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BANGKOK: Reyataz/rtv Approved for Treatment-Experienced; Once Daily PI Regimen- Invirase/rtv (1600/100mg), pilot study results
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REYATAZ (atazanavir) GRANTED APPROVAL FOR USE WITH LOW-DOSE RITONAVIR IN TREATMENT-EXPERIENCED HIV-INFECTED PATIENTS
On July 6, 2004, the Division of Antiviral Drug Products approved a new dosing regimen for REYATAZ. In antiretroviral-experienced patients the recommended dose is
REYATAZ 300 mg (two 150 mg capsules) once daily plus ritonavir 100 mg once daily taken with food.
For antiretroviral-naïve patients the recommended dose remains as REYATAZ 400 mg (two 200 mg capsules) once daily taken with food.
The data to support the new dosing regimen came from study AI424-045, a study of patients who had failed at least two regimens containing medications from the three ARV drug classes available at the time of enrollment. This 48-week trial to evaluated the efficacy and safety of REYATAZ 300 mg + ritonavir 100 mg once daily or REYATAZ 400 mg + saquinavir 1200 mg once daily compared to lopinavir/ritonavir 400/100 mg twice daily each with tenofovir and a nucleoside reverse transcriptase inhibitor in treatment-experienced patients.
REYATAZ/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. The HIV RNA change from baseline was -1.58 log10 copies/mL for REYATAZ/ritonavir and -1.70 log10 copies/mL for lopinavir/ritonavir.
Study AI424-045 was not large enough to reach a definitive conclusion that REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measures of proportions below the HIV RNA lower limit of detection. The proportion of patients with HIV RNA < 400 copies/mL and < 50 copies/mL at week 48 was 55% and 38% for REYATAZ/ritonavir and 57% and 45% for lopinavir/ritonavir, respectively.
The major revisions to the package insert are summarized below.
INDICATIONS AND USAGE:
Information that should be considered when initiating therapy with REYATAZ was added as follows. This data pertains to REYATAZ/ritonavir.
The following points should be considered when initiating therapy with REYATAZ:
o In antiretroviral-experienced patients with prior virologic failure, coadministration of REYATAZ with ritonavir is recommended.
o In Study AI424-045 REYATAZ/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. This study was not large enough to reach a definitive conclusion that REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV RNA lower limit of detection. (See Description of Clinical Studies)
o The number of baseline primary protease inhibitor mutations affects the virologic response of REYATAZ/ritonavir (See CLINICAL PHARMACOLOGY: Microbiology)
o There are no data regarding the use of REYATAZ and ritonavir in therapy-naive patients.
CLINICAL PHARMACOLOGY
Microbiology
∑ A table was included to provide information regarding HIV RNA response at week 48 by number and type of baseline protease inhibitor mutations and baseline phenotype in treatment-experienced subjects (study AI424-045). In summary, the HIV RNA response rates (< 400 copies/mL) were 75% for both REYATAZ/ritonavir and lopinavir/ritonavir in patients with 0-2 baseline primary protease inhibitor mutations. In patients with 3-4 baseline primary protease inhibitor mutations the response rates were 41% and 43% for REYATAZ/ritonavir and lopinavir/ritonavir, respectively. In patients with 5 or more baseline primary protease inhibitor mutations the response rates were 0% and 23% for REYATAZ/ritonavir and lopinavir/ritonavir, respectively.
Table 1. HIV RNA Response by Number and Type of Baseline PI Mutation, Antiretroviral-Experienced Patients in Study AI424-045, As-Treated Analysis
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Virologic Response= HIV RNA<400 copies/ml-b
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ATV/rtv
n=110
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LPV/rtv
n=113
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# & type of baseline PI mutations-a
3 or more primary PI mutations including-c:
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D30N
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75% (6/8)
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50% (3/6)
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M36I
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20% (3/15)
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33% (6/18)
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M46I/L/V
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24% (4/17)
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23% (5/22)
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L54V/L/T/M/A
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31% (5/16)
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31% (5/16)
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A71V/T/I
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34% (10/29)
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39% (12/31)
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V77I
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47% (7/15)
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44% (7/16)
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V82A/F/T/S/I
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29% (6/21)
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27% (7/26)
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I84V
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13% (1/8)
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33% (2/6)
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N88D
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63% (5/8)
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67% (4/6)
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L90M
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10% (2/21)
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44% (11/25)
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NUMBER OF BASELINE MUTATIONS-a
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ATV/r
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LPV/r
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All patients as-treated
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58% (64/110)
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59% (67/113)
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0-2 PI mutations
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75% (50/67)
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75% (50/67)
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3-4 PI mutations
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41% (14/34)
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43% (12/28)
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5 or more PI mutations
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0% (0/9)
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28% (5/18)
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a- Primary mutations include any change at D30N, V32, M36, I47, G48, I50, I54, A71, G73, V77, V82, I84, N88, and L90.
b- Results should be interpreted with caution because subgroups were small.
c- There were insufficient data (N<3) for PI mutations V32I, I47V, G48V, I50V, and F53L.
Table 2. Baseline Phenotype By Outcome, Antiretroviral Experienced Patients in Study AI424 045, as-treated Analysis
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Virologic Response=HIV RNA<400 c/ml-b
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Baseline Phenotype-a
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/rtv N=111
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LPV/rtv n=111
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0-2
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71% (55/78)
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70% (56/80)
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>2-5
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53% (8/15)
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44% (4/9)
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>5-10
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13% (1/8)
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33% (3/9)
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>10
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10% (1/10)
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23% (3/13)
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a- Fold change in in vitro susceptibility relative to wild-type reference.
b- Results should be interpreted with caution because the subgroups were small.
WARNINGS
PR Interval Prolongation
o The following statement was added -- There have been rare reports of second-degree AV block and other conduction abnormalities and no reports of third-degree AV block
o Information regarding reports of first-degree AV block from Study 045 was added.
PRECAUTIONS
o A subsection regarding rash was included to state that the incidence of rash in controlled clinical trials (n=1597) was 21% . The median time to onset of rash was 8 weeks after initiation of REYATAZ and the median duration of rash was 1.3 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Dosing with REYATAZ was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical studies was 0.4%. REYATAZ should be discontinued if severe rash develops. Cases of Stevens-Johnson syndrome and erythema multiforme have been reported in patients receiving REYATAZ.
Drug Interactions
o A change to the clinical comment for the interaction between efavirenz and REAYATAZ was made to distinguish the dose adjustment of REYATAZ/ritonavir/efavirenz 300/100/600 mg once daily applies to treatment-naïve subjects. Appropriate dosing recommendations for efavirenz and REYATAZ in treatment-experienced subjects have not been established.
Boosted Invirase (1600/100rtv) Once Daily Pilot Study
Here is press release from Roche but I will report the study data to you.
Clinical trial demonstrates high potency combined with good tolerability
Bangkok, Thailand, 13 July 2004: Data from a new study with the HIV protease inhibitor Invirase (saquinavir) has demonstrated the best HIV RNA response yet seen in a large group of HIV-infected patients given highly active antiretroviral therapy. 1-8
The data announced today at the XV International AIDS Conference in Bangkok show that a convenient once daily regimen of boosted Invirase plus 2 NRTIs delivers excellent antiviral potency:
96% of patients achieving HIV RNA levels of <400 copies/ml
91% achieving undetectable levels of virus (<50 copies/ml) after 24 weeks.
CD4 count increase of 109 cells/mm3 at 24 weeks
CD4 count of 380 cells/mm3.
Commenting on the results, Michael S. Saag, Professor of Medicine and Director, UAB AIDS Outpatient Clinic, Birmingham, Alabama, USA said "The antiviral efficacy of Invirase shown in this study is the best we have seen across similar HAART studies. The good news for patients is that the outstanding level of HIV suppression achieved is also combined with good tolerability."
The data are reported from the induction phase of the STACCATO study in which once daily Invirase/r 1600/100 mg + 2 NRTIs was administered to 167 treatment-naive HIV-infected patients for 24 weeks.
The STACCATO study is being conducted in participation with the HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT). Dr. Jintanat Ananworanich, coordinator for STACCATO at HIV-NAT said, "These data demonstrate that Invirase, when combined with ritonavir, is a highly active regimen. The level of response we have seen could make a real difference both in terms of clinical outcome and adherence to therapy."
More about the study
The STACCATO study (Swiss-Thai-Australia Treatment Interruption Trial) is an international open label randomized study designed to evaluate the efficacy, safety and tolerability of continuous daily boosted Invirase + two NRTIs versus CD4 cell count guided treatment interruption. Prior to randomisation to the comparative phase of the study patients participate in a 24 week induction study.
The induction study population reported here was made of the first 74 men and 93 women to be enrolled into STACCATO. At the start of the induction study the median HIV RNA was 4.7 log10 copies/ml and median CD4 count 256 cells/mm3. The 2NRTIs used was d4T/ddI which was later changed to Tenofovir/3TC.
Using an intent-to-treat analysis, at 24 weeks the median reduction in HIV RNA was -2.9 log10 copies/ml, with a median CD4 count increase of 109 cells/mm3. Of the 167 patients entered into the study two were lost to follow up. Drug-related adverse events were mostly mild and self limiting; no severe or life-threatening events were recorded.
References:
1. Ananworanich J, Ruxrungtham K, Siangphoe U et al. XV IAC, 2004, poster TuPeB4469
2. Gulick RM, Ribaudo HJ, Shikuma CM et al. New Eng J Med 2004; 350: 1850-1861
3. Podzamczer D, Gathe J, Schwartz R et al. 9th EACS 2003; oral F1/3
4. Raffi F, Saag M, Cahn P et al. 2nd IAS 2002; abstract 38
5. Schurmann D, Gathe J, Sanne I et al. HIV 6, 2002; poster PL14.4
6. Staszewski S, Gallant JE, Pozniak A et al. 10th CROI 2003; poster 564b
7. Van Leth F, Phanuphak P, Ruxrungtham K, et al. Lancet 2004; 363:1253-1263
8. Walmsley S , Bernstein B, King, M et al. N Engl J Med, 2002, 346:2039-2046
HIV-NAT
The primary goal of HIV-NAT is to conduct HIV clinical research in Thailand according to the ICH Harmonised Tripartite Guideline and the Declaration of Helsinki for Good Clinical Practice. Studies at HIV-NAT are of several kinds: investigator-initiated to answer locally relevant research questions; participation in pharmaceutical industry sponsored multi-centre trials; collaboration with bodies such as the US National Institutes of Health and operation research conducted as part of the Columbia University MTCT+ initiative and the Thai Red Cross "treat parents and save orphans' project.
HIV-NAT is grateful to patients for their participation in STACCATO and to the following Swiss organizations: Swiss National Science Foundation through the Swiss HIV Cohort Study, State of Geneva, Sidaide Foundation, Wilsdorf Foundation, for financial support. We thank Roche for financial support and supply of Invirase and to Abbott and Gilead for providing ritonavir and tenofovir respectively for use in the study.
Received: from
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