Published in the Bulletin of Experimental Treatments for AIDS April 1998 issue, by the San Francisco AIDS Foundation.

Selected Highlights from 5th Conf. on Retroviruses and Opportunistic Infections Main Page

• New Anti-HIV Drugs
• Hydroxyurea
• Protease Inhibitor and Other Drug Combinations
• Opportunistic Infections
• Miscellaneous

April 1998 Table of Contents

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Selected Highlights from the 5th Conference on Retroviruses and Opportunistic Infections

Protease Inhibitor and Other Drug Combinations

Harvey S. Bartnof, MD

5-Drug and 6-Drug Anti-HIV Combinations

Three interesting posters described using 5-drug or 6-drug combinations to treat HIV/AIDS. The 6-drug combination was an attempt at salvage therapy reported by Cassy Workman, MD, and colleagues from Sydney, Australia. She treated 12 people with AIDS who had been heavily pretreated with many anti-HIV therapies (including the first 3 approved protease inhibitors) and in whom all prior regimens had failed. However, none of the patients had ever taken nelfinavir or nevirapine. The combination used in the study was nelfinavir (1,000 mg every 8 hours), hard-gel saquinavir (600 mg every 8 hours), nevirapine (200 mg every 12 hours), d4T (40 mg every 12 hours), 3TC (150 mg every 12 hours) and ddI (400 mg once daily). Medications to counteract side effects were used. The mean baseline HIV RNA viral load was 170,065 copies/mL. Three of the 12 patients who had experienced previous drug intolerance again had the same reactions and had to discontinue treatment. Of the remaining 9, all had undetectable HIV viral load (limit of detection 400 copies/mL) after 12 weeks. CD4 counts increased from 30 to 370 cells/mm³ (baseline not stated). Results after 12 weeks were not presented. The authors concluded that even with only 2 new anti-HIV drugs in a regimen, the recycling of drugs for salvage therapy can lead to initial viral load suppression, even in people who have been heavily pre-treated. They also concluded that further studies are indicated.

A poster presentation from the University of Amsterdam in the Netherlands described a study in which 8 anti-HIV drug-naive and 1 drug-experienced patient used a 5-drug combination. The regimen was indinavir, nevirapine, abacavir, AZT and 3TC (all at standard doses). The median baseline HIV RNA viral load was 4.9 log copies/mL and the mean CD4 count was 360 cells/mm³. Follow-up through 12 weeks was reported. All 9 patients (100%) had undetectable HIV viral loads (limit of detection 50 copies/mL) by week 8, continuing through week 12. CD4 cell counts after therapy were not reported. After starting therapy on day 0, blood samples were drawn on days 1, 2, 3, 4 and 8, and later at weeks 2, 4 and 8. The authors calculated that the rate of HIV viral load decrease was faster in the 5-drug group than in a 4-drug comparison group consisting of 35 drug-naive HIV positive patients. That group took nelfinavir, saquinavir, d4T and 3TC for 12 weeks. After 8 weeks (12 week data not available) the 4-drug group had a median viral load of 2.2 log copies/mL. The 5-drug group also had a faster rate of HIV viral load decrease than a 3-drug control arm consisting of 15 drug-naive HIV positive patients. These patients received ritonavir, AZT and 3TC. Other data have associated the rate of HIV viral load decrease with durability of HIV suppression.

A third poster was authored by Steve Scheibel, MD, Brad Saget, PhD, and colleagues from San Francisco. Co-authors included researchers from Roche Molecular Systems in Alameda, CA. The drug combination used in this study included alpha interferon plus 3-4 nucleoside reverse transcriptase inhibitors (AZT, ddI and ddC, with or without 3TC). Four patients were described (1 started treatment before and 1 during HIV seroconversion). Patients have been monitored for 2-3 years. After the first 7 weeks, HIV plasma RNA was undetectable (limit of detection less than 10-20 copies/mL) and HIV blood cultures were negative. The authors also described analysis of 1 patient's lymph node after 78 weeks of treatment. No HIV RNA was detected by in situ hybridization. At that time, blood mononuclear cells revealed HIV proviral (integrated into the human chromosome) DNA measured at less than or equal to 10 copies per 150,000 cells.

Workman C and others. Salvage therapy using 6 drugs in heavily pretreated patients. CROI. Abstract and poster presentation 426.

Twice Daily Indinavir plus AZT plus 3TC

A study compared a treatment arm taking twice-daily indinavir (1,000 or 1,200 mg) plus AZT plus 3TC to a control arm taking 800 mg indinavir 3 times daily plus AZT plus 3TC. The study included 87 patients (20% women); all were naive to protease inhibitors and 3TC. Baseline median HIV viral load was 4.7 log copies/mL and baseline CD4 cell count was 266-294 cells/mm³.

Interim results at 32 weeks for 38 of 87 patients show that 70% of both twice-daily indinavir arms had undetectable viral load (limit of detection 500 copies/mL) compared to 45% of the control arm. Sixty percent of both twice-daily indinavir arms had undetectable viral load using a test with a limit of detection of 50 copies/mL, compared to 40% of the control arm. A CD4 cell count increase of 50 cells/mm³ was seen in both twice-daily arms, compared to a 160 cells/mm³ increase in the control arm.

Serious adverse side effects occurred in 13% of participants in the 1,200 mg twice-daily arm and 7% of those in the 1,000 mg twice daily arm. Kidney stones occurred in 13% of the 1,200 mg arm, 7% of the control arm and 3% of the 1,000 mg arm. Nausea and vomiting occurred in 51-56% of participants in all 3 arms. Reasons for discontinuation due to adverse events included nausea and vomiting (14-17% of all arms), kidney stones (3% of the control arm, none in the other 2 arms) and neutropenia (3% of the 1,200 mg arm).

While it appears that twice-daily dosing of indinavir has equivalent or better anti-HIV effects than the standard 800 mg dose, the lower CD4 cell count increase is noteworthy. The higher rate of kidney stones in the 1,200 mg arm when compared with the standard dose is worrisome. The nausea and vomiting rates in all 3 arms, and the subsequent discontinuation rates, are higher than in previous indinavir studies. A larger study is underway to confirm these results. Until then, it may be premature for all patients taking indinavir to switch to a twice-daily dose of 1,000 or 1,200 mg.

Nelfinavir plus Ritonavir Twice Daily

A study looked a twice-daily dosing of nelfinavir (500-750 mg) plus ritonavir (400 mg). The study included 20 participants (25% women). At 20 weeks of follow-up, those taking the 500 mg dose of nelfinavir twice daily had only a small CD4 cell count increase. Only 30% of those taking higher dose nelfinavir had undetectable viral load (limit of detection 20 copies) at 16 weeks.

Adverse events reported were mild-to-moderate diarrhea (45%) and nausea (20%). Sixty percent of participants added other anti-HIV therapies after 16 weeks or later to the double protease inhibitor combination. The nelfinavir dose in this double protease inhibitor combination may have been too low. It is likely that to be effective, the 2 protease inhibitors must be part of a regimen that includes additional anti-HIV drugs.

Nefinavir plus Hard-Gel Saquinavir Twice Daily

A study looked at participants taking twice-daily nelfinavir at 1,250 mg plus twice-daily hard-gel saquinavir (Invirase) at 1,000 mg plus standard doses of d4T and 3TC. The study included 12 women. Participants were protease inhibitor-naive and had minimal exposure to d4T and 3TC. Mean baseline HIV viral load was 4.9 log copies/mL and mean baseline CD4 cell count was 343 cells/mm³.

At 16 weeks, viral load was undetectable (limit of detection 400 copies/mL) in 18% (6 of 7 participants). An ultrasensitive viral load test was not used. Participants experienced a CD4 cell count increase of 119 cells/mm³. The regimen was well tolerated; no significant adverse events were reported. The study is ongoing and will continue for a total of 12 months.

Soft-Gel Saquinavir plus Nelfinavir plus Nucleoside Analogs

A combination regimen of soft-gel saquinavir (800 mg) taken 3 times daily plus nelfinavir (750 mg) 3 times daily plus 2 nucleoside analogs shows continued benefits through 32-48 weeks. The Spice study included 150 patients (15% women); all were protease inhibitor-naive. Mean baseline HIV viral load was 4.8 log copies/mL and mean baseline CD4 cell count was 301 cells/mm³. The most common nucleoside analogs added were 3TC plus either AZT or d4T.

After 32 weeks, 83% had undetectable viral load (limit of detection 400 copies/mL), and 70% had undetectable viral load on a more sensitive test (limit of detection 50 copies/mL). The mean CD4 cell increase was 134 cells/mm³. Eight percent experienced adverse events (nausea, diarrhea, weakness) or intercurrent illness; no deaths occurred. Virologic failure occurred in 8%. Researchers concluded that the 4-drug regimen was better than 2 protease inhibitors alone or 1 protease inhibitor with 2 nucleoside analogs.

A second study included 15 patients (7% women), all of whom were protease inhibitor-naive. Median baseline viral load was 39,917 copies/mL and median CD4 cell count was 327 cells/mm³.

After 48 weeks, 90% (9 of 10) had undetectable viral load (limit of detection 500 copies/mL). The median CD4 cell count increase was 172 cells/mm³. Adverse events included diarrhea (40%), headache (20%) and abdominal pain (13%). Fifty-three percent did not take 2 nucleoside analogs throughout the study.

Twice-Daily Versus 3-Times-Daily Nelfinavir

A study showed that twice-daily nelfinavir (1,250 mg) plus d4T plus 3TC was as effective as standard 3-times-daily nelfinavir (750 mg) plus d4T plus 3TC. The Phase III, double-blind, randomized study included 289 patients (11% women). Participants had less than 2 weeks prior protease inhibitor therapy and were naive to either d4T or 3TC. Mean baseline viral load was 5.0 log copies/mL and mean CD4 cell count was 188-301 cells/mm³.

After 32 weeks, 80% in each arm had undetectable viral load (limit of detection 400 copies/mL). In a subset analysis, 78% of the twice-daily arm and 53% of the 3-times-daily arm had undetectable viral load using a more sensitive test (limit of detection 50 copies/mL). CD4 cell count increase was 181 cells/mm³ in the twice-daily arm and 155 cells/mm³ in the 3-times-daily arm. The peak plasma level of nelfinavir was 57% higher, the area under the curve was 13% higher and the trough level was 23% lower in the twice-daily arm.

Moderate or severe adverse events included diarrhea (12-13% in each arm), nausea (2% in twice-daily arm and 4% in 3-times-daily arm). Three patients stopped treatment in the twice-daily arm due to adverse events (1 due to diarrhea and 2 due to rash). Adherence was determined to be very good in both arms. The study will continue through 96 weeks.

Zorilla C and others. A study in HIV positive women of quadruple therapy: nelfinavir, saquinavir, stavudine and lamivudine. CROI. Abstract and poster presentation 722.

Nevirapine plus Nelfinavir plus d4T

A study involved 25 participants (16% women) taking nevirapine plus nelfinavir plus d4T; they had no prior protease inhibitor or non-nucleoside reverse transcriptase inhibitor (NNRTI) therapy, and no more than 6 months of prior d4T therapy. Mean baseline HIV viral load was 4.5 log copies/mL and mean CD4 cell count was 372 cells/mm³. There were no significant changes in blood concentrations of all 3 drugs (maximum levels, trough levels and "area under the curve" levels).

After 21 weeks in 9 of 25 patients analyzed, 90% had undetectable viral load (limit of detection 400 copies/mL). These participants had a CD4 cell count increase of 60 cells/mm³. Twelve percent discontinued the study due to adverse events, including rash, increased liver enzymes and/or increased lipase (a pancreatic enzyme). Sixteen percent had drug interruptions due to rash and increased liver enzymes. Researchers concluded that larger studies are warranted.

Skowron G and others. Stavudine, nelfinavir and nevirapine: preliminary safety, activity and pharmacokinetic interactions. CROI. Abstract and poster presentation 350.

Delavirdine/Nelfinavir and Delavirdine/Rifabutin Interactions

A study showed that use of delavirdine (Rescriptor) increases nelfinavir concentration ("area under the curve") by 100%, but reduces concentration of an active metabolite of nelfinavir by 50%. Nelfinavir decreases delavirdine concentration by 40%.

Twenty-one percent of subjects receiving both drugs experienced low white cell counts (neutropenia); in 2 of 5 cases, neutropenia was severe or life-threatening. Further study of the delavirdine/nelfinavir combination is ongoing.

In addition, researchers found that delavirdine increases the concentration of rifabutin by over 200% and decreases the concentration of delavirdine, requiring a delavirdine dosage increase to greater than 600 mg 3 times daily. They concluded that delavirdine should not be taken with rifabutin.

Cox SR and others. Delavirdine and rifabutin: pharmacokinetic evaluation in HIV-1 patients with concentration-targeting of delavirdine. CROI. Abstract 344.

Harvey S. Bartnof, MD, has been a member of the Scientific Advisory Committee at the SF AIDS Foundation since 1987.

Page last updated 5 May 1998