[Show abstract][Hide abstract] ABSTRACT: Background: Raltegravir (RAL) is indicated in combination with other antiretroviral therapies (ARTs) for the treatment of HIV-1 infection in pediatric patients (pts) 2-18 years old (yo) in the US and elsewhere.
Methods: This was a multicenter, open-label, noncomparative, 24-week study of 2 oral formulations of RAL in Russian children and adolescents with HIV-1 infection. Pts 12 to <18 yo received the film-coated tablet (400 mg bid). Pts 2 to <12 yo (weight [wt] ≥7 to <25 kg) received the chewable tablet (wt-based dose of ~6 mg/kg, maximum 300 mg bid). Pts 6 to <12 yo (wt ≥25 kg) could receive either formulation. Safety was the primary endpoint and included all enrolled pts who received at least one dose of RAL. For efficacy, missing HIV RNA (vRNA) values were handled with the Observed Failure approach.
Results: Thirty-two pts were enrolled; 4 received the film-coated tablet (median age 10.5 y) and 28 received the chewable tablet (median age 7 y), in addition to background ART chosen by the investigator. The majority were white (97%) and treatment naïve (81%). At baseline, median vRNA was 4.6 (range 3-6) log10 copies(c)/mL, and median CD4 count was 518 (range 22-1295) cells/mm3. Twenty-nine pts (91%) completed the study. Clinical adverse events (AEs) were reported by 12 pts (37.5%), all on the chewable tablet; 4 (12.5%) had AEs that were considered drug-related: diarrhea, vomiting, abdominal pain/nausea, and somnambulism; all resolved and none led to discontinuation. One pt (3%), who received the chewable tablet, had a laboratory AE (decreased platelet count), which was considered drug-related and resolved after 84 days. No serious AEs were reported. At week 24, 86.2% of pts achieved ≥1 log10 decline from baseline vRNA or vRNA <200 c/mL, and 44.8% and 72.4% had vRNA <40 and <200 c/mL, respectively. The mean increase from baseline in CD4 count was 267 cells/mm3. Virologic failure occurred in 4 pts; post-baseline RAL resistance mutations were identified in 2 of the 3 pts with genotype data available: L74I + N155H, and L74I alone.
Conclusion: In HIV-infected Russian children and adolescents 2 to <18 yo, RAL given as the 400-mg film-coated tablet or the pediatric chewable tablet, in combination with other ARTs for up to 24 weeks, was generally safe and well tolerated, had a favorable antiretroviral effect, and demonstrated immunological benefit.
IDWeek 2014 Meeting of the Infectious Diseases Society of America; 10/2014
[Show abstract][Hide abstract] ABSTRACT: IMPAACT P1097 was a multicenter trial to determine washout pharmacokinetics and safety of in utero/intrapartum exposure to raltegravir in infants born to HIV-infected pregnant women receiving raltegravir-based antiretroviral therapy. Twenty-two mother-infant pairs were enrolled; evaluable pharmacokinetic data was available from 19 mother-infant pairs. Raltegravir readily crossed the placenta, with median cord blood/maternal delivery plasma raltegravir concentration ratio 1.48 (range, 0.32-4.33). Raltegravir elimination was highly variable and extremely prolonged in some infants; [median t½ 26.6 hours (range 9.3-184 hours)]. Prolonged raltegravir elimination likely reflects low neonatal UGT1A1 enzyme activity and enterohepatic recirculation. Excessive raltegravir concentrations must be avoided in the neonate, since raltegravir at high plasma concentrations may increase the risk of bilirubin neurotoxicity. Sub-therapeutic concentrations, which could lead to inadequate viral suppression and development of raltegravir resistance, must be avoided as well. Two ongoing IMPAACT studies are investigating further the pharmacology of raltegravir in neonates.
[Show abstract][Hide abstract] ABSTRACT: Doravirine (DOR) is an investigational NNRTI (aka MK-1439) that retains activity against common NNRTI-resistant mutants. We have previously reported the Part 1 results from a two-part, randomized, double-blind, Phase IIb study in ART-naïve HIV-1-positive patients (1). At doses of 25, 50, 100 and 200 mg qd, DOR plus open-label tenofovir/emtricitabine (TDF/FTC) demonstrated potent antiretroviral activity comparable to EFV 600 mg qhs plus TDF/FTC and was generally well tolerated at week 24. DOR 100 mg was selected for use in patients continuing in Part 1 and those newly enrolled in Part 2.
Journal of the International AIDS Society 01/2014; 17(4 Suppl 3):19532. · 3.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. IMPAACT P1066 is a Phase I/II open label multicenter trial to evaluate safety, pharmacokinetics (PK), tolerability and efficacy of multiple raltegravir (RAL) formulations in HIV-infected youth. Methods. Dose selection for each cohort (I: 12 to <19 years; II: 6 to<12 years; and III: 2 to<6 years) was based on review of short term safety (4 weeks) and intensive pharmacokinetic (PK) evaluation. Safety data through Weeks 24 and 48, and Grade >3 or serious adverse events (AE) were assessed. The primary virologic endpoint was achieving HIV RNA<400 copies/mL or ≥1 log10 reduction between baseline and week 24. Results. The targeted PK parameters (AUC0-12 hr and C12 hr) were achieved for each cohort allowing dose selection for two formulations. Of 96 final dose subjects, there were 15 subjects with Grade 3+ clinical AEs (1 subject with drug related [DR] psychomotor hyperactivity and insomnia); 16 subjects with Grade 3+ laboratory AEs (1 with DR transaminase elevation); 15 subjects with serious clinical AEs (1 with DR rash); 2 subjects with serious laboratory AEs (1 with DR transaminase increased). There were no discontinuations due to AEs and no DR deaths. Favorable virologic responses at Week 48 were observed in 78.9%, with a mean CD4 increase of 156 cells/uL (4.6%). Conclusions. 400 mg BID of RAL film-coated tablet (6 to <19 years, and ≥25 kg) and 6 mg/kg BID (maximum dose 300 mg) of RAL chewable tablet (2 to<12 years) were well-tolerated and showed favorable virologic and immunologic responses.
[Show abstract][Hide abstract] ABSTRACT: Background
Two randomised, placebo-controlled trials—BENCHMRK-1 and BENCHMRK-2—investigated the efficacy and safety of raltegravir, an HIV-1 integrase strand-transfer inhibitor. We report final results of BENCHMRK-1 and BENCHMRK-2 combined at 3 years (the end of the double-blind phase) and 5 years (the end of the study).
Integrase-inhibitor-naive patients with HIV resistant to three classes of drug and who were failing antiretroviral therapy were enrolled. Patients were randomly assigned (2:1) to raltegravir 400 mg twice daily or placebo, both with optimised background treatment. Patients and investigators were masked to treatment allocation until week 156, after which all patients were offered open-label raltegravir until week 240. The primary endpoint was previously assessed at 16 weeks. We assessed long-term efficacy with endpoints of the proportion of patients with an HIV viral load of less than 50 copies per mL and less than 400 copies per mL, and mean change in CD4 cell count, at weeks 156 and 240.
1012 patients were screened for inclusion. 462 were treated with raltegravir and 237 with placebo. At week 156, 51% in the raltegravir group versus 22% in the placebo group (non-completer classed as failure) had viral loads of less than 50 copies per mL, and 54% versus 23% had viral loads of less than 400 copies per mL. Mean CD4 cell count increase (analysed by an observed failure approach) was 164 cells per μL versus 63 cells per μL. After week 156, 251 patients (54%) from the raltegravir group and 47 (20%) from the placebo group entered the open-label raltergravir phase; 221 (47%) versus 44 (19%) completed the entire study. At week 240, viral load was less than 50 copies per mL in 193 (42%) of all patients initially assigned to raltegravir and less than 400 copies per mL in 210 (45%); mean CD4 cell count increased by 183 cells per μL. Virological failure occurred in 166 raltegravir recipients (36%) during the double-blind phase and in 17 of all patients (6%) during the open-label phase. The most common drug-related adverse events at 5 years in both groups were nausea, headache, and diarrhoea, and occurred in similar proportions in each group. Laboratory test results were similar in both treatment groups and showed little change after year 2.
Raltegravir has a favourable long-term efficacy and safety profile in integrase-inhibitor-naive patients with triple-class resistant HIV in whom antiretroviral therapy is failing. Raltegravir is an alternative for treatment-experienced patients, particularly those with few treatment options.
Merck Sharp & Dohme.
The Lancet Infectious Diseases 07/2013; 13(7):587–596. · 19.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:: STARTMRK, a Phase III non-inferiority trial of raltegravir-based versus efavirenz-based therapy in treatment-naïve patients, remained blinded until its conclusion at 5 years. We now report the final study results. METHODS:: Previously untreated patients without baseline resistance to efavirenz, tenofovir, or emtricitabine were eligible for a randomized study of tenofovir/emtricitabine plus either raltegravir or efavirenz. Yearly analyses were planned, with primary and secondary endpoints stipulated at Weeks 48 and 96, respectively. The primary efficacy outcome was the percentage of patients with vRNA levels <50 copies/mL counting non-completers as failures (NC=F). Changes from baseline CD4-count were computed using an observed-failure approach to missing data. No formal hypotheses were formulated for testing at Week 240. RESULTS:: Overall, 71/281 raltegravir recipients (25%) and 98/282 efavirenz recipients (35%) discontinued the study; discontinuations due to adverse events occurred in 14 (5%) and 28 (10%) patients in the respective groups. In the NC=F efficacy analysis at Week 240, 198/279 (71.0%) raltegravir recipients and 171/279 (61.3%) efavirenz recipients had vRNA levels <50 copies/mL, yielding a treatment difference (Δ [95% CI]) of 9.5 [1.7, 17.3]. Generally comparable between-treatment differences were seen in both protocol-stipulated sensitivity analyses as well as in the prespecified subgroup analyses. The mean [95% CI] increments in baseline CD4-counts at Week 240 were 374 and 312 cells/mm in the raltegravir and efavirenz groups, respectively (Δ [95% CI] = 62 [22, 102]). Overall, significantly fewer raltegravir than efavirenz recipients experienced neuropsychiatric (39.1% versus 64.2%, p <0.001) or drug-related clinical adverse events (52.0% versus 80.1%, p <0.001). CONCLUSIONS:: In this exploratory analysis of combination therapy with tenofovir/emtricitabine in treatment-naive patients at Week 240, vRNA suppression rates and increases in baseline CD4 counts were significantly higher in raltegravir than efavirenz recipients. Over the entire study, fewer patients experienced neuropsychiatric and drug-related adverse events in the raltegravir group than in the efavirenz group. Based on better virologic and immunologic outcomes after 240 weeks, raltegravir/tenofovir/emtricitabine appeared to have superior efficacy compared to efavirenz/tenofovir/emtricitabine.
[Show abstract][Hide abstract] ABSTRACT: Background Uncertainty exists about the best treatment for people with HIV-1 who have virological failure with
first-line combination antiretroviral therapy of a non-nucleoside analogue (NNRTI) plus two nucleoside or nucleotide analogue reverse transcriptase inhibitors (NtRTI). We compared a second-line regimen combining two new classes of drug with a WHO-recommended regimen.
Methods We did this 96-week, phase 3b/4, randomised, open-label non-inferiority trial at 37 sites worldwide. Adults with HIV-1 who had confirmed virological failure (plasma viral load >500 copies per mL) after 24 weeks or more of first-line treatment were randomly assigned (1:1) to receive ritonavir-boosted lopinavir plus two or three NtRTIs (control group) or ritonavir-boosted lopinavir plus raltegravir (raltegravir group). The randomisation sequence was computer generated with block randomisation (block size four). Neither participants nor investigators were masked to allocation. The primary endpoint was the proportion of participants with plasma viral load less than 200 copies per mL at 48 weeks in the modified intention-to-treat population, with a non-inferiority margin of 12%. This study is registered with ClinicalTrials.gov, number NCT00931463.
Findings We enrolled 558 patients, of whom 541 (271 in the control group, 270 in the raltegravir group) were included in the primary analysis. At 48 weeks, 219 (81%) patients in the control group compared with 223 (83%) in the raltegravir group met the primary endpoint (difference 1·8%, 95% CI –4·7 to 8·3), fulfilling the criterion for non-inferiority. 993 adverse events occurred in 271 participants in the control group versus 895 in 270 participants in the raltegravir group, the most common being gastrointestinal.
Interpretation The raltegravir regimen was no less efficacious than the standard of care and was safe and well tolerated. This simple NtRTI-free treatment strategy might extend the successful public health approach to management of HIV by providing simple, easy to administer, effective, safe, and tolerable second-line combination antiretroviral therapy.
[Show abstract][Hide abstract] ABSTRACT: Purpose of study: Safety and efficacy of raltegravir (RAL) in patients (pts) with HIV and hepatitis B and/or C (HBV/HCV) co-infection were evaluated in a double-blind fashion for 5 years in STARTMRK and 3 years in BENCHMRK-1&2. Methods: In STARTMRK, treatment-naïve pts received RAL 400 mg bid or efavirenz (EFV) 600 mg qhs, both with tenofovir+emtricitabine (TDF/FTC), for up to 240 weeks. In BENCHMRK-1&2, highly treatment-experienced pts with multidrug-resistant virus and failing other therapies received double-blind RAL 400 mg bid or placebo, both with optimized background therapy (OBT), for up to 156 weeks. Pts with stable chronic HBV/HCV could enroll if baseline AST and ALT were=5×upper limit of normal. Summary of results: 743 pts received RAL and 519 received comparator. Hepatitis co-infection was present in 6% (34/563) of treatment-naïve pts (HBV=4%, HCV=2%, HBV+HCV=0.2%) and 16% (114/699) of treatment-experienced pts (HBV=6%, HCV=9%, HBV+HCV=1%). Safety and efficacy results at the end of double-blind treatment are shown by study, treatment group and co-infection status. Liver enzyme elevations were more common in pts with HIV+HBV/HCV co-infection than in pts with HIV infection alone, in the RAL and control groups. Most liver enzyme changes occurred in the first 48 weeks of treatment, with minimal further increases (data not shown). Conclusion: RAL was efficacious and generally well tolerated for up to 5 years in pts with HIV+HBV/HCV co-infection. The majority of grade 3 and grade 4 liver enzyme elevations occurred during the first year of treatment and were more common among co-infected pts than among HIV mono-infected pts, irrespective of treatment group.
Journal of the International AIDS Society 11/2012; 15(6):18415. · 3.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Raltegravir as initial HIV therapy was examined in a double-blind study; 160 patients were randomized to raltegravir (400 mg bid after dose-ranging), 38 to efavirenz, both with tenofovir/lamivudine. At week 240, HIV-RNA remained <50 copies per milliliter in 68.8% (raltegravir) versus 63.2% (efavirenz), and CD4 increases were 302 versus 276 cells per microliter, respectively. Early HIV-RNA decline predicted later CD4 increases in both groups. Raltegravir resistance was observed in 3 of 10 raltegravir recipients with virologic failure. Few drug-related adverse events were reported after week 48. Raltegravir had minimal effect on laboratory values, including lipids. Raltegravir with tenofovir/lamivudine showed durable efficacy and good tolerability over 5 years.
[Show abstract][Hide abstract] ABSTRACT: Background: As the paradigm of HIV treatment has evolved to lifelong therapy with greater relevance of co-morbidities, long-term efficacy and safety data are essential to distinguish regimens. We now report 192 wk results from STARTMRK, a Phase III study of RAL- vs efavirenz (EFV)-based therapy in treatment (tx)-nave patients.
Methods: 563 patients were randomized to RAL or EFV, both with tenofovir/emtricitabine (TDF/FTC), in a double-blind study comparing standard efficacy endpoints and metabolic parameters. Primary analysis was at Wk 48 and secondary analysis at Wk 96. Standard efficacy endpoints were analyzed at Wk 192. Nominal p-values and 95% CI are reported.
% (n/N) of Patients with HIV RNA <50 copies/mL
Change from BL in CD4 Cell Count (cells/mm3)
RAL - EFV,µ
RAL - EFV
4.2* (-1.9, 10.3)
25.8 (4.4, 47.2)
2.4* (-4.3, 9.0)
15.2 (-12.2, 42.6)
6.6* (-0.8, 14.0)
35.9 (3.4, 68.3)
9.0* (1.6, 16.4)
59.8 (24.1, 95.4)
Non-Completer=Failure (NC=F): Patients who discontinued tx regardless of reasons were considered as failures thereafter.
Observed Failure (OF): Patients who discontinued tx due to lack of efficacy were considered as failures thereafter; BL values carried forward for virologic failures.
Difference between RAL and EFV (95%CI)
µ RAL would be considered non-inferior to EFV if the lower bound of the 95% CI for the difference in % response was above -12%, and superior to EFV if the lower bound exceeds 0.
*p-value for non-inferiority <0.001
Drug-related clinical adverse events (AEs) occurred less often with RAL than EFV (50% vs 80%; p<0.001). RAL was generally well tolerated with few discontinuations due to clinical AEs (5% RAL, 8% EFV). At Wk 192, RAL had less impact on fasting lipids than EFV.
Conclusion: After 4 years of treatment, RAL + TDF/FTC is associated with superior antiretroviral efficacy and CD4 responses vs. EFV + TDF/FTC in treatment-nave patients. The long-term tolerability and metabolic profile of this integrase-based regimen appear favorable.
Infectious Diseases Society of America 2011 Annual Meeting; 10/2011
[Show abstract][Hide abstract] ABSTRACT: We compared 3 years of antiretroviral therapy with raltegravir or efavirenz as part of a combination regimen in the ongoing STARTMRK study of treatment-naive patients infected with human immunodeficiency virus (HIV).
Eligible patients with HIV-1 RNA (vRNA) levels >5000 copies/mL and without baseline resistance to efavirenz, tenofovir, or emtricitabine were randomized in a double-blind, noninferiority study to receive raltegravir or efavirenz, each combined with tenofovir/emtricitabine. Outcomes included viral suppression, adverse events, and changes from baseline metabolic parameters. Dual energy X-ray absorptiometry scans were obtained on a convenience sample of patients at prespecified time points to assess changes in body fat composition.
At week 156 counting noncompleters as failures, 212 (75.4%) of 281 versus 192 (68.1%) of 282 had vRNA levels <50 copies/mL in the raltegravir and efavirenz groups, respectively [Δ (95% CI) = 7.3% (-0.2, 14.7), noninferiority P < .001]. Mean changes from baseline CD4 count were 332 and 295 cells/mm³ in the raltegravir and efavirenz arms, respectively [Δ (95% CI) = 37 (4, 69)]. Consistent virologic and immunologic efficacy was maintained across prespecified demographic and baseline prognostic subgroups for both treatment groups. Fewer drug-related clinical adverse events (49% vs 80%; P < .001) occurred in raltegravir than efavirenz recipients, with discontinuations due to adverse events in 5% and 7%, respectively. Elevations in fasting lipid levels (including LDL- and HDL-cholesterol) were consistently lower in the raltegravir than efavirenz group (P < .005). Fat gain was 19% in 25 raltegravir recipients and 31% in 32 efavirenz recipients at week 156.
When combined with tenofovir/emtricitabine in treatment-naive patients, raltegravir produced durable viral suppression and immune restoration that was at least equivalent to efavirenz through 156 weeks of therapy. Both regimens were well tolerated, but raltegravir was associated with fewer drug-related clinical adverse events and smaller elevations in lipid levels. Clinical Trials Registration. NCT00369941.
[Show abstract][Hide abstract] ABSTRACT: The aim was to examine the long-term safety and efficacy of raltegravir in patients with HIV-1 and hepatitis B virus (HBV) and/or hepatitis C virus (HCV) coinfection in three double-blind, randomized, controlled Phase III studies.
In STARTMRK, treatment-naïve patients received raltegravir 400 mg twice a day (bid) or efavirenz 600 mg at bedtime, both with tenofovir/emtricitabine. In BENCHMRK-1 and -2, highly treatment-experienced patients with multi-drug resistant virus and prior treatment failure received raltegravir 400 mg bid or placebo, both with optimized background therapy. Patients with chronic HBV and/or HCV coinfection were enrolled if baseline liver function tests were ≤5 times the upper limit of normal. HBV infection was defined as HBV surface antigen positivity for all studies; HCV infection was defined as HCV RNA positivity for STARTMRK and HCV antibody positivity for BENCHMRK.
Hepatitis coinfection was present in 6% (34 of 563) of treatment-naïve patients (4% HBV only, 2% HCV only and 0.2% HBV+HCV) and 16% (114 of 699) of treatment-experienced patients (6% HBV only, 9% HCV only and 1% HBV+HCV). The incidence of drug-related adverse events was similar in raltegravir recipients with and without hepatitis coinfection in both STARTMRK (50 vs. 47%) and BENCHMRK (34 vs. 38.5%). Grade 2-4 liver enzyme elevations were more frequent in coinfected vs. monoinfected patients, but were not different between the raltegravir and control groups. At week 96, the proportion of raltegravir recipients with HIV RNA <50 HIV-1 RNA copies/mL was similar between coinfected and monoinfected patients (93 vs. 90% in STARTMRK; 63 vs. 61% in BENCHMRK).
Raltegravir was generally well tolerated and efficacious up to 96 weeks in HIV-infected patients with HBV/HCV coinfection.
HIV Medicine 05/2011; 13(2):127-31. · 3.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Raltegravir is the first integrase strand transfer inhibitor approved for the treatment of HIV-1 infection. As the first agent in this new class of antiretroviral therapies, raltegravir has demonstrated safety and efficacy in treatment-naive as well as heavily pretreated HIV-infected patients failing therapy with multidrug-resistant virus. Raltegravir has a favorable drug interaction profile that permits both administration to a wide, demographically diverse patient population and coadministration with many other therapeutic agents, including antiretroviral agents and supportive medications, without restrictions or dose adjustment. Data through 96 weeks of follow-up in three phase III studies, protocol 021 (STARTMRK) in treatment-naive patients, and protocols 018 (BENCHMRK-1) and 019 (BENCHMRK-2) in treatment-experienced patients, demonstrated the potent and durable antiretroviral and immunologic effects and the favorable long-term safety profile of raltegravir in both treatment-naive and treatment-experienced patients. Raltegravir represents an important addition to the current armamentarium for the treatment of HIV infection.
Annals of the New York Academy of Sciences 03/2011; 1222:83-9. · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Raltegravir has demonstrated potent and durable efficacy and a favorable safety profile in 3 phase III studies in treatment-naïve and treatment-experienced patients with HIV-1 infection. This manuscript provides a review of the raltegravir safety profile using data from these and other studies in the clinical development program.
Comprehensive 96-week safety data from STARTMRK (raltegravir versus efavirenz, each with tenofovir/emtricitabine) and BENCHMRK (raltegravir versus placebo, each with optimized background therapy) are summarized. A cumulative meta-analysis of raltegravir 400 mg bid was conducted across the entire development program.
In STARTMRK, drug-related adverse events (AEs) occurred less frequently with raltegravir than efavirenz. In BENCHMRK, the most common drug-related AEs occurred at generally similar frequencies in both groups. Drug-related serious AEs were uncommon. Rash was observed in raltegravir-treated patients at a higher frequency than placebo but a lower frequency than efavirenz. Depression and immune reconstitution inflammatory syndrome occurred at similar rates for raltegravir and comparators. Isolated elevations of creatine kinase were more common with raltegravir than placebo but occurred without clinical manifestations. The frequency of aminotransferase elevations was greater in patients with viral hepatitis co-infection, but similar in the raltegravir and comparator groups. The relative risk (95% CI) of cancer was 0.75 (0.30, 1.91) indicating no difference between raltegravir and comparator. Overall trends in the cumulative meta-analysis were similar to those observed in the phase III studies.
Long-term data from the phase III clinical trials demonstrate that raltegravir was generally well-tolerated in both treatment-naïve and treatment-experienced patients with HIV infection.
Current HIV research 01/2011; 9(1):40-53. · 1.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We analyzed the 96-week results in the overall population and in prespecified subgroups from the ongoing STARTMRK study of treatment-naive HIV-infected patients.
Eligible patients with HIV-1 RNA (vRNA) levels >5000 copies per milliliter and without baseline resistance to efavirenz, tenofovir, or emtricitabine were randomized in a double-blind noninferiority study to receive raltegravir or efavirenz, each combined with tenofovir/emtricitabine.
At week 96 counting noncompleters as failures, 81% versus 79% achieved vRNA levels <50 copies per milliliter in the raltegravir and efavirenz groups, respectively [Delta (95% confidence interval) = 2% (-4 to 9), noninferiority P < 0.001]. Mean change in baseline CD4 count was 240 and 225 cells per cubic millimeter in the raltegravir and efavirenz groups, respectively [Delta (95% confidence interval) = 15 (-13 to 42)]. Treatment effects were consistent across prespecified baseline demographic and prognostic subgroups. Fewer drug-related clinical adverse events (47% versus 78%; P < 0.001) occurred in raltegravir than efavirenz recipients. Both regimens had modest effects on serum lipids and glucose levels and on body fat composition.
When combined with tenofovir/emtricitabine in treatment-naive patients, raltegravir exhibited durable antiretroviral activity that was noninferior to the efficacy of efavirenz through 96 weeks of therapy. Subgroup analyses were generally consistent with the overall findings. Both regimens were well tolerated.
[Show abstract][Hide abstract] ABSTRACT: We evaluated the long-term efficacy of raltegravir according to HIV-1 subtype (B and non-B) using data from three phase III studies in treatment-experienced (BENCHMRK-1 and 2) and treatment-naive (STARTMRK) HIV-infected patients.
HIV-1 subtypes were identified from baseline plasma specimens using genotypic data of the PhenoSense GT test (Monogram Biosciences, South San Francisco, California, USA). Non-B subtypes were combined for the current analyses due to small numbers of each specific subtype. An observed failure approach was used (only discontinuations due to lack of efficacy were treated as failures). Resistance evaluation was performed in patients with documented virologic failure.
Seven hundred and forty-three patients received raltegravir and 519 received comparator (efavirenz in STARTMRK; optimized background therapy in BENCHMRK). Non-B subtype virus (A, A/C, A/D, A/G, A1, AE, AG, B/G, BF, C, D, D/F, F, F1, G, and complex) was isolated at baseline in 98 (13%) raltegravir recipients and 62 (12%) comparator recipients. Subtypes AE and C were most common, isolated in 41 and 43 patients, respectively. The proportion of raltegravir recipients achieving HIV RNA less than 50 copies/ml was similar between non-B and B subtypes (STARTMRK: 94.5 vs. 88.7%; BENCHMRK-1 and 2: 66.7 vs. 60.7%); change in CD4 cell count also was similar between non-B and B subtypes (STARTMRK: 243 vs. 221 cells/μl; BENCHMRK-1 and 2: 121 vs. 144 cells/μl). Phenotypic resistance to raltegravir in non-B virus was associated with integrase mutations observed previously in subtype B virus.
In phase III studies in treatment-naive and treatment-experienced patients, raltegravir showed comparable and potent clinical efficacy against B and non-B HIV-1 subtypes.
AIDS (London, England) 04/2010; 25(11):1365-9. · 4.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BENCHMRK-1 and -2 are ongoing double-blind phase III studies of raltegravir in patients experiencing failure of antiretroviral therapy with triple-class drug-resistant human immunodeficiency virus infection. At week 96 (combined data), raltegravir (400 mg twice daily) plus optimized background therapy was generally well tolerated, with superior and durable antiretroviral and immunological efficacy, compared with optimized background therapy alone.
[Show abstract][Hide abstract] ABSTRACT: Results: In total, 743 pts received RAL and 519 received comparator across the 3 studies. Hepatitis co-infection was present in 16% (114/699) of treatment-experienced pts (HBV=6 %, HCV=9 %, HBV+HCV=1 %) and in 6% (34/563) of treatment-naïve pts (HBV=4 %, HCV=2 %, HBV+HCV=0.2 %). Selected safety and efficacy results at week 96 are shown for pts with (+) HBV/HCV and those without (-) HBV/HCV co-infection.