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Author Topic: Isentress  (Read 7888 times)

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Offline veritas

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« on: February 06, 2009, 04:45:37 AM »

Latest from the FDA on Isentress:

On January 29, 2009, the Food and Drug Administration (FDA) granted traditional approval for Isentress (raltegravir) 400 mg tablets in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients.  The product label and patient package insert have been updated to include 48 week data from Studies 018 and 019.   

Major changes include the following:

Section 2: DOSAGE AND ADMINISTRATION, Section 5.2: Drug Interactions and Section 7.2, Effect of Other Agents on the Pharmacokinetics of Raltegravir was updated to include the recommendation to increase raltegravir dose to 800 mg twice daily during coadministration with rifampin. Additionally, caution is recommended when coadministering raltegravir with other strong UGT1A1 inducers due to reduced raltegravir plasma concentrations

Section 6 ADVERSE REACTIONS was updated to include the 48 week safety and laboratory data from Protocols 018 and 019

Patients with Co-existing Conditions
Patients Co-infected with Hepatitis B and/or Hepatitis C Virus
In the clinical studies, P018 and P019, subjects with chronic (but not acute) active hepatitis B and/or hepatitis C virus co-infection (N = 114/699 or 16%) were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal (ULN). The rates of AST and ALT abnormalities were higher in the subgroup of subjects with hepatitis B and/or hepatitis C virus co-infection for both treatment groups. In general the safety profile of ISENTRESS in subjects with hepatitis B and/or hepatitis C virus co-infection was similar to subjects without hepatitis B and/or hepatitis C virus co-infection. Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 25%, 31% and 12%, respectively, of co-infected subjects treated with ISENTRESS as compared to 8%, 7% and 8% of all other subjects treated with ISENTRESS.

Postmarketing Experience
The following adverse reactions have been identified during postapproval use of ISENTRESS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Skin and Subcutaneous Tissue Disorders: rash, Stevens-Johnson syndrome
Psychiatric Disorders: depression (particularly in patients with a pre-existing history of psychiatric illness), including suicidal ideation and behaviors

Section 7.1 Effect of Raltegravir on the Pharmacokinetic of Other Agents was revised to include information on hormonal contraceptives and etravirine as follows:

In drug interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: hormonal contraceptives,lamivudine, tenofovir, etravirine.

Section 7.2, Effect of Other Agents on the Pharmacokinetics of Raltegravir now includes a table of selected drug interactions with corresponding clinical comment for each interaction. In addition, information on etravirine, efavirenz, rifampin and omeprazole was added.

Section 12.3 Pharmacokinetics was updated to include results from food effect study as follows:

Effect of Food on Oral Absorption
ISENTRESS may be administered with or without food. Raltegravir was administered without regard to food in the pivotal safety and efficacy studies in HIV-infected patients. The effect of consumption of low-, moderate- and high-fat meals on steady-state raltegravir pharmacokinetics was assessed in healthy volunteers. Administration of multiple doses of raltegravir following a moderate-fat meal (600 Kcal, 21 g fat) did not affect raltegravir AUC to a clinically meaningful degree with an increase of 13% relative to fasting. Raltegravir C12 hr was 66% higher and Cmax was 5% higher following a moderate-fat meal compared to fasting. Administration of raltegravir following a high-fat meal (825 Kcal, 52 g fat) increased AUC and Cmax by approximately 2-fold and increased C12 hr by 4.1-fold. Administration of raltegravir following a low-fat meal (300 Kcal, 2.5 g fat) decreased AUC and Cmax by 46% and 52%, respectively; C12 hr was essentially unchanged. Food appears to increase pharmacokinetic variability relative to fasting.

The Special Populations subsection was revised to state:

UGT1A1 Polymorphism
There is no evidence that common UGT1A1 polymorphisms alter raltegravir pharmacokinetics to a clinically meaningful extent.  In a comparison of 30 subjects with *28/*28 genotype (associated with reduced activity of UGT1A1) to 27 subjects with wild-type genotype, the geometric mean ratio (90% CI) of AUC was 1.41 (0.96, 2.09).

Table 4 Drug Interactions was updated to include results from the etravirine, rifampin and omeprazole studies.

Section 12.4 Microbiology, Resistance was updated to include the Week 48 data from studies 018 and 019 as follows.

The mutations observed in the HIV-1 integrase coding sequence that contributed to raltegravir resistance (evolved either in cell culture or in subjects treated with raltegravir) generally included an amino acid substitution at either Q148 (changed to H, K, or R) or N155 (changed to H) plus one or more additional substitutions (i.e., L74M, E92Q, T97A, E138A/K, G140A/S, V151I, G163R, H183P, Y226C/D/F/H, S230R and D232N). Amino acid substitution at Y143C/H/R is another pathway to raltegravir resistance. By Week 48 in the BENCHMRK trials, at least one of the 3 primary raltegravir resistance-associated substitutions, Y143C/H/R, Q148H/K/R, and N155H, was observed in 63 (64.3%) of the 98 virologic failure subjects with evaluable genotypic data from paired baseline and raltegravir treatment-failure isolates. Some (n=18) of those HIV isolates harboring one or more of the 3 primary raltegravir resistance-associated substitutions were evaluated for raltegravir susceptibility yielding a median decrease of 47.3-fold (mean 73.1 60.8-fold decrease, ranging from 0.9- to 200-fold) compared to baseline isolates.
Section 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility was updated to include the two year carcinogenicity study results.

Carcinogenicity studies of raltegravir in mice did not show any carcinogenic potential. At the highest dose levels, 400 mg/kg/day in females and 250 mg/kg/day in males, systemic exposure was 1.8-fold (females) or 1.2-fold (males) greater than the AUC (54 M●hr) at the 400-mg twice daily human dose. Treatment related squamous cell carcinoma of nose/nasopharynx was observed in female rats dosed with 600 mg/kg/day raltegravir for 104 weeks. These tumors were possibly the result of local irritation and inflammation due to local deposition and/or aspiration of drug in the mucosa of the nose/nasopharynx during dosing. No tumors of the nose/nasopharynx were observed in rats dosed with 150 mg/kg/day (males) and 50 mg/kg/day (females) and the systemic exposure in rats was 1.7-fold (males) to 1.4-fold (females) greater than the AUC (54 μM●hr) at the 400-mg twice daily human dose.
Section 14 CLINICAL STUDIES was updated with the 48 week study results from Protocols 018 and 019.

The complete revised label can be found on the FDA web site at http://www.fda.gov/cder/foi/label/2009/022145s001lbl.pdf

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antivir

Offline veritas

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Offline Inchlingblue

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Re: Isentress
« Reply #3 on: February 10, 2009, 06:04:31 PM »
The following quote is from Merck's presentation on Isentress at CROI (link in post above):

"Also, the study showed that ISENTRESS did not demonstrate non-inferior virologic efficacy at maintaining viral load suppression. As a result of the viral load findings in these trials, Merck discontinued these two studies."

They don't explain any further. Does this mean that Isentress was inferior at viral load suppression?

Offline freewillie99

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Re: Isentress
« Reply #4 on: February 10, 2009, 06:25:48 PM »
er. Does this mean that Isentress was inferior at viral load suppression?

No, it doesn't mean that.
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Offline Inchlingblue

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Re: Isentress
« Reply #5 on: February 10, 2009, 06:41:22 PM »
No, it doesn't mean that.

I was reading further and it does mean that. I'm not sure what the implications of that are, however. It doesn't necessarily mean that Issentress is not potent, etc, but it does mean that in this particular study, more patients on the Issentress arm experienced virologic failure. It's the reason that Merck "discontinued" the study and is now further evaluating the results.

Offline Miss Philicia

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Re: Isentress
« Reply #6 on: February 10, 2009, 08:23:11 PM »
Merck reports new positive data from Phase III study of HIV drug

Tuesday, February 10, 2009; Posted: 08:21 AM

Feb 10, 2009 (Datamonitor via COMTEX) -- MRK | Quote | Chart | News | PowerRating -- Merck and Co has reported positive data from new subgroup analyses of a Phase III study that compared the company's integrase inhibitor Isentress to efavirenz, an antiretroviral prescribed for previously untreated HIV-infected patients.
According to the company, Isentress was found to be as effective as efavirenz at suppressing viral load and provided improvements in immune system function across a broad spectrum of patient subpopulations through 48 weeks. The use of Isentress in previously untreated HIV-infected patients is an investigational use of the drug. Both medicines were taken in combination with tenofovir/emtricitabine.

In other Phase III studies, BENCHMRK-1 and -2, Isentress in combination with optimized background therapy (OBT) demonstrated greater reductions in viral load compared to placebo plus OBT through 96 weeks of therapy in treatment-experienced patients with triple-class resistant HIV who were failing antiretroviral therapy.

According to the company, Isentress is the first integrase inhibitor approved for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients with evidence of viral replication with HIV-1 strains resistant to multiple antiretroviral agents. This indication is based on analyses of plasma HIV-1 RNA levels up through 48 weeks in two controlled studies of Isentress.

These studies were conducted in clinically advanced, three-class antiretroviral [nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)] treatment-experienced adults. In these studies the use of other active agents with Isentress is associated with a greater likelihood of treatment response. The safety and efficacy of Isentress have not been established in treatment-naive adult or pediatric patients, the company said.

Daniel Berger, clinical associate professor, College of Medicine, University of Illinois at Chicago and medical director of NorthStar Medical Center, said: "As physicians continue to use Isentress in treatment-experienced patients, newly presented longer-term data from BENCHMRK-1 and -2 continue to inspire confidence among clinicians when treating patients that are more advanced in their treatment course.

"Furthermore, the STARTMRK studies in treatment-naive patients showed that Isentress may become an important new option for a broader spectrum of patients beginning treatment for HIV infection, if the drug is approved for this use."

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Offline freewillie99

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Re: Isentress
« Reply #7 on: February 10, 2009, 10:30:13 PM »
I was reading further and it does mean that.

Evidently you have reading comprehension issues.
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Offline Ann

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Re: Isentress
« Reply #8 on: February 11, 2009, 08:43:50 AM »
Evidently you have reading comprehension issues.


Instead of handing out one-liners and insults, why don't you take the time to explain WHY it doesn't mean that? This forum is meant for people to help one another, not throw insults about. If you can't say something helpful, say nothing.

And yes, this is a warning.

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Offline Assurbanipal

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Re: Isentress
« Reply #9 on: February 11, 2009, 11:50:24 AM »
The following quote is from Merck's presentation on Isentress at CROI (link in post above):

"Also, the study showed that ISENTRESS did not demonstrate non-inferior virologic efficacy at maintaining viral load suppression. As a result of the viral load findings in these trials, Merck discontinued these two studies."

They don't explain any further. Does this mean that Isentress was inferior at viral load suppression?

Hi Inchling

I don't think one can get quite to that conclusion.  What the results showed is that for those people who were doing ok on Kaletra to start with, switching to Isenstress was inferior for viral load suppression for a small but significant group. 

If you were going to test for which was inferior overall you wouldn't want to bias the test by starting out with a group that was doing all right on one of the drugs you were testing.  But if the people in the trial had done just as well on Isentress as Kaletra you would know that Isentress was not inferior -- since you had already biased the test in Kaletra's favor as it were.

By the way, John posted some of the graphs in his research news thread that he picked up from NATAP.  They show the better blood lipids pretty dramatically.  They also graph the difference in viral load suppression. http://natap.org/2009/CROI/croi_05.htm


**** edits -- spells 9, types 2
« Last Edit: February 11, 2009, 11:52:21 AM by Assurbanipal »
5/06 VL 1M+, CD4 22, 5% , pneumonia, thrush -- O2 support 2 months, 6/06 +Kaletra/Truvada
9/06 VL 3959 CD4 297 13.5% 12/06 VL <400 CD4 350 15.2% +Pravachol
2007 VL<400, 70, 50 CD4 408-729 16.0% -19.7%
2008 VL UD CD4 468 - 538 16.7% - 24.6% Osteoporosis 11/08 doubled Pravachol, +Calcium/D
02/09 VL 100 CD4 616 23.7% 03/09 VL 130 5/09 VL 100 CD4 540 28.4% +Actonel (osteoporosis) 7/09 VL 130
8/09  new regimen Isentress/Epzicom 9/09 VL UD CD4 621 32.7% 11/09 VL UD CD4 607 26.4% swap Isentress for Prezista/Norvir 12/09 (liver and muscle issues) VL 50
2010 VL UD CD4 573-680 26.1% - 30.9% 12/10 VL 20
2011 VL UD-20 CD4 568-673 24.7%-30.6%
2012 VL UD swap Prezista/Norvir for Reyataz drop statin CD4 768-828 26.7%-30.7%
2014 VL UD - 48
2015 VL 130 Moved to Triumeq

Offline veritas

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Re: Isentress
« Reply #10 on: February 13, 2009, 05:05:14 AM »

Resuts of switchmark study and what it means according to John Hopkins:

"The results of the SWITCHMRK studies do not indicate that Isentress isn't a good drug, OR that you can't switch from a boosted PI to Isentress. Instead, they teach us several important lessons:

1. Isentress needs to be combined with other active drugs (something we already knew from the BENCHMRK studies).

2. Don't switch from a boosted PI to a drug with a lower barrier to resistance unless you're sure about the activity of the other drugs in the regimen.

3. Just because a clinical trial allows you to enroll in a study doesn't mean you should. It is important that physicians and investigators use appropriate clinical judgment before enrolling a patient in any clinical trial. "


Offline Inchlingblue

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Re: Isentress
« Reply #11 on: February 16, 2009, 06:45:23 PM »
This is Dr. Joel Gallant's take on this study:

"SWITCHMRK: Switching from Kaletra plus nukes to Isentress plus nukes was a bad idea in a bad study. This study allowed participants to make this switch no matter how much prior ART experience and failure they'd had. As a result, some probably ended up on Isentress monotherapy because of nuke resistance, so it's not suprising there was more failure. It's OK to make switches to Isentress, but only if you're confident that the other drugs in the regimen are fully active."

NOTE: Thanks, Veritas, this was taken from his Q&A that you turned me on to. It says pretty much what your post, above, says (which I think is also from that site).  I was just able to understand it better, because I didn't realize that some of the participants probably already had nuke resistance, which would explain what amounted to Isentress monotherapy not working.
« Last Edit: February 16, 2009, 06:53:06 PM by Inchlingblue »

Offline veritas

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Re: Isentress
« Reply #12 on: February 23, 2009, 07:55:24 AM »

No Residual Raltegravir Activity After Resistance Emerges
  16th Conference on Retroviruses and Opportunistic Infections, February 8-11, 2009, Montreal
Mark Mascolini
A study of 4 people who stopped only raltegravir in a salvage regimen after emergence of integrase mutations found no evidence that the drug exerts residual activity after mutations evolve.
"Even if further observations will be useful to be certain" of this finding, Marc Wirden and Paris colleagues concluded, "it seems unnecessary to keep this drug in such a context. Moreover, the withdrawal of raltegravir avoids the risk of accumulating mutations for future compounds within this class."
The four patients were taking a raltegravir-containing regimen with a stable, detectable viral load for at least 2 months. Wirden and coworkers measured viral load and CD4 count at day 0 (the day patients stopped only raltegravir), then for up to 90 days as the patients continued the same regimen. A substantial viral load gain during this time would indicate that raltegravir had been exerting some antiviral activity after resistance mutations emerged. In the last month of raltegravir therapy, the hallmark integrase mutation N155H emerged in patients A, C, and D, while the classic Q148H mutation arose in patient B. Virus from all 4 patients also had evidence of other mutations with these signature mutations. Trough raltegravir concentrations were in the therapeutic range (from 118 to 268 ng/mL) when these people stopped raltegravir, then quickly became undetectable.
Follow-up continued for 28 days in patients A and C, for 90 days in patient B, and for 42 days in patient D. Variations in viral load during follow-up were minimal:
Patient A: -0.04 log, +51 CD4s
Patient B: -0.17 log, +25 CD4s
Patient C: +0.19 log, -56 CD4s
Patient D: -0.20 log, +252 CD4s
Wirden and colleagues noted that all viral load variations were well below a meaningful cutoff of 0.5 log.
Regardless of what other antiretrovirals people were taking with raltegravir, integrase mutations did not disappear during follow-up. Because of this finding, the investigators suggested, "the discussion remains open about impact [of these mutations] on replication capacity."
1. Wirden M, Simon A, Schneider L, et al. Raltegravir interruption has no effect on HIV-1 RNA plasmatic level in patients harboring viruses with resistance-associated mutations to this drug. 16th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2009. Montreal. Abstract 622. (This poster is online at http://www.retroconference.org/2009/PDFs/622.pdf.)
Background: Raltegravir (RAL) is today the first drug available in the new antiretroviral class of integrase inhibitors. This compound is powerful and its use is increasing in HIV treatment especially in a context of drug resistances to the earliest classes. However, the emergence of resistance mutations has been already associated to RAL-regimen failure, with high resistance levels in vitro. It is important to know whether a residual antiretroviral activity of RAL is still present in such a context in vivo, and so whether it could be useful to keep the drug in the subsequent salvage therapy.



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