|
|
By Jules Levin, Executive Director of NATAP
RITONAVIR + SAQUINAVIR
Abstract (Birmingham, England)
At the 3rd International Congress on Drug Therapy in HIV Infection, in early November '96, Dr. William Cameron of the University of Ottawa in Canada presented data from extended follow-up of participants in both Groups I and II, for the aforementioned study of individuals receiving the combination of the two protease inhibitors.
The data for Group I (treatment arm A--400 mg bid RTV+400 mg bid SQV, and treatment arm B--600 mg bid RTV+400 mg bid SQV) extends to 20 weeks. The data for Group II (treatment arm C--400 mg tid RTV+400 mg tid SQV, and treatment arm D--600 mg bid RTV+600 mg bid SQV) extends to 12 weeks for this data set.
For the participants in treatment arm A, the median CD4 increase from baseline and median viral load decrease at 20 weeks are 75 CD4 and 3.21 log. For the participants in arm B, the median CD4 increase was 120 cells from baseline; the median decrease from baseline in viral load was 3.17 log. About 80% of the 51 evaluable participants from arms A and B were below the limit of detection, for viral load, of 200 copies/ml.
The participants in treatment arm C, at 12 weeks, experienced a median reduction in viral load from baseline of 2.68 log, and a median increase from baseline in CD4 of about 100. The participants in arm D experienced a median CD4 increase of 120, and a median reduction in viral load of 2.73. At 12 weeks, for arms C and D, the proportion of evaluable study participants below the limit of detection, for viral load, was 75% and 70%, respectively.
Commentary: The differences in viral load and CD4 between groups or arms are not statistically significant. It is uncertain which of the dose regimens may be superior simply by comparing CD4 and viral load differences.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| *Includes one patient that dose escalated to 600mg bid RTV |
|
||||||||||||||||||||||||||||||||||||||||||
| *Patient dose excalated to 600mg bid RTV |
Commentary: In table 6, the side effects and lab abnormalties profiles are more favorable for the 400/400 bid group. Note the discontinuations in the 400/400 tid group. The 600/600 group have the highest incidence of ADEs and lab abormalities. In table 7, participants with normal baseline LFTs (SGPT) and who are Hepatitis B and þHepatitis C antibody negative, have a lower incidence of elevations of LFTs. Those with Hepatitis B or C antibody at baseline indicate higher incidence of elevated LFTs. But, it appears to be the 600/600 bid regimen that causes the highest incidence of LFT elevation. 20 weeks data is normally too short upon which to base treatment decision making. However, when selecting a dose regimen, you may want to consider both--the combination's efficacy (CD4 and viral load) as well as the safety and tolerability profile.
Cameron showed a graph indicating that the drug concentration in the plasma (blood levels) of 600 mg bid dose of ritonavir are higher than the plasma concentrations of 400 mg bid ritonavir. Additionally, the chart indicated using 600 mg bid ritonavir raises the both the plasma concentration level and trough level of saquinavir above those resulting from combining only 400 mg bid ritonavir with the same dose of saquinavir.
Ritonavir + AZT + ddC
Abstract (Birmingham, England) November 1996
On page 38 (also, see page 26) of this book, we summarized the 60-week follow-up data of this study, reported at the Int'l. AIDS Conference in Vancouver, B.C. during July 1996. Here is the 72-week follow-up data, of this study, reported by Dr. Jean-Pierre Chauvin, of Abbott-France.
This is an open-label pilot study of antiretroviral-naive individuals with moderately advanced HIV. All study participants received open-label 600 mg twice per day (every 12 hrs) of ritonavir for 14 days followed by the addition of 200 mg three times per day (every 8 hrs) of AZT and 0.75 mg three times per day of ddC. Study participants initiated therapy with the ritonavir liquid formulation, and were switched to the oral gel capsule formulation of ritonavir after 54 weeks.
A total of 32 patients were enrolled with the following entry criteria: baseline CD4 counts of between 50 and 250; or, a drop of 200 cells to a level of less than 350 cells over a recent 6 month period; or, 250 to 350 cells with symptoms.
Mean and median baseline CD4 counts were 170 and 152, respectively; mean plasma viral load and cellular viral load levels were 4.7 log (about 50,000 copies/ml-- the Roche RT-PCR test with lower limit of detection of 200 copies/ml), and 3.2 logs per 107 cells (peripheral blood mononuclear cell culture), respectively.
Chauvin reported 11 patient discontinuations after 24 weeks-- 6 with ritonavir-related adverse events and 5 with non-ritonavir related adverse events; 21 completed 24 weeks; subsequently, there were 4 additional discontinuations as 17 completed 72 weeks.
Plasma Viral Load. At 72 weeks, the mean reduction in viral load was about 1.9 logs from baseline for 17 evaluable study participants, compared to decreases of 1.94 at 24 weeks, and 1.6 at 52 weeks. The proportion of patients with viral load below the lower limit of detection (200 copies/ml) was about 52% (n=17) at 72 weeks, compared to about 48% at 28 weeks, and 22% at 52 weeks.
Mean cellular viremia (infectious cells) was about 2.5 logs below baseline at 72 weeks, compared to decreases of 1.06 logs at week 2, 2.41 logs at week 24, and about 2.4 logs at 52 weeks. About 70% of patients (n=17) had negative HIV cell cultures (defined as less than 5 infectious cells per 107 PBMC) at week 72, compared to about 60% at week 60 (n=15).
CD4. The mean CD4 increases from baseline were about 160 at week 72 (n=17), compared to increases of 130 at week 24, and 170 at week 52.
The dose escalation method, which is now recommended for ritonavir, was not used in this study. A total of 6 patients discontinued due to GI intolerance; two patients discontinued due to liver toxicity (one grade III, one grade IV); several patients experienced elevated triglyceride levels.
Commentary: When comparing viral load changes and the proportion with undetectable viral load from the time point of prior to 52 weeks and after 52 weeks, bear in mind that at about 52 weeks, patients were switched from the oral liquid ritonavir to the gel capsules. Apparently, compliance may have improved after the switch to the gel capsule.
Ritonavir + AZT + 3TC
Abstract (Birmingham, England) November 1996
Thirty-one treatment-naive individuals were randomized to begin triple therapy (ritonavir 600 mg + AZT 300 mg + 3TC 150 mg--all 3 drugs were administered twice daily (every 12 hours, bid) simultaneously or to the delayed group where ritonavir was initiated alone followed by the addition of AZT and 3TC three weeks later. The immediate vs delayed comparison is to detect if there is a difference in effect due to the 3-week delay in adding AZT/3TC. Dr. Sven Danner, of the University of Amsterdam, reported the preliminary virological and immunological data from this ongoing open-label two arm study. Dr. Daan Notermans, of the Academic Medical Center in Amsterdam, reported results from a study of the RNA load in the lymphoid tissue from tonsillar biopsies of 6 study participants who continued on treatment in this ritonavir/AZT/3TC study.
Group 1, the immediate group had median baseline RNA, CD4 and CD8 of 5.27 log (about 187,000 copies/ml), 177 cells, and 1,027 cells, respectively. Group 2, which delayed AZT/3TC for 3 weeks, had median baseline RNA, CD4 and CD8 of 5.37 (about 235,000 copies/ml), 134 cells, and 927 cells.
CD4. For group 1 (the immediate group, baseline=177 CD4) at 8 weeks, there was about a 100 cell median increase from baseline (n=16); for group 2 (delayed, baseline=134 cells), there was about a 75 cell median increase from baseline (n=16); at 12 weeks, the median CD4 increase from baseline was about 130 for group 1 (n=16) and about 80 for group 2 (n=16); at 24 weeks, the median CD4 increase was about 175 for the immediate (group 1, n=9) group and about 100 for the delayed (group 2, n=12) group. Danner said the difference in CD4 at 24 weeks between groups 1 and 2 may be due to the difference at baseline.
|
Week |
Basel. |
8 |
12 |
16 |
24 |
|
n-1/2 |
17/16 |
17/16 |
16/16 |
14/16 |
9/12 |
|
grp. 1 |
177 |
+100 |
+130 |
+105 |
+175 |
|
grp. 2 |
134 |
+75 |
+80 |
+80 |
+100 |
CD8. For the immediate-group 1 (baseline=1027), there was a median cell increase from baseline of about 150 at week 8, 100 cells decrease below baseline at week 16, and back to about a 200 increase above baseline at week 24; for the delayed-group 2 (baseline= 927), the median increase from baseline was about 200 at week 8, a 50 cell increase above baseline at week 16; at week 24, the CD8 was about equal to the baseline.
|
Week |
Baseline |
8 |
16 |
24 |
|
n-1/2 |
17/16 |
17/16 |
14/16 |
9/12 |
|
Group 1 |
1,027 |
+150 |
-100 |
+200 |
|
Group 2 |
927 |
+200 |
+50 |
even |
Plasma Viral Load. During the initial 4 weeks of therapy, the reduction in viral RNA appears to decline slightly more steeply and quickly for the immediate group than the delayed group; however, at week 4 (AZT/3TC is added at week 3) the median decline from baseline appears about equal for both groups at about 2.2 log. At weeks 8 and 12 (2.5 and 2.6 vs 2.6 and 2.75), the reduction in RNA is slightly more for the delayed group than for the immediate group; but, by week 16 both groups have pulled to about even in their median reduction from baseline in viral load (about 2.8 log for both groups); at week 24, both groups appear to have about equal reductions in viral load of about 2.8 log.
|
||||||||||||||||||||||||||||
|
The CD4, CD8 and viral load numbers (including those in the tables)
are based upon estimations of line graphs, and therefore are approximations. |
The CD4, CD8 and viral load numbers (including those in the tables) are based upon estimations of line graphs, and therefore are approximations.
Proportion with RNA Below Detectability. For those study participants who remained on full doses of study medications (some study participants discontinued or interrupted therapy), 100% in group 1 (immediate) were below detectability (the Roche Amplicor test was used with a median lower level of detection of 238 copies/ml) at week 16 (n=12); about 85% of those in group 2 (delayed, n=13) were undetectable at week 16; at week 24 100% of both groups (grp 1-n=6, grp 2-n=8) were below the limit of detection.
Adverse Events and Withdrawals. A total of 8 study participants (24%) withdrew from study (5 were in immediate-group 1, and 3 were in delayed-group 2). Of the 5 group 1 individuals who withdrew, one withdrawal each occurred in weeks 5, 8, 12, and 20. Of the 3 group 2 individuals who withdrew, one each occurred at weeks 13, 16, and 24. The frequency of occurrence of adverse events given as reason for withdrawal: nausea and/or vomiting- 7; asthenia or malaise- 5; diarrhea- 3; abdominal pain- 2; dizziness- 1; night sweats- 1; palpitations- 1; some individuals complained of multiple adverse events as reasons for withdrawal.
Dr. Danner said, the results obtained to date do not point to a difference in antiretroviral potential between the two groups over the first three weeks; also he said, the incomplete reduction in viral load seen after 3 weeks (when compared to the reduction seen after 16 weeks) is not due to lack of potency, nor to rapidly developing resistance. He reported, one patient had mutations at 41 and 215, but was still undetectable; and, another patient had a V82A mutation after a few weeks, but was also undetectable. At baseline, two patients had A71T mutations and another had an A71V mutation.
Lymphoid Tissue. For each of the six participants who received tonsillar biopsies, investigators have baseline and six month values. Investigators said, 90% of a tonsillar biopsy consists of lymphoid tissue (Haase et al, Science, in press 1996); tonsillar biopsy under local anasthesia is a safe and simple procedure. The tissue RNA load was measured with the Chiron ultra-sensitive bDNA test. The lower limit of detection of the test is 500 copies; this calculates to 30,000 copies per gram of tissues (or 30 copies per mg of tissue) and is 1.84 log. Notermans reported that by week 24, in all of the six patients, the tissue RNA was below the limit of detection of the test (500 copies).
Notermans requested that standards for anti-retroviral therapy be reset to include reducing HIV RNA levels in the lymphoid tissue in addition to reduction in the peripheral blood. He continued: "we need to follow-up to see how sustained the suppression is; and, we need to know other things, such as what happens to the level of pro-viral DNA in the lymphoid tissue. Even if we manage to suppress the virus strong and long enough, is reconstruction of the immune system possible?"
Commentary. Although the lymph tissue load was below 500 copies, residual virus may still be present and replicating. We don't yet understand the implications. Other researchers present at this meeting, said more refined methodology need to be used; a more refined methodology may yield a more definitive understanding of virus activity in lymph tissue. A goal is to be able to correlate virus activity in lymph tissue with virus activity in plasma (blood circulation); and, to correlate treatment effect on one compartment with treatment effect on the other compartment. If correlations can be established, it may not be necessary to measure viral burden in lymph tissue. There is controversy about pro-viral DNA. If present, some believe it may be defective and not significant, while others do not agree and think the presence of pro-viral DNA is important.
Go to the HIV Protease Inhibitor Report Menu
Go to the Protease Inhibitor Menu
Go to the HIVpositive.us Main Menu
39