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Sustained Antiretroviral Efficacy of Raltegravir after 192 Weeks of Combination ART in Treatment-Naive HIV-1 Infected Patients
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Reported by Jules Levin
CROI 2010 Feb 16-19 SF
E. Gotuzzo1, B.-Y. Nguyen2, M. Markowitz3, F. Mendo4, W. Ratanasuwan5, C. Lu2, J. Zhao2, B. Homony2, R. Barnard2, H. Teppler2, and the Protocol 004 Part II
Study Team
1Hospital Nacionale Cayetano Heredia, Lima, Peru; 2Merck Research Labs, West Point, PA, United States; 3Aaron Diamond AIDS Research Center, New York, NY, United States; 4Hospital Nacionale Edgardo Rebagliati, Lima, Peru; 5Siriraj Hospital, Bangkok, Thailand
from Jules: data says a greater CD4 count increase is associated with a faster decline in viral load, decline by week 8, as you know raltegravir has shown faster or steeper viral load decline slopes in their studies.
Abstract
Objectives: Phase II study evaluating long term efficacy, safety and tolerability of raltegravir (RAL), an HIV-1 integrase inhibitor, vs efavirenz (EFV), combined with tenofovir/lamivudine (TDF/3TC), in ART-naive HIV-1-infected patients (pts).
Methods: Multicenter, double-blind, randomized study evaluating RAL 400mg bid (after 100, 200, 400 or 600mg bid for first 48 weeks) vs EFV 600mg qd, both with TDF/3TC, in ART naive pts with HIV-1 RNA ≥5000 copies/mL and CD4+ T-cells ≥100/uL. This abstract presents complete 192 week data. Exploratory analyses investigated the potential relationship between early virologic response and long term CD4 response.
Results: 198 pts were randomized and treated; 160 pts received RAL and 38 received EFV. Baseline information and dose-ranging results to week 144 have been presented previously. At week 192, 75% of RAL pts vs 74% of EFV pts sustained HIV-1 RNA <400 copies/mL; 74% of both groups sustained <50 copies/mL (non-completer=failure). RAL and EFV groups showed similar increases in CD4+ T-cells (295 vs 274/uL, respectively). One pt in the EFV group and none in the RAL group met the protocol definition of virologic failure after week 144. Cumulative rates of drug-related clinical adverse events (AEs) remained less frequent in the RAL vs EFV group (55% vs 76%, respectively). Drug-related AEs occurring in >10% of total pts were nausea (RAL 13%, EFV 11%), dizziness (9%, 26%), and headache (9%, 24%). Grade 3 and 4 laboratory abnormalities remained infrequent, generally ≤5% in the RAL group and ≤8% in the EFV group. RAL had minimal effect on total or LDL cholesterol, or triglycerides. Cumulative neuropsychiatric AEs remained less frequent with RAL (38%) than EFV (63%). There were no drug-related serious AEs in pts receiving RAL. Exploratory analyses showed that the change in CD4 count at week 192 was predicted by week 8 vRNA decrease: each vRNA log decline at week 8 yielded additional 145 and 131 cell increases at week 192 for RAL and EFV, respectively.
Conclusions: In ART-naive pts, RAL with TDF/3TC had potent and durable antiretroviral activity, drug-related AEs were less frequent in pts treated with RAL compared to EFV.
Background
· Raltegravir (RAL) is now approved for use in combination regimens for the treatment of HIV infection1.
· Week 96 data from Phase III studies in treatment-naïve2 and treatment-experienced3 patients have demonstrated potent efficacy and good overall tolerability.
· Protocol 004 (P004) is a Phase II study of RAL vs efavirenz (both with tenofovir/3TC) in treatment-naïve patients that has demonstrated sustained efficacy and good general tolerability up to Week 1444.
· This poster presents updated P004 data to Week 192, including:
- Exploratory analysis: Relationship between early viral load decline and long-term change in CD4 counts
Results
* With TDF/3TC, **geometric mean, Defined as history of clinical diagnosis of AIDS at baseline.
* Abnormal dreams, acute psychosis, adjustment disorder with depressed mood, auditory hallucination, completed suicide, concentration impaired, confusional state, delirium, depressed level of consciousness, depressed mood, depression, depressive symptom, dizziness, dysthymic disorder, hallucination, hallucination visual, insomnia, major depression, nervous system disorder, nightmare, psychotic disorder, somnolence, suicidal behavior, suicidal ideation, suicide attempt.
Cases included: 1 pt with B-cell lymphoma, 2 pts with Kaposi’s sarcoma, 1 pt with both basal cell carcinoma and squamous cell carcinoma (SC), 1 pt with both gastrointestinal carcinoma and SC
RAL taken twice daily; EFV taken once daily; both with TDF/3TC.
* Incidence at least 10% in either treatment group; all intensity levels included
Efficacy Analysis
· After Week 144 there were no new virologic failures (relapses) on RAL and 1 failure on EFV.
– Patient had HIV RNA ≤300 copies/mL so resistance testing was not performed
*After Week 48 patients in all RAL groups continued at 400 mg b.i.d. All patients also received TDF/3TC.
Non-completer equals failure (NC=F) approach treats all discontinuations as failures.
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