Raltegravir (MK-0518) is an inhibitor of the HIV integrase enzyme, and has no cross resistance with currently available classes of antiretroviral (ARV) medications. It is the first drug in its class to advance through registrational studies. Previous studies have demonstrated impressive potency at 24 weeks in patients with resistance to 3 classes of ARVs as well as in patients on initial therapy.(1,2) Sixteen-week interim analyses of raltegravir in highly experienced patients from the current trials, called BENCHMRK-1 and BENCHMRK-2, were presented at the conference.(3,4) Methods
The trials are ongoing randomized, double blind, placebo-controlled phase III studies. BENCHMRK-1 is being held in Europe, Asia and the Pacific region, and Peru. BENCHMRK-2 is taking place in North and South America. Study participants had resistance to at least 1 drug in each of the nucleoside analogue, nonnucleoside, and protease inhibitor classes of ARVs and had an HIV RNA viral load of >1,000 copies/mL on ARV therapy. The 699 subjects were randomized 2:1 to raltegravir + an optimized background regimen (OBT) or to an OBT alone. All groups in the two studies had similar baseline characteristics. The mean baseline CD4 count was approximately 155 cells/µL, and the mean baseline HIV RNA was 4.6 log10 copies/mL. Patients had been treated previously with a median of 12 ARV agents; 30-40% were predicted by genotype and phenotype to have 0-1 active agents in their background regimens (genotypic and phenotypic sensitivity scores [GSS, PSS]). Results
The results of the trials were presented together. At 16 weeks, by intention-to-treat analysis (with noncompletion of the trial counted as a treatment failure), rates of virologic suppression and CD4 increases were significantly greater in the raltegravir groups:
| ||Raltegravir + OBT||Placebo + OBT||Raltegravir + OBT||Placebo + OBT|
|HIV RNA <400 copies/mL (% of patients)||77||41||77||43|
|HIV RNA <50 copies/mL (% of patients)||61||33||62||36|
|Mean CD4 increase (cells/µL)||83||31||86||40|
For the smaller number of patients whose data were available at 24 weeks, results were similar to the 16-week data.
In combined analysis, raltegravir recipients had higher rates of virologic suppression to <400 copies/mL than placebo recipients in all reported subgroups, including those stratified according to baseline viral load, CD4 count, GSS and PSS, and first use or absence of enfuvirtide or darunavir in the OBT. Raltegravir appeared to be effective even in the majority of patients with genotypic or phenotypic sensitivity scores of 0: at 16 weeks, the HIV RNA was <400 copies/mL in 61% of raltegravir recipients vs 5% of placebo recipients with PSS = 0, and results were similar in patients with GSS = 0. In patients who received raltegravir in combination with first-time use of either enfuvirtide or darunavir, 90% had HIV RNA of <400 copies/mL, compared with 55-63% of patients who received placebo with one of these agents.
Adverse effects and laboratory abnormalities appeared similar in raltegravir and placebo groups. Compared with the placebo group, the raltegravir group in BENCHMK-2 (but not in BENCHMK-1) had a somewhat higher rate of gastrointestinal symptoms and headache, whereas the raltegravir group in BENCHMK-1 had higher lipid and transaminase elevations.
In most patients with virologic failure on raltegravir, 2 and possibly 3 pathways involving resistance mutations in integrase were identified; the significance of these findings requires further investigation. Conclusions
These preliminary results confirm that raltegravir is both potent and tolerable in patients with resistance to multiple ARV medications. Raltegravir was surprisingly effective even in many patients who were predicted to have no active agents in the background regimen, at least at the16-week point, but its durability and resiliency need to be elucidated further. As with all ARV medications, it is most effective when combined with other active drugs.
The new integrase inhibitor and CCR5 antagonist classes of medication give patients with extensive drug resistance significantly better options for effective treatment. And, the arrival of these new classes may soon shift treatment paradigms for both experienced and treatment-naive patients. Raltegravir currently is available in the United States through expanded access programs. References
- Grinsztejn B, Nguyen BY, Katlama C, et al. Potent efficacy of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus: 24-week data. In: Program and abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco. Abstract H-1670b.
- Markowitz M, Nguyen BY, Gotuzzo F, et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, as part of combination ART in treatment -naive HIV-1 infected patients. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0214.
- Cooper D, Gatell J, Rockstroh J, et al; BENCHMRK-1 Study Group. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles. Abstract 105aLB.
- Steigbigel R, Kumar P, Eron J, et al; BENCHMRK-2 Study Group. Results of BENCHMRK-2, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles. Abstract 105bLB.