Published in the Bulletin of Experimental Treatments for AIDS 1999 Year-End issue, by the San Francisco AIDS Foundation.

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HAART and Experimental Approaches to Treatment

Anti-HIV Drug Resistance Testing

Anti-HIV Therapies Early in the Pipeline

Anti-HIV Therapy Trials: New Studies and Follow-Up of Existing Trials

New Anti-HIV Drug Interactions, Toxicities, and Dosing Options

HIV Transmission

OIs and Cancers

Year-End 1999 Table of Contents

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Conference Notes -- Anti-HIV Therapy Trials: New Studies & Follow-Up of Existing Trials

Harvey S. Bartnof, MD

The most impressive anti-HIV drug trial results at the 39th ICAAC were presented during the late-breaker session. Thirty-six-week interim results of the potent double PI combination of ABT-378 plus ritonavir (ABT-378/r) were reported by Joseph Eron, MD, from the University of North Carolina at Chapel Hill. ABT-378 is more potent than any PI currently marketed or in development. Its effects are magnified when taken with low-dose ritonavir (100 mg). A total of 100 treatment-naive participants were started on ABT-378 200-400 mg plus ritonavir 100-200 mg for three weeks; d4T (Zerit) and 3TC (Epivir) were then added. The baseline HIV RNA viral load was approximately 100,000 copies/mL. After 36 weeks, using a stricter intent-to-treat analysis (i.e., all people enrolled were included), results showed that 81-87% had an undetectable viral load (limit of detection 400 copies/mL). Of the 68 people randomized to take ABT-378 400 mg plus ritonavir 100 mg, 87% had an undetectable viral load. Using a lower viral load limit of 50 copies/mL, 75-81% were undetectable. The same 68 people had an 81% undetectable rate. The CD4 cell counts increased approximately 200 cells/mm³. Only one of the 100 participants discontinued the trial. Using an as-treated analysis (i.e., only those still taking the study drugs were included), 95% had an undetectable viral load (less than 400 copies/mL).

In a second study, 70 treatment-experienced people were enrolled. All had taken only one PI in the past; none had taken an NNRTI. In this blinded trial, ABT-378 400 mg, ritonavir 200 mg, nevirapine (Viramune, an NNRTI), and two NRTIs (including one new NRTI) were started. The NRTI drugs most commonly used were 3TC plus either d4T or AZT (Retrovir). The median baseline HIV RNA viral load was approximately 4 log copies/mL, while the median baseline CD4 cell count was 349 cells/mm³. Two-thirds of these people had a four-fold or greater resistance to their previous PI. One-third had a four-fold or greater resistance to three or more PIs. In an intent-to-treat analysis, the results after 36 weeks indicated that 67% had an undetectable viral load (less than 400 copies/mL). In the as-treated analysis, 78% had an undetectable viral load. Results using the more sensitive test (which measures viral load down to 50 copies/mL) were not yet available. CD4 cell count increased by approximately 100 cells/mm³. One person in this second study stopped therapy due to adverse events. The most common adverse events were nausea, diarrhea, headaches, and weakness, yet all doses were very well tolerated. Cholesterol (fat) levels increased somewhat. This study is ongoing; meanwhile, expanded access to this very potent anti-HIV drug has already begun.

At the 39th ICAAC, Jay Lalezari, MD, of Quest Clinical Research in San Francisco presented an update of T-20 in HIV positive people. The fusion inhibitor T-20 has shown significant benefits for 55 people at 16 weeks; all had significant prior anti-HIV drug experience. The dose of T-20 was 50 mg self-injected under the skin twice daily. It was added to participants' anti-HIV drug regimens that were determined on the basis of genotypic resistance testing.

Before starting T-20, participants had taken a median of 11 prior anti-HIV drugs; 93% had taken drugs from all three of the first anti-HIV drug classes. Just prior to initiation of T-20 therapy, the median baseline HIV RNA viral load was 4.9 log copies/mL; median CD4 cell count was 70 cells/mm³. Ninety-three percent had HIV strains resistant to at least one PI, while 87% had resistance to NNRTIs or NRTIs. Results at 16 weeks showed that 36% had an undetectable viral load (less than 400 copies/mL); 60% had a 1 log copies/mL decrease in viral load or an undetectable viral load. The most common side effect was a reaction at the injection site.

Serious adverse reactions occurred in 7%, without a clear trend. None stopped therapy due to adverse reactions.

T-20 was well tolerated, with a response in this population similar to the response to "mega-HAART" (also called multiple drug rescue therapy, or MDRT) in heavily treatment-experienced persons. A few people developed resistance to T-20. (The newest fusion inhibitor, T-1249, however, displays activity against T-20-resistant HIV.) It is quite promising that this first drug in the fifth class of anti-HIV therapies shows benefits in heavily pretreated persons. T-20 is produced by Triangle Pharmaceuticals.

Tenofovir DF is a nucleotide reverse transcriptase inhibitor prodrug being developed by Gilead Sciences. One 48-week trial enrolled 189 HIV positive people with inadequate HIV RNA viral load suppression. The once-daily 300 mg dose led to the greatest decrease in viral load (0.76 log copies/mL) at 24 weeks. Among 11 people who continued through week 52, one had mild kidney toxicity (increased creatinine), known to occur with other drugs in its class, including adefovir (Preveon). The study is ongoing. These late-breaker results were presented at the 39th ICAAC by Robert Schooley, MD, from the University of Colorado.

Final analysis of Study 006 was presented at the 39th ICAAC by Schlomo Staszewski, MD, from Goethe University in Frankfurt, Germany. Triple therapy demonstrated persistent benefits through week 72. The efavirenz triple therapy arm also continued to outperform the indinavir/AZT/3TC arm and the efavirenz/indinavir arm. The study enrolled 1,266 HIV positive people without prior therapy with an NNRTI, PI, or 3TC; 83-87% had no prior anti-HIV therapy. Women comprised 14-18% of the total, while non-Whites made up roughly 40%. The mean baseline HIV RNA viral load was approximately 4.8 log copies/mL; the mean baseline CD4 cell count, 340 cells/mm³.

Results after 72 weeks showed that the triple therapy efavirenz arm had significantly more people (67%) with an undetectable viral load (less than 400 copies/mL) than either of the other two arms. Forty-four percent of people in the indinavir/AZT/3TC arm had an undetectable viral load, compared with 49% in the efavirenz/indinavir arm. All results used the stricter intent-to-treat analysis. Using a more sensitive viral load test (measuring viral loads down to 50 copies/mL), the efavirenz triple arm still had significantly more people whose viral loads were undetectable (60%) than either of the other arms (40% in the indinavir triple therapy arm, 46% in the efavirenz/indinavir double therapy arm). CD4 cell counts increased significantly in all three arms in those who were still on therapy at 72 weeks. Each of the efavirenz-containing arms had an increase of approximately 225 cells/mm³, while the indinavir triple therapy arm had an increase of approximately 200 cells/mm³.

The efavirenz triple therapy arm had a 24% discontinuation rate. This was significantly lower than the rate in the other two arms (41% in the indinavir triple therapy arm and 35% in the efavirenz/indinavir arm). The discontinuation rate due to adverse events was 7% in each of the two efavirenz-containing arms. In contrast, the rate in the indinavir triple therapy arm was 41%.

Durability of viral suppression was also the most potent in the efavirenz triple therapy arm. Among people taking efavirenz triple therapy who achieved viral load suppression, 75% still had undetectable levels at 72 weeks, compared with approximately 58% in each of the other two arms. (In this analysis, any reason for discontinuation was considered a factor when researchers were evaluating continued suppression after initial undetectability.) In a similar analysis whereby only viral load rebound was used to measure nondetectability after initial suppression, 85% of the efavirenz triple therapy arm was still undetectable at 72 weeks. This compared with approximately 75% in the other two arms. The duration of response analyses also showed persistent benefits in the efavirenz triple therapy arm for those people with a baseline HIV viral load of 100,000 copies/mL or greater.

These 72-week results indicate the potency and durability of the efavirenz triple therapy combination, even among people with very high baseline viral loads. When compared with the standard triple therapy arm of indinavir/AZT/3TC, efavirenz triple therapy was better in every viral load analysis. Efavirenz triple therapy allows one to spare a PI when and if viral rebound occurs. CD4 cell count increases were quite similar when comparing the two treatments.

An interim analysis of the Women's First Study was presented at the 39th ICAAC by R. Clark, MD, and colleagues from Louisiana State University in New Orleans. Thirty-two women completed 48 weeks of the study and were analyzed. Seventeen of the women took twice-daily saquinavir (Invirase) 1,000 mg plus twice-daily nelfinavir (Viracept) 1,250 mg and standard dosing of d4T and 3TC. The other 15 women took the same total daily dosing of saquinavir plus nelfinavir (divided into three doses every eight hours), plus d4T and 3TC. None of the women had previously taken d4T, 3TC, or any PI. The entry HIV RNA viral load requirement was at least 10,000 copies/mL. Results for the 32 women who completed at least 48 weeks are as follows: an undetectable viral load (less than 50 copies/mL) occurred in 67% of those in the twice-daily arm, compared with only 50% of those in the three-times-daily arm. CD4 cell count increases were 182 cells/mm³ in the twice-daily arm and 170 cells/mm³ in the three-times-daily arm.

Side effects included significant increases in blood cholesterol and glucose (sugar), but an insignificant increase in blood triglycerides (a type of fat). Rates of discontinuation and of fat redistribution were not stated. There were no unexpected adverse events. The authors concluded that the twice-daily, double-PI, four-drug regimen was well tolerated and showed significant benefits after 48 weeks.

Once-daily nevirapine plus once-daily ddI and d4T has an easy dose schedule and is effective, according to François Raffi, MD, of the HIV Research Unit at CISIH in Nice, France. Forty treatment-naive people took the once-daily 400 mg dose of nevirapine and standard 400 mg dose of ddI once daily, with standard twice-daily dosing of d4T. They were compared with 60 similar treatment-naive people who took nevirapine 200 mg every 12 hours, with the same ddI and d4T dosing. The median baseline HIV RNA viral load was 4.7 log copies/mL, while the median CD4 cell count was 432 cells/mm³.

Results after one year showed that in the standard dose arm, 61% had an undetectable viral load based on an intent-to-treat analysis. CD4 cell count increased by 188 cells/mm³. In the experimental, once-daily nevirapine arm, 68% had an undetectable viral load, while the CD4 cell count increased by 152 cells/mm³. A non-life-threatening skin rash, a known nevirapine side effect, occurred in 24% of the 100 total participants. This led to discontinuation in one-third (8) of those 24 persons. Six percent discontinued due to hepatitis, 3% due to neuropathy, and 2% due to increased amylase (a pancreatic enzyme). The authors concluded that the once-daily nevirapine plus once-daily ddI arm with d4T displays "potent immunologic and antiviral effects, sustained over 12 months." The triple combination is also a very simple regimen.

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