|
|
Update on Agouron's Nelfinavir
NELFINAVIR PLUS d4T
Abstract Mo.B.413
Dr. Joseph Gathe of Houston's Montrose Clinic presented the latest results of a Phase II study comparing nelfinavir plus d4T with d4T alone (protocol #510). Early safety and efficacy data were first presented by the company at a community meeting in Washington, D.C. last January.
Study participants had CD4 counts of greater than 200 cells/mm3 and viral loads above 15,000 copies/ml with no prior d4T and protease inhibitor experience. A total of 39 people (27 men and 2 women) were randomly assigned to receive one of the 4 treatment regimens: 500, 750, or 1,000 mg of nelfinavir three times per day plus d4T, or d4T alone. Mean baseline CD4 counts and viral loads are listed below (Table 1B).
| Treatment Group |
Viral Load (copies/ml) |
CD4 counts (cells/mm3) |
| d4T |
66,445 |
390 |
| d4T + 500 mg NFV |
81,467 |
367 |
| d4T + 750 mg NFV |
80,386 |
334 |
| d4T + 1,000 mg NFV |
56,448 |
310 |
After 2 months of therapy, the mean reductions in viral load were 1.7 logs in the 500 mg nelfinavir + d4T group, 2.2 logs in the 750 mg nelfinavir + d4T group, and 2.4 logs in the 1,000 mg nelfinavir + d4T group. Mean increases in CD4 counts in those respective groups were 105, 125, and 130 cells/mm3. By contrast, in the d4T alone group, the mean 2-month viral load reduction was 0.8 log and the mean CD4 count increase was 88 cells/mm3.
Sustained reductions in viral load in people who received continuous therapy with both nelfinavir and d4T were observed. Data were presented based on 6 or 7 persons in each treatment group for whom both virologic and immunologic data were available. After 5 months, viral loads remained 1.3, 1.7, and 1.9 logs below baseline for the 500 mg nelfinavir + d4T, the 750 mg nelfinavir + d4T, and the 1,000 mg nelfinavir + d4T groups. At month 5, mean CD4 increases ranged from 85 to 110 cells/mm3 above baseline in those groups.
People who received d4T monotherapy for 2 months were then allowed to add nelfinavir in a 3-month extension phase of the study. Three months after nelfinavir was added to d4T, viral load decreased by 1.7 logs and CD4 counts increased to 175 cells/mm3 from baseline values. These findings were observed in 7 persons for whom the data were available at that time.
The combination of nelfinavir and d4T was safe and generally well tolerated over a 5-month follow-up period. Diarrhea was the main adverse reaction related to nelfinavir in the study, affecting two of the 11 persons (18%) receiving 500 mg nelfinavir plus d4T, three of 10 (30%) in each of the higher dose groups. Dr. Gathe reported that no one had to withdrawn from the study due to diarrhea and that over-the-counter anti-diarrheal medications were able to control this adverse event.
NELFINAVIR + AZT + 3TC
Abstract L.B.B. 6031
Dr. Marty Markowitz and colleagues at the Aaron Diamond AIDS Research Center, Rockefeller University, in New York reported preliminary results from a pilot study of triple therapy with nelfinavir in combination with AZT and 3TC in antiretroviral-naive, chronically HIV-infected people.
The study objectives are to 1.) assess the safety, efficacy and pharmacokinetics of nelfinavir in combination with AZT and 3TC; 2.) to determine the significance of prolonged viremia; 3.) to understand the nature of CD4 and CD8 production post-therapy; and 4.) to model the second phase of decay of free virus and virus producing cells.
A total of 12 antiretroviral-naive, HIV-infected individuals with a baseline plasma viral load of greater than 10,000 copies/mL were initiated on 750 mg three times per day of nelfinavir plus 200 mg three times per day of AZT and 150 twice per day of 3TC.
Baseline mean and median plasma viral loads were 5.32 logs or 209,011 HIV RNA copies/mL and 4.91 logs or 81,270 copies/mL, respectively. Viral load levels ranged from 4.26 to 5.94 logs or 177,990 to 864,900 copies/mL. Mean and median CD4 counts at baseline were 258 and 253 cells/mm3, respectively. CD4 counts ranged from 37 to 557 cells/mm3.
One person had an AIDS-defining illness, Pneumocystis carinii pneumonia or PCP, prior to study entry. Other HIV-related conditions documented at baseline were nephropathy and myopathy (1 person), eosinophilic pustular folliculitis (1), oral candidiasis (1), and hairy leukoplakia (1). Resolutions of myopathy, molluscum contagiosum, oral candidiasis, and oral hairy leukoplakia were observed with the triple therapy. In addition, marked improvements in nephropathy and eosinophilic pustular folliculitis were noted with therapy. No new HIV-related infections or neoplasms were observed over 25 weeks of therapy.
One of the 12 participants withdrew at week 6 due to severe (grade 4) elevation of CPK and moderate (grade 2) diarrhea associated with abdominal cramping.
Mean reduction in plasma viral RNA was 2.62 logs below baseline by week 8. Aviremia was achieved as measured by both plasma viral load (less than 500 HIV RNA copies/mL) and PBMC cultures (less than 0.1 TCID50/106 PBMC) in all remaining 11 persons by week 12 of therapy. All 11 persons remained aviremic at week 16.
The levels of plasma RNA were also measured by a newer, more sensitive viral load test with a lower limit of assay detection of 25 copies/mL. By week 8, the mean RNA levels fell below the detectability level of this test.
Following the initial phase of rapid and potent suppression (about 2 logs) of viral load in the first 2 to 3 weeks, a second and slower phase of viral decay was observed with a mean half-life (T1/2) of about 17 days.
After 12 weeks of therapy, a mean and median CD4 count increase of 109 and 98 cell/mm3 was observed.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
vRNA = plasma viral load in copies/mL; PBMC cultures measured in tissue culture infective dose 50 per 1 million PBMCs; CD4 measured in cells/cu mm. The baseline vRNA values were based on Chiron's second generation bDNA test with a lower limit of detection of 500 equivalent copies/mL. The week 16 vRNA values were based on Chiron's third generation bDNA test with a lower limit of detection of 25 copies/mL. |
Dr. Markowitz concluded that nelfinavir in combination with AZT and 3TC produced an uniform aviremia after three months of uninterrupted therapy and holds promise in controlling HIV replication in HIV-infected individuals.
NELFINAVIR RESISTANCE
Abstract (Drug Resistance Workshop)
Dr. Amy Patick of Agouron reported new findings of nelfinavir resistance profile in HIV+ people. Based on a preliminary analysis of a small number of patients' viral isolates, a novel mutation at position 30 of the protease enzyme was found to be the predominate cause of resistance associated with nelfinavir treatment. Other mutations were also observed, however, their contribution to the development of viral resistance to nelfinavir was not significant (see also Appendix C).
Go to the The XIth International Conference on AIDS Menu
Go to the HIV Protease Inhibitor Report Menu
Go to the Protease Inhibitor Menu
Go to the HIVpositive.us Main Menu
39