutic benefit of maintaining inactive or partially inactive NRTIs in failing salvage regimens has been demonstrated in several studies. Studies have shown that in the presence of resistance mutations, the inclusion of NRTIs has been associated with improved outcomes, namely diminished viral replication and increased immune response.Citation4–Citation8 For instance, the inclusion of lamivudine, abacavir, or tenofovir in salvage regimens continues to contribute to viral RNA suppression.Citation4–Citation7 However, the therapeutic benefits of retaining NRTIs in such regimens do not necessarily outweigh the risks of incurring possible drug interactions and toxicity, in addition to the increased treatment costs. The current availability of effective salvage regimens, including new classes of antiretrovirals such as integrase inhibitors, entry inhibitors, and newer generations of non-nucleoside reverse transcriptase or protease inhibitors, may make it unnecessary to include failing NRTIs in settings where these new drugs are available.Citation9
Given the toxicities associated with NRTIs and the effectiveness of new antiretrovirals, there is a need to determine the efficacy of NRTI-sparing regimens compared to traditional salvage therapies. Emerging evidence suggests that NRTI-sparing regimens are non-inferior to NRTI-inclusive regimens in treatment experienced patients.Citation10 One large randomized clinical trial comparing NRTI-omitting to NRTI-including regimens have shown no difference in virological outcomes for the two treatment arms.Citation11 Moreover, another study documented equal proportions of viral suppression in salvage regimens comprised of boosted darunavir, etravirine, raltegravir, and maraviroc with or without NRTIs.Citation12 These findings support the potential equivalence of NRTI-sparing regimens in maintaining viral suppression, limiting toxicity, and reducing treatment costs.
The primary objective of this study (VERITAS – Virologic Efficacy of Removing an Inactive Therapy from an Antiretroviral Salvage regimen), therefore, was to evaluate the impact of removing an inactive NRTI, as determined by genotypic data, on virological response. We hypothesized that the removal of inactive NRTIs would not affect the ability of the regimen to maintain an undetectable viral load (HIV-RNA below 50 copies/ml). We also sought to evaluate the safety of the simplified regimen via hepatic and renal measurements, and evaluate its financial impact.
The primary endpoint was the proportion of patients with an undetectable viral load at week 24. Secondary endpoints consisted of the proportion of participants with undetectable viral load at week 48, and the variation in CD4 cell counts between baseline and weeks 24 and 48. The long-term safety of the NRTI-sparing regimen was also evaluated. The safety parameters examined included any serious adverse events (including AIDS-defining events, new AIDS progression events or death), the incidence of Grade III and IV elevations of aspartate aminotransferase (AST), alanine transaminase (ALT), bilirubin, creatinine, and abnormal glomerular filtration rates. We also examined any discontinuation of the regimen that was due to adverse events.
Ethics
Ethical approval was provided by the Veritas Independent Review Board. All patients signed a written consent form agreeing to participate in the study and allowed us to use their anonymous data for research analyses.
Methods
Study design
This was a prospective, open-label, non-randomized proof-of-concept pilot study. All patients were followed at Clinique médicale l'Actuel, a community-based clinic that specializes in HIV and sexually transmitted infections.
Treatment intervention
Patients taking at least four antiretrovirals (ARVs) had one or more inactive NRTIs removed from their regimen. Inactivity was determined by genotypic sensitivity scoring (GSS). A GSS score of 0 was indicative of complete drug resistance, while a score of 0.5 was attributed to partial ARV resistance. Antiretrovirals with a GSS score of 1 were considered to be fully active. Fusion, integrase, and entry inhibitors (for viruses with R5 tropism), if never taken by patients, were considered fully active. If genotyping was unavailable for new antiretrovirals from existing classes (e.g. darunavir, etravirine), GSS score was determined by the Standford University HIVdb Program.Citation13 In instances where two drugs were inactive, the decision as to which drug will be removed was made jointly by the patient and the physician. In all cases, patients had to keep at least three drugs in their regimen, of which at least two were considered partially or fully active (with a combined GSS of at least 1, 0). Patients taking at least five ARVs at baseline (excluding mini-doses of ritonavir) with undetectable viral loads at week 12 could have a second inactive NRTI removed at week 24. A maximum of two ARVs could be removed from a regimen.
The research project was supported by a research grant from Janssen-Ortho Inc., Canada.
Inclusion criteria
HIV-positive patients, with the ability to provide informed consent, aged between 18 and 75 on a stable regimen consisting of at least four ARVs (excluding mini-doses of ritonavir) for a minimum of 6 months, and receiving treatment for 2 years or more were eligible to participate. Patients with (i) undetectable viral loads for at least 6 months prior to study start; (ii) baseline CD4 cell count greater than 250 cells/ml; (iii) GSS data showing resistance to at least two classes of ARVs, and (iv) taking at least one inactive NRTI as per their historical GSS data were included.
Exclusion criteria
Patients suffering from a severe chronic disease were excluded from the study. However, those with a chronic liver disease who were compensated were able to participate. Patients believed to be unable to follow the study protocol, receiving NRTIs for the treatment of chronic hepatitis B infection, and women who were pregnant, lactating, or were likely to become pregnant during the course of the study were also excluded.
Statistical analyses
Descriptive statistics were used to examine the characteristics of patients who were enrolled in the study. Intent-to-treat (ITT) and per-protocol (PP) analyses were performed at 48 weeks. Differences between baseline, week 24 and week 48 were examined using chi-squared or matched-samples t-tests (two-sided). All analyses were performed using the Statistical Package for the Social Sciences (SPSS) 17.0.
Results
Thirty-one male patients participated in the study. Patients were male with a median age of 50 years, Caucasian (n = 29, 94%), MSM (n = 29, 94%) and have been HIV-positive for a median of 18 years ().The baseline ARV regimens are presented in . At baseline, 71% of patients (n = 22) were taking four ARVs, while the remainder were taking five ARVs. Treatment regimens for patients taking four ARVs consisted mainly of two NRTIs with one boosted protease inhibitor (PI) and either a NNRTI (non-nucleoside reverse-transcriptase inhibitor) or an integrase inhibitor (INI) (n = 16/22), while most regimens for patients taking five ARVs included two NRTIs, one boosted PI, an INI and a NNRTI (n = 6/9). Over half of the patients (54%) had a regimen which included raltegravir. Prior to NRTI removal, patients maintained viral suppression for a mean of 2.7 years (SD 1.8). The last resistance test was performed on average 4.4 years (SD 2.3) since baseline. The majority of patients (n = 29) had either lamivudine (3TC) or emtricitabine (FTC) removed. The remaining patients had zidovudine (AZT) (n = 1) or tenofovir (TDF) (n = 1) removed. After week 24, three more patients had a second ARV removed from their regimen. The medications that were stopped were abacavir (ABC) (n = 2) and 3TC (n = 1).
Table 1. Patient characteristics at baseline (n = 31).
Table 2. Baseline drug regimen (n = 31).
All patients were followed until the primary endpoint (week 24). One patient was removed from the study at week 26, as the treating physician needed to remove an active NRTI (TDF) due to a creatinine elevation. The remaining 30 patients completed the study at 48 weeks.
Primary and secondary endpoints
After removing at least one inactive NRTI, all patients (100%) maintained their viral load below the level of detection after 24 weeks of follow-up.
At 48 weeks, all 30 remaining patients maintained an undetectable viral load (PP = 100%; ITT = 97%). Changes in CD4 cell counts between baseline and weeks 24 and 48 were also examined. Participants had a median gain of zero CD4 (IQR: − 70,+80; mean +10) and 20 CD4 (IQR: − 50,+133; mean +39) compared to baseline at 24 and 48 weeks, respectively. Neither observed difference was statistically significant.
Safety parameters
No serious adverse events or AIDS-defining illnesses were observed throughout the 48 weeks of follow-up. Seven patients had a Grade I elevation of AST, three of which already had a Grade I elevation at baseline. Ten patients had a Grade I or II elevation of ALT, and six of the latter were elevated at baseline. Three cases of Grade III bilirubin were observed. However, two of the cases were Grade II at baseline, and both returned to Grade II at week 48. The other patient was Grade III at baseline. Six patients had a Grade I elevation of creatinine, four of which were incident cases. Three patients had abnormal glomerular filtration rates (GFR). These three patients also had Grade I creatinine elevation, with one patient having an elevated GFR at baseline. Normal GFR levels were observed at the following laboratory test for two of the patients. One patient discontinued treatment with active TDF and switched to raltegravir due to adverse events (creatinine 138 μmol/l, GFR 49 mL/min/1.73m2 proteinuria and glycosuria) at week 26.
Financial impact
On average, the regimens cost $30 842 CDN (range: $20 903–$39 557 CDN) per year. After removing one ARV, we estimated the annual cost to be 11% lower; notably savings of $3 319 CDN (range: $3 039–$6 237 CDN) were observed. Removing two ARVs translated to a mean annual savings of $8 630 CDN (range: $8 232–9 427 CDN), which is 24% less than the mean annual cost of a full regimen.
Discussion
This study evaluated the efficacy, safety, and cost-effectiveness of removing inactive NRTIs from an ARV regimen in experienced patients with controlled viral load. All patients had undetectable viral loads at week 24 (ITT = 100%) and week 48 (PP = 100%, ITT = 97%). These results suggest that the removal of inactive NRTIs is effective as patients are able to maintain viral suppression at 48 weeks. Moreover, the improved regimen was well-tolerated by patients. No serious adverse events or AIDS-defining illnesses were noted. While three patients had Grade III laboratory abnormalities (bilirubin), none of the latter had normal baseline measures and only one patient maintained Grade III levels at 48 weeks. Only one patient was excluded from the study due to the discontinuation of an active NRTI (TDF). Though he had normal test results at baseline, he had elevated creatinine levels, reduced glomerular filtration, and developed proteinuria and glycosuria. These adverse events resulted from TDF toxicity rather than regimen simplification. In addition to the benefits of reduced pill burden, removal of NRTIs from ARV regimens can alleviate the financial burden which patients, and private or government insurance, face. The removal of at least one NRTI in our patient population translated to a mean annual saving of 11% (24% for those who discontinued two NRTIs) of the overall treatment cost.
A post hoc, exploratory analysis was performed for the 30 patients who completed the study for an additional 96 weeks to confirm the stability of the simplification strategy.Citation14 Since study completion, six patients had subsequent changes in their ARV regimen, either due to toxicity or a need of treatment simplification. None of the patients with changes in therapy exhibited virologic failure at the time of treatment change. Among the 24 patients who maintained the same regimen since baseline, 22 (92%) had viral loads < 50 copies/ml, the other two patients had confirmed virologic failure, one with genotypic resistance, inferring that viral suppression can be maintained through 144 weeks when inactive NRTIs are removed. While the observed changes in CD4 cell counts at 24 and 48 weeks were not clinically relevant, the mean gain of CD4 cells at 144 weeks proved to be significant for patients that kept the same ARV regimen throughout the course of the follow-up (mean +118, P < 0.0001). At 144 weeks, no new laboratory abnormalities were observed, providing additional evidence on the safety of removing inactive NRTIs.
Our findings are analogous with other studies examining the removal of NRTIs from failing treatment regimens.Citation11,Citation12 The AIDS Clinical Trial Group (ACTG) ‘OPtimized Treatment that Includes or Omits NRTIS’ (OPTIONS) trial demonstrated that after 48 weeks, patients in the omit-NRTI arm fared as well as those in the include-NRTI arms. Patients in both arms achieved viral suppression (64% omit-NRTI and 66% include-NRTI), and both arms had the same rate of virologic failure (25%).Citation11 Comparatively, patients in both groups had similar median gains of CD4 cells and safety and tolerability measures did not differ between NRTI and omit-NRTI arms.Citation11 Patients not taking NRTIs also had significantly fewer deaths.Citation11
Observational studies by other groups examining the utility of inactive or partially active NRTIs on virologic efficacy had similar findings. In an observational study of 122 patients with triple class failure, patients received salvage regimens containing a minimum of three agents, including raltegravir, maraviroc, etravirine, and/or darunavir.Citation12 In these regimens, at least two fully active drugs were present, and in close to two-thirds of cases three active drugs were present. For approximately half of these patients, partially active NRTIs were included in the regimens. The rate of virologic suppression (VL < 50 copies/ml) at 48 weeks was 78% and did not differ between individuals whose regimens did and did not contain NRTIs.Citation12 Meanwhile, in the TMC125-C214 trial, virological outcomes were examined for 86 patients who received etravirine in addition to various background regimens.Citation15 After 24 weeks, 93% of patients had VLs < 400 copies/ml. Rates of virological suppression were similar for patients who did and did not have NRTIs in their background regimen (91 vs 93%, respectively).Citation15 In another study, a subgroup analysis was performed of the DUET trials which examined the effect of background regimen on treatment-experienced patients receiving etravirine in their treatment regimens.Citation16–Citation19 Virologic response at 48 weeks (VL < 50 copies/ml) was examined.Citation19 Although activity of background agents was a predictor of virologic response, virologic response was not influenced by the number of recycled NRTIs.Citation19 To our knowledge, the only study which did report differences in virological outcomes was that by Scherrer et al., whereby HIV-infected individuals received raltegravir-based salvage regimens which either contained two NRTIs or less than two NRTIs.Citation20 In both groups, virological suppression rates at week 24 were just over 70%.Citation20 However, whether differences between groups in virologic outcomes were found depended on the type of statistical analysis conducted.Citation20,Citation21 Furthermore, as noted by Imaz et al., the two study groups may not have been equivalent and there may have been important differences in intrinsic remaining activity of the NRTI and the total number of fully active drugs in the regimen.Citation21 While these studies showed that salvage regimens can be constructed without inactive NRTIs, our study is probably the first to show that inactive NRTIs can be removed from a salvage regimen that includes them, once virologic control is achieved.
Nonetheless, caution should be used when selecting such regimens. Certain NRTI/PI sparing regimens may not be as successful in maintaining viral suppression as compared to others and may even contribute to the development of new resistance mutations. The ROCnRAL study, for instance, had lipohypertrophic patients with controlled viremia switch to a maraviroc and raltegravir regimen.Citation22 At 20 weeks, five patients had virologic failure, three due to integrase resistance mutations and two had low plasma ARV concentrations. Consequently, viral load was controlled when patients reverted back to their original regimen.Citation22 The combination of maraviroc plus raltegravir can therefore not be recommended as salvage therapy given its inability to maintain viral suppression.
While comparisons between our study and current evidence can be drawn to advocate for the safety and efficacy of salvage regimens in which inactive NRTIs are excluded, certain limitations need to be addressed. Patients had either 3TC or FTC removed in 94% of cases, which are the least toxic of ARVs. Moreover, our patients mainly had one NRTI removed based on the genotypic sensitivity score of each drug, and we only removed a non active one, whereas comparative studies excluded all NRTIs from regimens (active or not). We can therefore not directly compare our results to these studies. However, because we have been more precise and conservative in the drug selection, we can be confident about the conclusion and recommend the removal of inactive drugs in a similar context. This is a pilot study, the small sample size and non-randomized nature of our study limit the generalizability of our findings.
Conclusion
Removing one or two inactive NRTIs from a regimen in patients taking four or more ARVs that have known partial or full activity with a controlled viral load appears to be safe, maintains virological suppression through 48 weeks, and substantially reduces treatment costs.
Disclaimer Statements
Contributors
BT, NM and RT: concept and study design. NM and CG: statistical analysis. BT, CG, NM and CC: wrote the manuscript. DL, SL. HD, SV, MB and MAJ: manuscript review and commentary.
Funding
The research project was supported by a research grant from Janssen-Ortho Inc., Canada.
Conflicts of interest
There are no conflicts of interest to declare.
Ethics approval
Ethical approval was provided by the Veritas Independent Review Board.
Clinical trials registration number
TMC114HIV4054
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