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TMC114/r is well tolerated by treatment-experienced patients in POWER 1, 2 and 3: integrated clinical safety analysis
  Reported by Jules Levin
XVI IAC Toronto, Aug 2006
Valdez-Madruga J,1 Lafeuillade A,2 Beatty G,3 Spinosa-Guzman S,4 El Malt M,4 Lefebvre E5 1Centro de Referencia e Treinamento DST/AIDS, Mariana-Sao Paulo, Brazil; 2Chalucet Hospital, Toulon, France; 3University of California, San Francisco, USA; 4Tibotec BVBA, Mechelen, Belgium; 5Tibotec Inc, Yardley, USA poster TUPE0062
In a pooled Week 24 efficacy analysis of POWER 1, 2 and 3, 67% of patients achieved >/=1 log10 reduction in VL and 42% reached a VL of <50 copies/mL.
The current 24-week pooled analysis was undertaken to assess the clinical safety of the recommended dose for treatment-experienced patients, TMC114/r 600/100mg bid, in POWER 1, 2 and 3.
48 Week TMC114 Study results were reported at IAC, here is link to report: link to IAC Report:
TMC-114 48 Week Study Results: lipids, potency, safety - (08/29/06)
The rationale for pooling the data was based on similarities between the trials, including patient BL disease characteristics, TMC114/r dosing, efficacy and safety outcomes.
Pooled clinical safety results from the POWER trials are presented. Results of the integrated analysis of laboratory parameters are discussed in a separate presentation (TUPE0063).
All POWER 1-3 patients using TMC114/r 600/100mg bid in their initial regimen were included in this analysis (de novo; n=458), as well as POWER 1 and 2 patients randomized to receive CPI(s) (n=124).
The protease inhibitor (PI) TMC114 (darunavir), co-administered with low-dose ritonavir (TMC114/r), demonstrated significantly better efficacy than control PIs (CPI[s]) among treatment-experienced patients in the controlled POWER 1/2 (TMC114-C213/C202) studies. Similar efficacy was seen in an analysis of a large, open-label patient group (POWER 3) (TMC114-C215/C208). This pooled analysis assesses the clinical safety of the recommended treatment-experienced dose, TMC114/r 600/100mg bid, in POWER 1, 2 and 3.
Methods: Patients were PI-, NRTI- and NNRTI-experienced, with 31 primary PI mutation at baseline (BL). Adverse events (AEs) were evaluated in all POWER 1-3 patients using TMC114/r 600/100mg bid in their initial regimen (de novo; n=458) and POWER 1 and 2 patients using CPI(s) (n=124).
Results: The majority of AEs were grade 1-2 in severity. Frequency of discontinuations and the most common AEs are shown in the table below. The frequency of serious AEs (SAEs) was 15% for TMC114/r versus 14% for CPI; no individual SAE occurred in >1% of patients. Eleven TMC114/r patients died with no case considered at least possibly related to TMC114/r treatment.


Conclusions: TMC114/r is generally well tolerated by treatment-experienced patients. The incidence of diarrhea with TMC114/r was lower than with CPI(s). TMC114/r is expected to provide a valuable HIV therapy option.
Of the 458 patients receiving TMC114/r 600/100mg bid, 131 were from the POWER 1 and 2 studies and 327 were from POWER 3.
BL characteristics
-Demographic data and disease characteristics were similar across the treatment groups at BL (Table 1).
-The investigator-selected PIs used in the CPI arm were lopinavir (36%), saquinavir (35%), amprenavir or fosamprenavir (34%), atazanavir (17%), indinavir (2%) and nelfinavir (1%). Seventy-five percent of regimens were single-boosted PIs, 23% were double-boosted PIs and 2% were double PI combinations without low-dose ritonavir.


Discontinuation and exposure
-The mean duration of treatment was 35 weeks with TMC114/r and 32 weeks with CPI(s) (see Abstract table). There was a higher number of patient-years of exposure in the TMC114/r group (310) compared with the CPI group (75) due to the longer mean duration of treatment and the larger number of patients treated in the TMC114/r group.
-There was a low rate of treatment discontinuations due to AEs. The overall discontinuation rate was 11% of patients in the TMC114/r group and 81% of patients in the CPI group (3% vs 67%, respectively, due to virologic failure).
-TMC114/r was generally well tolerated and no specific toxicity was associated with TMC114/r treatment.
-The most common treatment-emergent AEs occurring in >/=10% of patients regardless of severity and causality are shown in Figure 1 (see Abstract table) (excluding injection-site reactions associated with ENF use, which occurred in 21% of TMC114/r and 22% of CPI patients receiving this drug)
- the incidence of diarrhea was lower in the TMC114/r arm than in the CPI arm (16% vs 28%)
-- similarly, the incidence of headache was lower in TMC114/r-treated patients than in CPI-treated patients (11% vs 20%).
-The majority of AEs were grade 1 (mild) or 2 (moderate) in severity; 29% of patients in each treatment group reported 31 grade 3/4 AE.
-Grade 2, 3 or 4 AEs occurring with an incidence of >/=2% in at least one of the treatment groups are shown in Table 3 (see Abstract table). The profile of grade 2-4 AEs was the same in the TMC114/r and CPI treatment groups.
-Overall, 15% of TMC114/r-treated patients and 14% of CPI-treated patients reported at least one SAE, the most common being pneumonia and metabolic acidosis; no individual SAE occurred in >1% of patients. The majority of SAEs did not lead to permanent treatment discontinuation.
-Rash (all grades, regardless of causality) occurred in 6% of TMC114/r-treated patients; the discontinuation rate due to rash was 0.3%. Rashes were generally mild-to-moderate and self-limited.
-Eleven patients died in the TMC114/r arms. Causes of death were illicit drug overdose, acute and chronic pulmonary emboli, anal cancer, multiple organ failure due to sepsis, bacterial endocarditis, acute respiratory failure, meningoencephalitis, septic shock, chronic cryptosporidial gastroenteritis, brain edema and an unknown cause; all deaths were considered by the investigator to be unrelated to the study medication. One patient died in the CPI group 2 weeks after follow-up.
-As diarrhea has been commonly observed in patients receiving PI-based highly active ART, and may impact clinical management and quality of life, further analyses were performed to better characterize this side effect.
-During the screening period, both the TMC114/r and CPI groups showed a low incidence of diarrhea (Figure 2). The proportion of patients receiving TMC114/r reporting diarrhea remained low and stable throughout the 24-week study, reaching a maximum of 6%.
Conversely, the proportion of patients receiving CPI(s) and experiencing diarrhea was higher and tended to increase over the 24-week treatment period. A maximum incidence of 17% was reported.


-Recurrences of diarrhea were less often reported with TMC114/r than with CPI treatment (17% vs 37%). Furthermore, the duration of episodes was shorter (median 18 vs 41 days in the TMC114/r and CPI groups, respectively). Antidiarrheal agents (loperamide and diphenoxylate hydrochloride/atropine sulfate) were used during the treatment period by 26% of TMC114/r and 36% of CPI patients.
-Time to treatment-emergent diarrhea is shown in Figure 3. There was a more rapid onset of diarrhea in the CPI group than in the TMC114/r group. For both groups, the greater proportion of events occurred by Week 12.


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