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Update on Abbott's Ritonavir
RITONAVIR IN ADVANCED HIV
Results from longer-term follow-up of people participating in a study of adding ritonavir or placebo to their existing antiretroviral therapy (protocol M94-247) were presented. Preliminary data from this study was first presented at the Third Conference on Retroviruses and Opportunistic Infections last January in Washington, D.C.
A total of 1,090 study participants were randomly assigned to receive 600 mg ritonavir twice daily (543 persons) or placebo (547 persons) in combination with existing antiretroviral therapy. Participants had CD4 counts of 100 cells/mm3 or fewer and at least 9 months of previous antiretroviral therapy. In addition, patients had no active opportunistic infections at study entry. After 16 weeks, people who have developed a clinical event are then allowed to receive open-label ritonavir. After 7 months, all participants were allowed to receive open-label ritonavir.
On average, people had received prior antiretroviral therapy for 2.3 years in each of the two treatment groups. People in the ritonavir group had received 1.7 years of prior AZT therapy while those in the placebo group had 1.9 years of AZT therapy. About 18% of the participants had no other concurrent antiretroviral therapy during the course of the study (i.e., they received either ritonavir alone or placebo). Majority of the participants (82%) had received ritonavir or placebo with concurrent antiretroviral treatments such as nucleoside monotherapy (AZT, d4T, ddI, or ddC) or nucleoside combination therapy (AZT+ddC, AZT+ddI, or AZT+d4T). 3TC was considered as an experimental drug at the time the study was started and was not permitted as a concurrent therapy.
In a subset of people for whom antiviral results were analyzed (80 persons in the ritonavir group and 70 in the placebo group), mean baseline viral loads were 5.25 logs or about 178,000 copies/mL and 5.13 logs or about 135,000 copies/mL, respectively.
In the ritonavir group, there was an initial decrease of viral load by 1.3 logs at week 2 which then returned to 0.6 log below baseline level at month 4. Viral load remain suppressed by 0.6 log at month 7. By contrast, viral load levels remain relatively unchanged in the placebo group over 7 months.
Changes in CD4 counts were also evaluated in a subset of the participants (108 persons in the ritonavir group and 107 in the placebo group). At baseline, mean CD4 counts were 31 and 26.4 cells/mm3 in ritonavir and placebo groups, respectively.
There was a mean CD4 count increase from baseline of about 35 cells/mm3 in the ritonavir group at week 2 which then increased to about 55 cells/mm3 at week 4. Elevations of CD4 counts from baseline remained in the range of 50 to 55 cells from month 1 to month 7. No CD4 count increases nor decreases were seen in the placebo group.
A total of 111 (20.4%) clinical events occurred in the ritonavir group as compared to 202 (36.9%) events in the placebo group over approximately 8 to 9 months. There was a 49% reduction in AIDS-defining events in those who received ritonavir compared to those who received placebo. A total of 68 deaths (13%) were reported in the ritonavir group versus 104 deaths (19%) in the placebo group over about 13 to 14 months. There was a 36% reduction in death in the ritonavir group relative to the placebo group. The effects of ritonavir on delaying disease progression and death were found to be statistically significant.
RITONAVIR + AZT + ddC
Abstract Mo.B.175
At the Third Conference on Retroviruses and Opportunistic Infection last January held in Washington, D.C., Abbott investigators from France first presented publicly the 6-month data from an open-label study of ritonavir in combination with AZT and ddC in people with advanced HIV disease (see page 29). The extended 60-week follow-up data, which was presented by Dr. Dominique Mathez of the Hôpital Raymond Poincaré at the International AIDS Conference in Vancouver, B.C., are summarized here.
All study participants received open-label 600 mg twice per day of ritonavir for 14 days followed by the addition of 200 mg three times per day of AZT and 0.75 mg three times per day of ddC. People were switched to the oral gel capsule formulation of ritonavir after 54 weeks of therapy with the initial oral distasteful liquid formulation of ritonavir.
A total of 32 HIV+ people with no previous antiretroviral therapy were enrolled into the study. Participants had baseline CD4 counts of between 50 and 250 cells/mm3, or a drop of 200 cells/mm3 to a level of less than 350 cells/mm3 over a recent 6 month period, or 250 to 350 cells/mm3 with symptoms.
Mean baseline CD4 counts were 170 cells/mm3; mean baseline plasma and cellular viral load levels were 4.7 logs or 50,000 copies/mL of HIV RNA (Roche RT-PCR assay with lower limit of detection of 200 copies/mL) and 3.2 logs per 107 cells (peripheral blood mononuclear cell culture), respectively. Mean CD4 counts were 304 cells/mm3 after 24 weeks of therapy in 21 evaluable persons and 338 cells/mm3 after 60 weeks in 17 evaluable persons, respectively, as compared to 170 cells/mm3 at baseline. The mean plasma viral load remained at 1.91 logs below baseline in the 17 study participants at week 60, compared with declines of 1.94 logs at week 24 and 1.29 logs at week 2. Mean cellular viremia (infectious cells) were 2.43 logs below baseline at week 60, compared decreases of 2.41 logs at week 24 and 1.06 logs at week 2.
More than half of the 17 participants had undetectable levels of HIV RNA (defined as below 200 copies/mL) in plasma after 60 weeks of therapy. Similarly, sixty percent of the 15 evaluable participants had negative HIV cell cultures (defined as less than 5 infectious cells per 107 PBMC) at week 60.
Dr. Mathez reported that 11 participants discontinued therapy during the first 24 weeks of the study due to the liquid formulation of ritonavir. She mentioned that a switch to the current soft gelatin capsule formulation had improved tolerance and had enhanced compliance.
RITONAVIR + AZT + 3TC
Abstract Th.B.933
Drs. Marty Markowitz and David Ho of the Aaron Diamond AIDS Research Center, Rockefeller University in New York, reported preliminary data from a study of ritonavir in combination with AZT and 3TC in newly infected HIV+ individuals.
The study was initiated based on the following hypotheses:
· "Combination antiviral therapy with AZT, 3TC and a potent protease inhibitor, ritonavir, can completely turn off viral replication in an HIV-1 infected host"; · "Twelve months uninterrupted triple therapy in this population may determine whether HIV-1 infection can be eradicated in a recently infected patient with a relatively intact immune system."
A total of 12 newly-infected gay men were enrolled and were treated with the liquid formulation of ritonavir in combination with AZT and 3TC within 90 to 120 days of infection. After 12 months of continuous triple therapy, study participants with minimum 9 months of undetectable viral load (less than 499 HIV RNA copies/mL) and PBMC co-culture (less than 0.1 tissue culture infective dose/106 PBMC) will be asked to undergo lymph node biopsy to detect any persistent viral activity. The decisions of whether to discontinue therapy will be made jointly by the study participants and investigators. At study entry, none of the participants were p24 antigen positive and all were HIV RNA positive as measured by Chiron's second generation branched DNA (bDNA) assay. Evidence of recent HIV infection was documented by negative HIV antibody by ELISA in 1 person, positive ELISA and evolving Western blot with minimum of two bands in 7 persons, and negative HIV antibody test within 120 days of screening with clinical history consistent with acute HIV infection in 4 persons.
Prior to initiating therapy, all participants had symptoms associated with acute infection; three mild, six moderate and three severe. Nine of 12 identified a precise time of infection that preceded the onset of symptoms by an average of 15 days (range 6-20 days). Therapy was initiated on average 65 days after the onset of symptoms (range 40 to 126 days).
Median plasma viral load level at baseline was 4.01 logs or 10,423 HIV RNA copies/mL and the mean baseline viral load level was 4.96 logs or 91,389 copies/mL. Baseline viral load levels ranged from 3.15 to 5.98 logs or 1,420 to 953,200 copies/mL. Median baseline CD4 and CD8 counts were 564 and 871 cells/mm3, respectively. Mean baseline CD4 and CD8 counts were 633 and 842 cells/mm3. Baseline CD4 counts ranged from 312 to 916 cells/mm3 and the CD8 counts ranged from 303 to 1,436 cells/mm3. CD4/CD8 ratios were inverted relative to normal ratios at baseline with a mean of 0.75 (range from 0.41 to 1.03).
The triple combination regimen was administered according to the following dose escalating schedule:
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| qd=daily, bid=twice daily, tid=3 times daily |
Three persons withdrew from the study; 1 due to an adverse event and 2 due to non-compliance. The first enrolled patient withdrew at day 28 due to adverse reactions to all three drugs. This patient had stopped ritonavir therapy on day 14 due to nausea and vomiting, and on day 28 he discontinued AZT and 3TC due to myalgia and fatigue. Two other participants withdrew from the study; one at month 2 and the other at month 5 at the discretion of the investigators due to their inability to comply with taking study medications and clinic visits. A fourth participant developed a ritonavir allergy and was treated with AZT and 3TC alone for the first 7 months and then indinavir was added.
There are 8 participants who have been on triple therapy for 4 to 10 months, and also included in the data analyses is the person who was on AZT and 3TC with added indinavir. CD4 response and viral load changes after 4 to 10 months of therapy in 9 evaluable participants are summarized in the following table:
|
Pt.# |
Duration of Rx (months) |
CD4 |
Plasma RNA |
PBMC culture |
|
2 |
10 |
864 |
<500 |
<0.1 |
|
3 |
9 |
344 |
<500 |
<0.1 |
|
5 |
8 |
736 |
<500 |
<0.1 |
|
6 |
7 |
1,205 |
<500 |
<0.1 |
|
7 |
6 |
708 |
<500 |
<0.1 |
|
8 |
5 |
822 |
<500 |
<0.1 |
|
9 |
4 |
1,095 |
<500 |
<0.1 |
|
11 |
4 |
482 |
<500 |
<0.1 |
|
12 |
4 |
523 |
<500 |
<0.1 |
All study participants have less than 100 copies/mL as measured by a variety of research methodologies, including the third generation Chiron bDNA test.
Drs. Markowitz and Ho concluded that the triple therapy results in prolonged aviremia by plasma viral load test and plasma and PBMC cultures. There was an increase in CD4 cell counts and a general improvement of the abnormal CD4/CD8 ratio. Ritonavir in combination with AZT and 3TC is well tolerated, particularly if the step-up dosing schedule is used. They noted that the feasibility of eradicating HIV from the study population of recently infected gay men with the triple therapy will require further evaluation.
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