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Author Topic: (MK-0518) doubles HIV suppression in treatment-experienced patients at 16 weeks  (Read 2235 times)

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Offline Ihavehope

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  • Yes, I'm a cry baby, AND WHAT?
Raltegravir (formerly MK-0518), Merck’s experimental integrase inhibitor, reduced HIV viral load to undetectable levels (below 50 copies/ml) in nearly two-thirds of highly treatment-experienced patients, according to two presentations at the Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles on Tuesday.

Integrase inhibitors are a new class of antiretroviral agents that target the integration step of HIV replication, in which viral genetic material is inserted into the DNA of human cells. By blocking this step in the viral life-cycle, researchers hope that integrase inhibitors will prevent the virus from reproducing and infecting more cells.

The data presented this week come from planned interim analyses from the ongoing BENCHMRK-1 and -2 studies, two identical Phase III randomised, placebo-controlled, double-blind trials involving heavily treated patients. BENCHMRK-1 included 350 participants in Europe, Asia and Peru, whilst BENCHMRK-2 included 349 patients in North and South America.

Participants in the BENCHMRK studies were resistant to all three major classes of antiretroviral drugs and had viral loads above 1,000 copies/ml. They were randomised on a two-to-one basis to receive either 400 mg raltegravir twice daily or placebo, in addition to optimised background therapy. The primary outcomes were the proportions of patients achieving viral loads below 400 and below 50 copies/ml. Data were also gathered on changes in CD4 cell count and drug safety.

Baseline characteristics were similar in the raltegravir and placebo arms of the two studies. The mean age was about 45 years, most (84-91%) were men and a majority (55-81%) were white, though BENCHMRK-2 included more people of other races/ethnicities. The mean baseline CD4 cell count was between 146 and 163 cells/mm3 and the mean baseline viral load ranged from about 30,000 to 50,000 copies/ml. About 90% had an AIDS diagnosis and the median duration of antiretroviral therapy use was about ten years.

Results from 16 weeks of follow-up were presented for all participants in the two studies, although the investigators noted that 24-week results are available for approximately 60% of patients. Both studies are scheduled to continue through 48 weeks.

After 16-24 weeks, approximately twice as many patients in the raltegravir arms achieved undetectable viral load. In the two studies combined, 77% of participants taking raltegravir had HIV RNA levels below 400 copies/ml, compared with 41-43% in the placebo arms (p < 0.001). Looking at viral loads below 50 copies/ml, the corresponding figures were 61-62% and 33-36% (p < 0.001).

Gains in CD4 cell count were also more impressive amongst the patients who received raltegravir, with a mean increase of 83 cells/mm3 in BENCHMRK-1 and 86 cells/mm3 in BENCHMRK-2. These gains were 2-3 times as large as those seen in patients who received placebo plus optimized background therapy (p < 0.001).

Researchers also presented data from analyses of patient subgroups, again combining data from both studies. Amongst those whose background regimens included both enfuvirtide (Fuzeon) or the newest protease inhibitor, darunavir (Prezista) – to which HIV is less likely to be resistant -- 98% in the raltegravir arm achieved viral suppression below 400 copies/ml, compared with 87% in the placebo group. This compared with rates of 74% and 29%, respectively, for patients not taking either of these newer drugs. For patients who had no other active drugs in their regimens, 61% in the raltegravir arm, but only 5% in the placebo arm, achieved HIV RNA levels below 400 copies/ml. In addition, participants who started with lower baseline viral loads or higher baseline CD4 cell counts had a better response to raltegravir

Raltegravir was well tolerated overall, and only a small number of participants discontinued the studies early. Side-effects – mostly mild-to-moderate – were seen with similar frequency in the raltegravir and placebo arms. The rate of serious drug-related adverse events was less than 3% across all arms.

Three times as many patients experienced virological failure on raltegravir compared with placebo (16% vs 51%). Though data are still limited, it appears that there are two distinct pathways that confer raltegravir resistance: N155H and Q148K/R/H. However, there was no indication of cross-resistance with other antiretroviral drug classes.

The researchers concluded that raltegravir demonstrated “potent and superior antiretroviral activity” compared to placebo plus optimized background therapy at 16 weeks, with “few adverse experiences leading to discontinuation.”

Raltegravir may also be an option for treatment-naive patients, having shown good antiviral activity in a study presented previously at the International AIDS Conference in Toronto last summer.

In a press conference announcing these data – and those from two studies of another new antiretroviral agent, the CCR5 inhibitor maraviroc - Dr John Mellors of the University of Pittsburgh said the results are as exciting as any since the development of HAART in the mid-1990s.
Infected: April 2005
12/6/06 - Diagnosed HIV positive
12/19/06 - CD4 = 240  22% VL = 26,300
1/4/07 - CD4 = 200 16% VL = ?
2/9/07 = Started Kaletra/Truvada
3/13/07 = CD4 = 386 22% VL ?

Offline Ihavehope

  • Member
  • Posts: 1,366
  • Yes, I'm a cry baby, AND WHAT?
Long-awaited data from two Phase III clinical trials of MK-0518 – recently given the generic name raltegravir and the brand name Isentress – were reported on Tuesday in a late-breaker session at the 14th Conference on Retroviruses and Opportunistic Infections. The studies, enrolling patients with multi-drug-resistant HIV and advanced infection, indicate that Merck’s experimental integrase inhibitor offers “potent and superior” antiretroviral activity to those in desperate need of new treatment options.

In order for HIV to successfully take over a CD4 cell's machinery so that it can produce new viruses, HIV's RNA is converted into DNA by the reverse transcriptase enzyme (nucleoside reverse transcriptase inhibitors can block this process). After the "reverse transcription" of RNA into DNA is complete, HIV's DNA must then be incorporated into the CD4 cell's DNA. This is known as integration. As their name implies, integrase inhibitors work by blocking this process.

Integrase inhibitors may offer a lot of hope for HIV-positive people, especially those who have developed HIV resistance to drugs that target HIV's two other major enzymes: reverse transcriptase and protease.

Even though the development of integrase inhibitors has been ongoing for several years, very few have made it into advanced clinical trials. One agent currently in the final stretch of development is Merck’s Isentress.

At the XVI International AIDS Conference in Toronto, encouraging Phase II data from a clinical trial of Isentress in HIV-positive patients starting therapy for the first time were presented. And at the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy this past September in San Francisco, the world got its first glimpse at promising results from a Phase II study involving treatment-experienced patients.

The data reported at CROI come from two Phase III studies: BENCHMRK-1 and BENCHMRK-2. The studies are randomized evaluations of Isentress (400mg twice daily) compared to placebo, both combined with an optimized background regimen (OBR), in patients with multiple-drug-resistant HIV and a history of treatment failure (including the regimens they were taking prior to enrollment).

The primary goal of the studies was to evaluate viral load and CD4 cell count results after 16 weeks. Patients not responding to their randomly selected treatment after 16 weeks are being given the option of taking open-label Isentress. 

BENCHMRK-1, conducted in Europe, Asia, the Pacific, and Peru, randomized 232 patients to Isentress plus OBR and 118 patients to placebo plus OBR. BENCHMRK-2, conducted in North and South America, assigned 230 patients to receive Isentress/OBR and 119 patients to receive placebo/OBR.

BENCHMRK-1 Results

At study entry, viral loads and CD4 counts averaged 40,519 copies and 156 cells in the Isentress group and 31,828 log and 153 cells in the placebo group. 

After 16 weeks of treatment, 77% of patients in the MK-0518 group had viral loads below 400, compared to 41% of patients in the placebo group. Viral load reductions below 50 – “undetectable” by today’s testing standards – were documented in 61% of Isentress-treated patients and 33% of the placebo recipients. 
A glimpse at 24-week data, involving a proportion of evaluable patients, indicated that 61% in the Isentress group had viral loads below 50, compared to 33% of those in the placebo group.   

CD4 counts at 16 weeks increased by 83 cells in the Isentress group and 31 in the placebo group.

BENCHMRK-2 Results

Upon entering the study, viral loads were approximately 48,000 log in both groups. CD4 counts were 146 in the Isentress group and 163 in the placebo group. 

Sixteen-week study results were similar to those seen in BENCHMRK-1. After nearly four months of treatment, viral loads were below 400 in 77% of the Isentress recipients and 43% of those receiving placebo. Approximately 62% of those in the Isentress group had viral loads below 50, compared to 36% in the placebo group.

Among those followed for 24 weeks, 62% in the Isentress group had viral loads below 50 copies, compared to 36% in the placebo group. 

CD4 counts at 16 weeks increased by 86 cells in the Isentress group, compared to an increase of 40 cells in the placebo group. 

Combined Study Results

Looking at both studies combined, 79% of patients in both Isentress groups had viral loads below 400 at 16 weeks, compared to 43% of patients in the placebo groups.

Treatment results were best among those who started therapy with Fuzeon® (enfuvirtide) and/or Prezista® (darunavir) for the first time as components of their OBRs. Among those who used both drugs in combination with Isentress, a whopping 98% had viral loads below 400 at 16 weeks, compared to 87% of those who combined both drugs with placebo. Among those who used Fuzeon without Prezista, 90% in the Isentress groups and 63% in the placebo groups saw their viral loads decrease below 400 at week 16 (similar results were seen among those who used Prezista without Fuzeon). As for those who didn’t use either medication, 74% in the Isentress groups still had viral loads below 400 at week 16, compared to 29% of patients in the placebo groups.

Also of interest were data involving phenotypic and genotypic sensitivity scores (PSS and GSS), determined using phenotypic and genotypic drug-resistance assays. Using PSS as an example, approximately 61% of patients in the Isentress groups who didn’t appear to be sensitive to any of the available antiretroviral drugs were still able to push their viral loads below 400 by week 16, compared to 5% of patients with similar phenotypic sensitivity scoring in the placebo groups. 

The study presenters also noted that responses to treatment were best among those with lower viral loads and higher CD4 counts at the time of study entry. Among those who entered the studies with viral loads above 100,000, 64% in the Isentress groups had viral loads below 400 at 16 weeks, compared to 88% in the Isentress groups who entered the study with viral loads below 100,000. Similar results were seen in those who began the study with fewer than 50 CD4 cells, compared to those with great than 50 or 200 CD4 cells.

Finally, side effects were similar between the Isentress groups and the placebo groups. Approximately 83% of the patients, regardless of which treatment they received, experienced at least one mild side effect. Serious side effects were also similar between the groups, documented in approximately 12% of patients. The most common side effects were diarrhea, injection site reactions (among those receiving Fuzeon), and headaches. 

In conclusion, the study authors stated that Isentress, combined with OBR, was associated with potent and superior antiretroviral activity compared to placebo plus OBR at 16 weeks. Partial data at week 24 showed similar responses. And when Isentress was combined with Fuzeon and/or Prezista, more than 90% of patients achieved viral loads below 400.

Sources:

Cooper DA, Gatell J, Rochstroh J, et al. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of raltegravir (MK-0518), a novel HIV- integrase inhibitor, in patients with triple-class resistant virus [Abstract 105a LB], 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, 2007.

Steigbigel R, Kumar P, Eron J, et al. Results of BENCHMRK-2, a phase III study evaluating the efficacy and safety of raltegravir (MK-0518), a novel HIV- integrase inhibitor, in patients with triple-class resistant virus [Abstract 105b LB], 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, 2007.


Infected: April 2005
12/6/06 - Diagnosed HIV positive
12/19/06 - CD4 = 240  22% VL = 26,300
1/4/07 - CD4 = 200 16% VL = ?
2/9/07 = Started Kaletra/Truvada
3/13/07 = CD4 = 386 22% VL ?

 


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