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Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial
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The Lancet July 7, 2007
Prof Adriano Lazzarin MD a , Thomas Campbell MD b, Bonaventura Clotet MD c, Prof Margaret Johnson MD d, Prof Christine Katlama MD e, Arend Moll MD f, William Towner MD g, Benoit Trottier MD h, Monika Peeters MSc i, Johan Vingerhoets PhD i, Goedele de Smedt MD i, Benny Baeten MSc i, Greet Beets MSc i, Rekha Sinha MD i and Brian Woodfall MD i, on behalf of the DUET-2 study group
Summary
Background
TMC125 (etravirine) is a non-nucleoside reverse-transcriptase inhibitor (NNRTI) with activity against NNRTI-resistant HIV-1 in phase IIb trials. The aim of DUET-2 is to examine the efficacy, tolerability, and safety of TMC125 in treatment-experienced patients.
Methods
In this continuing randomised, double-blind, placebo-controlled, phase III trial, HIV-1-infected patients on failing antiretroviral therapy with evidence of resistance to currently available NNRTIs and at least three primary protease inhibitor mutations were eligible for enrolment if on stable (8 weeks unchanged) antiretroviral therapy with plasma HIV-1 RNA greater than 5000 copies per mL. Patients were randomly assigned to receive either TMC125 (200 mg) or placebo, each given twice daily with darunavir-ritonavir, investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors, and optional enfuvirtide. The primary endpoint was the proportion of patients with confirmed viral load below 50 copies per mL at week 24 (FDA time-to-loss of virological response algorithm). Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00255099.
Findings
591 patients were randomised and treated (295 patients in the TMC125 group and 296 in the placebo group). By week 24, 51 (17%) patients in the TMC125 group and 73 (25%) in the placebo group had discontinued, mainly because of virological failure. 183 (62%) patients in the TMC125 group and 129 (44%) in the placebo group achieved confirmed viral load below 50 copies per mL at week 24 (difference 18%, 95% CI 11-26; p=0¥0003). The type and frequency of adverse events were much the same in the two groups.
Interpretation
In treatment-experienced patients, treatment with TMC125 led to better virological suppression at week 24 than did placebo. The safety and tolerability profile of TMC125 was generally comparable with placebo.
Introduction
The non-nucleoside reverse transcriptase inhibitors (NNRTIs) are common components of first-line antiretroviral therapy for HIV-1 infection, with proven efficacy and a low pill burden.1,2 However, drug resistance remains the primary cause of treatment failure3,4 and a single aminoacid substitution in HIV-1 reverse transcriptase can confer cross-resistance to currently available NNRTIs, restricting their use in treatment-experienced patients.5-8 Therefore, developing next-generation antiretrovirals with activity against resistant virus and a high genetic barrier to the development of resistance addresses a major unmet clinical need.
TMC125 (etravirine) is an NNRTI that has potent and broad in-vitro activity against HIV-1, including virus with NNRTI-resistance-associated mutations.9,10 Phase IIb studies in treatment-experienced patients infected with HIV-1 resistant to NNRTIs and protease inhibitors (PIs) have shown that TMC125 was active against HIV resistant to current NNRTIs, with a tolerability profile similar to the control group.11,12
We report here the 24-week results of the phase III DUET-2 trial, the aim of which is to assess the long-term efficacy, safety, and tolerability of TMC125 versus placebo for up to 96 weeks in treatment-experienced patients with NNRTI-resistant HIV-1 infection.
Methods
Patients
This continuing phase III, randomised, double-blind, placebo-controlled trial is being done in 103 centres in 12 countries (Australia, Belgium, Canada, France, Germany, Italy, Netherlands, Poland, Portugal, Spain, UK, USA) and consists of a 6-week screening period, a 48-week treatment phase (with the possibility to extend treatment for an additional 48 weeks), and a 4-week follow-up period.
Patients were recruited between November, 2005, and June, 2006. HIV-1-infected patients on failing antiretroviral therapy and aged at least 18 years were eligible if they had at least one NNRTI resistance-associated mutation either at screening or on historical genotype. NNRTI resistance-associated mutations were defined as: Ala98Gly, Leu100Ile, Lys101Glu/Pro/Gln, Lys103His/Asn/Ser/Thr, Val106Ala/Met, Val108Ile, Glu138Gly/Lys/Gln, Val179Ile/Phe/Gly, Tyr181Cys/Ile/Val, Tyr188Cys/His/Leu, Gly190Ala/Glu/Ser, Pro225His, Phe227Cys, Met230Ile/Leu, Pro236Leu, Lys238Asn/Thr, Tyr318Phe.13,14 Other eligibility criteria included: at least three primary PI mutations13 at screening; receipt of stable antiretroviral therapy for at least 8 weeks; and screening plasma HIV-1 RNA (viral load) over 5000 copies per mL.
Exclusion criteria included: any currently active AIDS-defining illness; life expectancy less than 6 months; acute viral hepatitis; chronic hepatitis B or C if aspartate aminotransferase or alanine aminotransferase concentrations were greater than five times the upper limit of normal; if female, pregnant, breastfeeding, or of child-bearing potential and not using adequate contraception. Disallowed medications included investigational drugs (except darunavir) and agents likely to affect cytochrome P450 3A4 metabolism significantly, or otherwise interact with HIV medications.
The protocol was reviewed and approved by independent ethics committees and institutional review boards and the trial was done in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. All patients gave written consent before any trial-related procedure.
Procedures
All patients received background antiretroviral therapy consisting of darunavir plus low-dose ritonavir (600/100mg twice daily), plus at least two investigator-selected approved antiretrovirals chosen from nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), and optional enfuvirtide, based on screening genotype (vircoTYPE HIV-1, Virco BVBA, Mechelen, Belgium) and historical treatment or resistance reports. No additional NNRTIs or PIs were allowed. TMC125 can be given with darunavir-ritonavir without dose adjustment.15 Since darunavir-ritonavir showed significant antiviral activity in treatment-experienced HIV-1-infected patients,16-18 this new PI was fixed in the underlying antiretroviral treatment background to increase the possibility of patients receiving at least two active drugs, considered desirable in this patient population.2,19
Investigators entered patient data, including intended enfuvirtide use, and double-blind randomisation was done by an interactive voice response system, based on an adaptive minimisation technique with biased coin assignment. Patients were stratified by enfuvirtide use (re-use, no use, or use for the first time [de novo]), previous darunavir use (yes or no), and screening plasma viral load (<30 000 or ≥30 000 HIV-1 RNA copies per mL), and randomised 1:1 to receive TMC125 (2X100 mg tablet) or placebo twice daily after a meal. Investigators, patients, and sponsor were blinded to treatment assignment throughout the trial period. A new formulation of TMC125 was used in this trial, such that the 200 mg dose used here shows comparable exposure to the 800 mg dose of the formulation used in the previous phase IIb trials (unpublished data).20
An independent data and safety monitoring board regularly assessed adverse events and laboratory abnormalities, and periodically reviewed the available safety and antiviral activity data. Patients were withdrawn from the trial if they experienced a grade 3 or 4 skin event or allergic reaction, a grade 4 adverse event or confirmed laboratory abnormality (with the exception of adverse events deemed to be doubtfully or not related to trial medication and also increases in non-fasting or asymptomatic glucose and lipid concentrations), had a disallowed change in regimen (changes or dose adjustments of NRTIs were allowed for tolerability reasons), became pregnant, or developed clinical hepatitis.
Patients could be withdrawn from the trial if they experienced lack or loss of virological response. A lack of response was defined as a decrease in plasma viral load from baseline of less than 0¥5 log10 copies per mL by week 8 or less than 1¥0 log10 copies per mL by week 12. Loss of response was defined as two consecutive measurements of plasma viral load greater than 0¥5 log10 copies per mL above the nadir after at least 12 weeks of treatment. Patients were eligible to receive TMC125 plus darunavir-ritonavir in an open-label rollover trial (TMC125-C217; ClinicalTrials.gov reference NCT00359021) if experiencing less than 1¥0 log10 copies per mL reduction from baseline in plasma viral load or loss of response, at week 24 or later. For all withdrawn patients, survival data will be provided every 6 months until the end of the trial (unless consent is withdrawn).
During the treatment period, patients were seen at baseline, weeks 2 and 4, and subsequently every 4 weeks until week 24. The primary endpoint was the proportion of patients who achieved a plasma viral load of less than 50 copies per mL at week 24. Plasma viral load was measured by Roche Amplicor HIV-1 monitor ultrasensitive assay (version 1.5; Roche Diagnostics, Basel, Switzerland).
Secondary endpoints were antiviral efficacy at all time points (including change from baseline in viral load and proportion of patients achieving viral load of <400 copies per mL, or ≥1 log10 viral load reduction), changes in CD4 cell count, and safety and tolerability. Safety assessments and clinical laboratory tests included the reporting of adverse events and HIV-related events, physical examinations, electrocardiographs, vital signs, haematology, biochemistry, and urinalysis. Additional secondary endpoints included changes in HIV-1 genotype or drug susceptibility; population pharmacokinetics; pharmacokinetics-pharmacodynamics of TMC125 and darunavir; and global health status by patient-reported outcomes. These analyses will be reported comprehensively elsewhere.
Viral genotyping was done with vircoTYPE HIV-1; phenotyping was done with Antivirogram (both Virco BVBA, Mechelen, Belgium). In subgroup analyses, viral sensitivity to darunavir was assumed on the basis of fold change in 50% effective concentration (FC) less than 10 and whereas viral sensitivity to enfuvirtide was assumed on the basis of de-novo use.
Statistical analysis
Sample size calculations took into account interim combined results of the darunavir POWER 1 and 2 trials21 and assumed that the expected response at week 24 in the placebo group would be 35% when enfuvirtide was re-used or not used and 60% when enfuvirtide was used de novo, and that the expected response at week 24 in the TMC125 group would be 55% when enfuvirtide was re-used or not used and 60% when used de novo. On the basis of a maximum of 40% of patients who used enfuvirtide de novo, 300 patients per treatment group were to be randomised and treated.
This trial was designed to have 95% power to detect a significant difference in the primary endpoint between treatment groups. All analyses used the intention-to-treat (ITT) population, defined as all randomised patients receiving at least one dose of trial medication, irrespective of compliance with the protocol. The overall significance level of the trial was 5% (two-sided); the three data and safety monitoring board interim analyses were accounted for by alpha spending, resulting in a significance level of 0¥048.
The primary endpoint used the time to loss of virological response (TLOVR) algorithm,22 which incorporates the non-completer=failure (NC=F) method after patient discontinuation and the last observation carried forward (LOCF) method for other missing data. Two consecutive values were needed to confirm response or loss of response. The Cochran-Mantel-Haenszel test, controlling for the stratification factors, was the primary analysis used to test the difference in virological response rates between the treatment groups at 24 weeks. Because the magnitude of the difference between the TMC125 and placebo groups was expected to be different between patients who re-used or did not use enfuvirtide versus those who used the drug de novo, it was first tested whether there was a significant statistical interaction effect between TMC125 and enfuvirtide use (Breslow-Day test for the homogeneity of odds ratios). If a significant statistical interaction was found (p<0¥20), separate Cochran-Mantel-Haenszel tests were to be done for the group of patients who re-used or did not use enfuvirtide, and the group of patients who used enfuvirtide de novo, with a Hochberg multiplicity correction applied.
Predefined subgroup analyses were done on the primary endpoint, including viral load below 100 000 or 100 000 copies per mL or greater, in addition to the 30 000 copies per mL stratification factor. Logistic regression models were used as sensitivity analyses and to examine the effect of baseline resistance parameters and sensitivity of the background antiretroviral regimen on the virological response parameter. In a logistic regression model, the overall effect of TMC125 versus placebo was also estimated across both enfuvirtide strata.
For the secondary endpoints of change from baseline in log10 plasma viral load and CD4 cell count, the least square means of the difference between the TMC125 and the placebo group and its two-sided 95% CI were estimated with analysis of covariance (ANCOVA). The TLOVR algorithm was also used when analysing the secondary virological response parameters. Additionally, a predefined analysis of the occurence of rash, nervous system, and psychiatric adverse events in the TMC125 versus placebo groups was completed by Fisher's exact test.
Role of the funding source
The study sponsor was involved in the design and conduct of the trial, and in the collection and analysis of the data. All authors had full access to the 24-week data. The corresponding author had final responsibility to submit the manuscript for publication.
Results
954 patients were screened; 593 were randomised (figure 1). All analyses include the 591 patients who started treatment, irrespective of their eligibility or compliance with the protocol (ITT population) and data were collected until January 18, 2007, when all patients had either received at least 24 weeks of treatment or discontinued. The median treatment duration was 33¥1 weeks (range 1¥9-56¥1) in the TMC125 group and 32¥2 weeks (2¥7-55¥1) in the placebo group. 51 (17%) patients in the TMC125 group and 73 (25%) in the placebo group discontinued prematurely, mainly because of virological failure. All patients used darunavir, with 23 (4%) re-using this drug. NNRTIs were used during screening by 56 (9%) patients. Enfuvirtide use was well balanced between treatment groups; overall, 148 (25%) patients re-used enfuvirtide (73 [25%] in the TMC125 group and 75 [25%] in the placebo group); 283 (48%) did not use the drug (143 [49%] in the TMC125 group and 140 [47%] in the placebo group), and 160 (27%) patients used the drug de novo (79 [27%] in the TMC125 group and 81 [27%] in the placebo group). The number and individual NRTIs used were similar between treatment groups and baseline characteristics were generally well balanced between the two groups (table 1).
At baseline, 382 (65%) patients had two or more NNRTI resistance-associated mutations, 533 (90%) had four or more NRTI resistance-associated mutations, 387 (66%) had four or more primary PI mutations, and 261 (44%) had three or more darunavir resistance-associated mutations. 417 (71%) patients had a baseline viral load over 30 000 copies per mL; 417 (71%) patients had CD4 cell count below 200 cells per ƒÊL. The three most prevalent NNRTI resistance-associated mutations were Lys103Asn (190 [32%] patients; 101 in the TMC125 group, 89 in the placebo group), Tyr181Cys (179 [30%] patients; 91 in the TMC125 group, 88 in the placebo group), and Gly190Ala (157 [27%] patients; 79 in the TMC125 group, 78 in the placebo group); 381 (64%) patients had at least one of these mutations. Of the 91 (15%) patients with no baseline NNRTI resistance-associated mutations, 85 had one or more from historical genotypes. Of the remaining six patients, four had phenotypic but not genotypic evidence of NNRTI resistance, while two had no evidence of such resistance and were entered into the trial in error.
183 (62%) patients in the TMC125 group achieved a confirmed viral load of less than 50 copies per mL at week 24, compared with 129 (44%) patients in the placebo group (difference in response rate 18%, 95% CI 11-26; p=0¥0003; figure 2). 221 (75%) patients in the TMC125 group achieved a viral load of less than 400 copies per mL at week 24, compared with 159 (54%) patients in the placebo group (difference in response rate 21%, 95% CI 14-29; p=0¥0001; figure 2). The mean change in viral load at week 24 was -2¥34 (SD 1¥31) log10 copies per mL in the TMC125 group and -1¥68 (1¥40) log10 copies per mL in the placebo group (p<0¥0001).
The proportion of patients achieving a virological response (viral load <50 and <400 copies per mL) according to the number of active background antiretrovirals is shown in figure 2. The TMC125 group achieved higher virological responses than the placebo group, irrespective of the number of active antiretrovirals in the underlying antiretroviral regimen. More patients had two active antiretrovirals in the TMC125 than did those in the placebo group, but virological responses remained better in the TMC125 group than in the placebo group when this was accounted for in the statistical model. Virological responses remained good despite very high viral loads at baseline: of the individuals with a viral load of 100 000 copies per mL or more at baseline, 56 (51%) in the TMC125 group and 22 (24%) in the placebo group reached a viral load of less than 50 copies per mL at week 24. Mean CD4 cell count increased in both groups, although the difference in response between the two groups was not significant (figure 2).
CDC category C AIDS-defining illness or death was reported for 14 (5%) patients in the TMC125 group, compared with 20 (7%) patients in the placebo group (p=0¥8630). CDC category C AIDS-defining illnesses were reported in 13 (4%) patients in the TMC125 group and 15 (5%) patients in the placebo group (p=0¥0020). There were four deaths in the TMC125 group and seven in the placebo group (p=0¥0217).
A statistical interaction was found between enfuvirtide use and treatment outcome (p=0¥0821), therefore the trial population was divided into two predefined patient groups: those that re-used or did not use enfuvirtide and those receiving enfuvirtide de novo.
Of the individuals who re-used or did not use enfuvirtide, 125 (58%) in the TMC125 group achieved a viral load below 50 copies per mL at week 24, compared with 74 (34%) in the corresponding placebo group (p<0¥0001; figure 3); viral load below 400 copies per mL at week 24 was achieved by 153 (71%) patients in the TMC125 group, compared with 96 (45%) patients in the corresponding placebo group (p<0¥0001; figure 3).
The effect of baseline NNRTI resistance-associated mutations on the proportion of patients achieving viral load below 50 copies per mL was examined in patients who re-used or did not use enfuvirtide, to ensure that these analyses were not confounded by enfuvirtide activity. A higher proportion of patients achieved viral load below 50 copies per mL in the TMC125 group than in the placebo group, independent of the number of detectable NNRTI resistance-associated mutations present at baseline (figure 3). Virological response in those who re-used or did not use enfuvirtide according to darunavir FC is shown in figure 4.
Of the patients who used enfuvirtide de novo, 58 (73%) in the TMC125 group achieved viral load below 50 copies per mL at week 24, compared with 55 (68%) in the placebo group (p=0¥3838); viral load below 400 copies per mL at week 24 was achieved by 68 (86%) in the TMC125 group and 63 (78%) in the placebo group (p=0¥2042). Virological response in de-novo users according to darunavir FC is shown in figure 4.
Adverse events were generally mild or moderate (grade 1 or 2), with no major differences in frequency or severity between TMC125 and placebo groups (table 2). The most common adverse events were diarrhoea, nausea, rash (any type), injection site reaction (related to enfuvirtide administration), headache, and fatigue, with the frequency of each being similar between the study groups. The frequency and type of serious adverse events, and the overall rate of discontinuation due to any adverse event, were similar between the TMC125 and placebo groups.
Rash was reported for 41 (14%) patients in the TMC125 group and 27 (9%) patients in the placebo group. Most rashes were described as erythematous or maculopapular and were of mild or moderate severity; no grade 4 skin events were reported while grade 3 skin events were reported for four (1%) patients in the TMC125 group and one (0¥3%) in the placebo group. When rash did occur in the TMC125 group, it was typically mild or moderate, reported early during the trial (median onset day 14), and resolved with continued dosing (median duration 16 days). Seven (2%) patients in the TMC125 group and none in the placebo group discontinued due to rash (any type). A similar occurrence of rash was reported in patients with and without a history of NNRTI-related rash.
Nervous system and psychiatric adverse events were reported with a similar nature, frequency, and severity in the TMC125 and placebo groups. Events were generally mild or moderate in severity; no grade 4 nervous system or psychiatric adverse events were reported in the TMC125 group, and grade 3 neuropsychiatric adverse events were reported with similar low frequency in both treatment groups (one patient in the TMC125 group and three in the placebo group).
Overall, no clinically relevant changes were recorded in laboratory measurements over the 24-week study period. Grade 3 or 4 changes in lipid, hepatic, and pancreatic laboratory investigations were generally similar between treatment groups.
Four patients in the TMC125 group and seven in the placebo group died because of adverse events that began during the treatment period. No deaths were deemed to be related to trial medication. In the TMC125 group, the causes of death were HIV wasting syndrome, Mycobacterium avium complex infection, progressive multifocal leukoencephalopathy, and myocardial infarction. The deaths in the placebo group were also mainly due to AIDS-related complications.
Discussion
At week 24, a significantly higher proportion of patients who received TMC125 with background antiretrovirals achieved a confirmed viral load of less than 50 copies per mL than did those who received placebo with background antiretrovirals, irrespective of the baseline viral load or presence of several NNRTI resistance-associated mutations. Furthermore, TMC125 had a tolerability profile much the same as placebo, with few clinically relevant differences.
This trial assessed two agents that were investigational at trial initiation-TMC125 and darunavir-both with potential activity in patients with infection resistant to NNRTIs and PIs. These findings support the concept of using more than one investigational agent in clinical trials of treatment-experienced patients.23 Darunavir-ritonavir was the only permitted PI component, and this was considered clinically appropriate since all patients had at least three documented primary PI mutations at trial entry and data suggested that significant antiviral responses can be achieved when darunavir-ritonavir is administered as part of antiretroviral therapy.18 This expectation is confirmed by the high virological responses seen in the placebo group, which are in line with those described previously in the darunavir phase IIb POWER studies at 24 weeks.16,17 That an additional 18% of patients achieved a viral load below 50 copies per mL in the overall TMC125 group compared with the placebo group is therefore noteworthy. A comparable difference in virological responses was also noted in the DUET-1 trial,24 despite the different but overlapping geographical locations of these trials.
Differences in virological response between the two groups were most apparent in patients with no active background antiretrovirals (44% in the TMC125 group vs 7% in the placebo group achieved viral load <50 copies per mL); for patients who received two or more active drugs in the background regimen the difference was smaller. In support of current guidelines,2,19 we report an incremental increase in virological response rate when one or two active background antiretrovirals were used in addition to TMC125. Indeed, several well-designed studies have shown that once there are three active agents in antiretroviral therapy, it is difficult to show improved virological responses by adding additional active agents.25-28 That patients receiving de-novo enfuvirtide, darunavir-ritonavir, and individually optimised NRTIs exhibited virological responses that were only slightly higher in the TMC125 group than in the placebo group is thus unsurprising.
The results of DUET-2 suggest that the sequential use of TMC125-ie, after virological failure on current NNRTI-based treatment-is now possible. Of note, a decreasing response was seen in the placebo group with increasing numbers of NNRTI resistance-associated mutations. The reasons for this are unclear, since no patients in the placebo group received NNRTIs and no correlation was found between the number of NNRTI resistance-associated mutations and number of resistance mutations associated with PIs or NRTIs. Although work is still in progress, preliminary analyses of data from the DUET trials have identified thirteen mutations associated with decreased virological responses to TMC125; the concurrent presence of three or more of these were required to substantially reduce virological efficacy. These mutations are Val90Ile, Ala98Gly, Leu100Ile, Lys101Glu/Pro, Val106Ile, Val179Asp/Phe, Tyr181Cys/Ile/Val, and Gly190Ala/Ser.29
The limitations of the trial included fixing the PI component of the background regimen as darunavir-ritonavir, since although more patients were sensitive to darunavir-ritonavir than any other PI, some might have been more sensitive to another PI. However, because coadministration of TMC125 and tipranavir is not recommended,30 darunavir-ritonavir was the PI component that was thought to offer the best potential for response in the trial patients. The exclusion of agents from new antiretroviral drug classes from the background regimen could be seen as a limitation, especially in this treatment-experienced population, although data for drug-drug interaction with TMC125 and these new classes were not available and the universal use of darunavir-ritonavir meant that all patients received at least one investigational agent. Additionally, although the trial population consisted of patients with detectable baseline NNRTI resistance as well as patients with documented NNRTI resistance from a historical genotype, currently available NNRTIs would not be anticipated to provide virological suppression comparable with that seen with TMC125 in the present trial in either patient subgroup.
Most data available on NNRTIs come from clinical trials done with efavirenz and nevirapine in treatment-naive patients,31-34 with very little available in the context of NNRTI resistance39 or in treatment-experienced patients with limited remaining treatment options. Thus that current treatment guidelines reflect the well-established role of NNRTIs in treatment-naive patients is not surprising.2,19 Clinical trials of NNRTIs (in combination with various NRTI-based background regimens) in this patient population produced virological responses in terms of viral load below 50 copies per mL in the range of 65-80% at week 48.31,33,34 The guidelines suggest, however, that currently available NNRTIs are unlikely to have virological activity in patients with NNRTI resistance after regimen failure, and are not recommended for inclusion in the subsequent treatment regimen.19 NNRTI experience was associated with treatment failure in the ACTG-398 study at 24 weeks with the findings of the 48-week analysis suggesting that efavirenz resistance (at baseline or development during the study) was associated with virological failure.40
This is an important issue in clinical practice, since although there are several important benefits of NNRTI-based therapy,1 cross-resistance limits the use of NNRTIs, especially in treatment-experienced patients,8 with single reverse transcriptase mutations leading to substantial resistance to currently available NNRTIs,1,41 and the increasing transmission of NNRTI-resistant viruses is also a concern.42 There is currently an unmet clinical need to expand the NNRTI class for treatment-experienced patients, including those with NNRTI resistance.
The magnitude of the results seen with TMC125 in DUET-1 and DUET-2 (56% and 62% of patients achieved undetectable viral loads at week 24), and the similarity of the responses across both trials done in different countries, indicate that the higher genetic barrier to resistance of TMC125 compared with currently available NNRTIs and its activity against NNRTI-resistant virus are central to the ability of TMC125, given as part of an antiretroviral regimen, to produce significantly better virological responses than the placebo group in treatment-experienced patients. The maintenance of the response to 24 weeks without additional clinically relevant tolerability concerns further suggests that TMC125 is an encouraging new agent in this antiretroviral class.
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