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 Drugs Combinations
• Opportunistic Infections
• Miscellaneous

April 1998 Table of Contents

Main Page

beta@sfaf.org

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

New Anti-HIV Drugs

Harvey S. Bartnof, MD

Abacavir

Fifteen abstracts included information regarding abacavir (brand name Ziagen, formerly known as 1592), the new twice-daily reverse transcriptase inhibitor from Glaxo Wellcome.

• Severe allergy to abacavir may be life-threatening if drug is re-started
• Abacavir has very good brain and cerebrospinal fluid (CSF) penetration
• 71% of HIV strains that are resistant to both AZT and 3TC are still sensitive to abacavir
• Abacavir plus current therapy is effective up to 48 weeks in an open-label study
• Abacavir plus a protease inhibitor shows benefits up to 16 weeks
• Abacavir in a 4-drug cocktail shows benefits up to 17 weeks
• Abacavir plus AZT plus 3TC demonstrate synergism (enhanced activity) against AZT-sensitive and AZT-resistant HIV strains

John Mellors, MD, from the University of Pittsburgh, presented 16-week, interim data of dual combination therapy using abacavir (300 mg twice daily) with one of 5 protease inhibitors in an open label trial. A total of 78 patients were enrolled, including 15 women. All had no prior HIV therapy, a baseline HIV viral load greater than 5,000 copies/mL and a CD4 cell count greater than 100 cells/mm³. The median baseline CD4 cell count was 349 cells/mm³, while the viral load was 4.7 log copies/mL.

After 4 months, HIV viral load became undetectable (limit of detection 400 copies/mL) in 54-85% of participants, a non-significant difference. The highest levels of undetectability occurred in the 2 arms that combined abacavir with either ritonavir (Norvir), nelfinavir (Viracept) or amprenavir, the experimental protease inhibitor from Glaxo Wellcome. From 50-70% of the participants in the 5 arms reached undetectability using a test with a limit of detection of 40 copies/mL. Viral load reductions ranged from 1.6 log copies/mL to 2.5 log copies/mL in the 5 arms, a non-significant difference. The study will continue for a total of 48 weeks.

Mellors described a specific, life-threatening allergic reaction that occurred when some patients restarted the medication after stopping it. The abacavir hypersensitivity reaction is defined as presumptive if fever occurs in addition to nausea, vomiting, malaise and/or rash. The hypersensitivity reaction is considered definite if all 5 symptoms occur. Thus far, the reaction has occurred within 3-42 days (median 9 days) after starting abacavir. Symptoms reportedly resolve within 1-2 days after abacavir is stopped. The rash is usually on the trunk and may be itchy. The incidence of abacavir-related hypersensitivity reaction is 3-5%. Note that a rash alone, without the other symptoms, does not constitute the abacavir hypersensitivity reaction.

If a presumptive or definite hypersensitivity reaction to abacavir has occurred, restarting the drug may be life-threatening. One HIV/AIDS patient in France died after restarting the drug following the resolution of initial abacavir-related allergic symptoms. It was reported that 4 patients required intensive care unit hospitalization after restarting abacavir.

Other reported side effects due to abacavir include nausea, headache, weakness, vomiting, diarrhea, insomnia and dizziness. As of January 1998, over 3,200 people with HIV/AIDS have taken abacavir in combination regimens. Approximately 1,800 of these were using open-label therapy. Glaxo Wellcome anticipates filing a New Drug Application for abacavir no later than June 1998. Expanded access for abacavir began on March 23, 1998. For further information, physicians may call 800-501-4672.

Data were also presented from a Phase II trial of 25 patients who were prescribed a 4-drug, twice-daily regimen of abacavir, amprenavir, AZT and 3TC. This combines 3 nucleoside analog reverse transcriptase inhibitors plus a protease inhibitor; all 4 drugs are manufactured by Glaxo Wellcome. Thirteen patients were antiretroviral drug-naive and HIV positive for less than 3 months, while the other 12 were chronically HIV-infected and had not previously taken 3TC or protease inhibitors. Baseline HIV viral loads were 192,000 copies/mL (in the newly HIV positive participants) and 57,000 copies/mL (in the chronic HIV positive participants). Baseline CD4 cell counts were 560 cells/mm³ and 343 cells/mm³, respectively.

After a mean of 17 weeks on study, interim results are as follows. The mean reduction in viral load after 8 weeks was 2.6 (newly infected) and 2.3 (chronic) log copies/mL. Viral load was undetectable in 70% (limit of detection 100 copies/mL). After 12 weeks, the mean CD4 cell count increases in the 2 groups were 172 and 126 cells/mm³, respectively.

The percentage of participants who left the study prematurely was 8% in the newly infected arm and 17% in the chronic arm, due to adverse events including nausea, vomiting and fatigue. A mild or moderate rash occurred in 38% of newly infected and 17% of chronic participants. Although the study is ongoing, the authors concluded that the 4-drug, twice-daily regimen is safe, well tolerated and leads to potent suppression of HIV viral load and increased CD4 cell counts in both newly infected and chronically infected participants.

A poster presentation from the University of Amsterdam described a 5-drug combination regimen that included abacavir, indinavir (Crixivan), nevirapine (Viramune), AZT and 3TC. The interim follow-up was 12 weeks for 9 HIV positive patients, including 8 who were naive to all HIV therapies. Starting from a median baseline HIV viral load of 4.9 log copies/mL, all 9 patients achieved undetectable viral load (limit of detection 1.7 log copies/mL) after only 4 weeks.

Tremblay C and others. 1592U89 as a component of 2- and 3-drug regimens against zidovudine-sensitive and zidovudine-resistant HIV isolates in vitro. CROI. Abstract 632.

Efavirenz

There were several presentations on efavirenz (brand name Sustiva, also known as DMP-266), the once daily, non-nucleoside reverse transcriptase inhibitor from Dupont Merck.

• 89% taking efavirenz plus indinavir had undetectable viral load after 60 weeks
• 100% taking efavirenz plus AZT plus 3TC had undetectable viral load after 24 weeks
• Efavirenz can be taken safely with birth control pills (ethinyl estradiol)
• Efavirenz can be taken safely with azithromycin (Zithromax); clarithromycin (Biaxin) should be avoided
• Efavirenz combined with nelfinavir does not require dose adjustments
• Efavirenz combined with amprenavir (141) decreases amprenavir concentration ("area under the curve") by 36%

Several clinical trials using efavirenz in combination therapy were presented. The first was trial DMP 266-005, a double-blind, placebo-controlled trial of 137 asymptomatic HIV positive participants (13% women). None had previously taken antiretroviral therapy. Participants were randomized to take AZT and 3TC plus either placebo, or efavirenz at a dose of 200 mg, 400 mg or 600 mg daily. After 16 weeks, the 33 patients randomized to placebo added efavirenz plus indinavir to their therapy of AZT plus 3TC. Baseline HIV viral load was 4.7 log copies/mL and baseline CD4 cell count was 329-395 cells/mm³.

After 24 weeks, HIV viral load was undetectable (limit of detection 400 copies/mL) in 96% of the 200 mg arm, 91% of the 400 mg arm, 100% of the 600 mg arm and 65% of the placebo/delayed therapy arm. At 16 weeks viral load was undetectable (limit of detection 40 copies) in 83%, 68%, 67% and 15%, respectively. Only a handful of patients had ultrasensitive viral load test results at 24 weeks. CD4 cell counts were increased in all groups after 24 weeks, with the 2 highest efavirenz dose arms achieving increases of approximately 175 cells/mm³. The lowest efavirenz dose arm had an increase of 105 cells/mm³, while the placebo/delayed therapy arm had an increase of only 90 cells/mm³.

Side effects were similar in all 4 arms for the first 16 weeks. Headache and dizziness were statistically more frequent the 3 efavirenz-containing arms compared to the placebo/delayed treatment arm. After 24 weeks, 18% of participants in the highest dose efavirenz arm discontinued due to adverse events, compared with 0-6% in the other arms. The results were statistically significant. Adverse events included rash, dizziness, anemia, pain and elevated liver function tests.

The results of this small study indicate that the most effective dose of efavirenz (600 mg), used in combination with AZT plus 3TC, is also associated with the highest rate of adverse events leading to discontinuation. There is a suggestion that a lower dose of 400 mg may be almost as effective without the high discontinuation rate.

A 60-week update of trial DMP 266-003 was also presented. The study was a randomized pilot study of 101 asymptomatic or mildly symptomatic HIV positive participants (14% women). Prior nucleoside analog therapy had been taken by 71% of enrollees. In the study, efavirenz dose was escalated to 600 mg daily and was combined with indinavir (800 or 1,000 mg) taken 3 times daily. The placebo arm was started on indinavir and, after 12 weeks, added efavirenz and d4T. The mean baseline HIV viral load was 5 log copies/mL. The mean CD4 cell count was 283 cells/mm³.

After 60 weeks, viral load was undetectable (limit of detection 400 copies/mL) in 89% of participants in the efavirenz arm and 68% of participant in the placebo/delayed therapy arm. Using an ultrasensitive test (calculated at less than 1 copy/mL) undetectable viral load was achieved in 81% and 68%, respectively. Viral load reductions were 2.5 and 1.9 log copies/mL, respectively, and CD4 cell count increases were 267 and 210 cells/mm³, respectively.

Approximately 20% of participants in each arm discontinued the study early, with 5% in each arm discontinuing due to adverse events. Rash was common, occurring in approximately 32% of each arm. One person in the efavirnez plus indinavir group stopped treatment due to rash.

In each arm, the time to viral load rebound was significantly longer for participants who achieved a viral load of less that 1 copy/mL than for those who only achieved a viral load of less than 400 copies/mL. The study results confirm the potency of efavirenz taken in combination with indinavir. For more information regarding expanded access to efavirenz, call 800-998-6854.

Piscitelli S and others. Effect of efavirenz (DMP 266) on the pharmacokinetics of 141W94 (amprenavir) in HIV-infected patients. Abstract 346.

Amprenavir

• Amprenavir (141) in combination with a protease inhibitor shows benefits
• Amprenavir triple combination with AZT plus 3TC shows benefits
• Amprenavir resistance is associated with a mutation at codon 150, different from other protease inhibitor mutations
• Amprenavir should not be taken with rifampin; rifabutin dose should be reduced if taken with amprenavir
• Side effects include headache, rash, nausea, vomiting, diarrhea and tingling around the mouth
• Amprenavir concentration ("area under the curve") is reduced by 36% when taken with efavirenz

Several presentations focused on the new protease inhibitor amprenavir from Glaxo Wellcome and Vertex Pharmaceuticals. Amprenavir has the advantage of twice daily dosing without specific food requirements. A New Drug Application (NDA) filing with FDA is expected by September 1998.

Joseph Eron, MD, from the University of North Carolina, presented 16 week interim data of double combination therapy using amprenavir with 1 of 3 other protease inhibitors. This was a randomized, open-label Phase I/II study. A total of 34 participants were enrolled (24% women). All were protease inhibitor- naive, and most had used nucleoside analog therapy within the prior 6 months. This study used a amprenavir dosage of 800 mg every 8 hours, rather than the standard dosage of 1,200 mg twice daily, to allow for the simultaneous administration of a second protease inhibitor. The other protease inhibitors used were soft-gel saquinavir (Fortovase) at 800 mg, indinavir at 800 mg or nelfinavir at 750 mg. The fourth arm was amprenavir monotherapy for 3 weeks, at which time standard doses of AZT plus 3TC were added. Baseline median HIV viral load was 4.6 log copies/mL and baseline CD4 cell count was 393 cells/mm³.

The 16 week data showed significant viral load reductions: 1.8 log copies/mL for amprenavir/nelfinavir, 2.8 log copies/mL for amprenavir/AZT/3TC, 2.9 for amprenvir/saquinavir and 3.8 for amprenavir/indinavir. The percentages of participants with undetectable viral load (limit of detection 400 copies/mL) were 50%, 66%, 100% and 80%, respectively. Using a test with a limit of detection of 20 copies/mL, the percentages of participants with undetectable viral load were 50%, 66%, 40% and 66%, respectively. CD4 cell counts increased in all groups.

The time interval of this study was rather short and the total number of participants was rather small. Yet the preliminary evidence showed that amprenavir combined with another protease inhibitor demonstrated anti-HIV efficacy, as did amprenavir combined with AZT plus 3TC. This study is ongoing.

Polk RE and others. Pharmacokinetic (PK) interaction between 141W94 (amprenavir) and rifabutin and rifampin after multiple dose administration. CROI. Abstract and poster presentation 340.

PMPA Prodrug

In a Phase I/II study of 36 patients, bis-poc PMPA, a once daily oral PMPA prodrug, showed benefits after 4 weeks. Viral load reduction was 1.2 log copies/mL at a dose of 300 mg. Side effects included reversible increased levels of creatinine phosphokinase (CPK), a muscle enzyme, and increased liver enzyme levels. The bioavailability of the drug increases when it is taken with food. The drug is a nucleotide analog. Resistance is associated with the K65R mutation. HIV strains that are resistant to multiple nucleoside analog drugs (Q151M mutation) retain sensitivity to PMPA. Future studies of bis-poc PMPA in combination regimes are planned.

Wainberg MA and others. The M184V substitution in reverse transcriptase increases sensitivity of both HIV-1 and SIV to PMPA. CROI. Abstract and poster presentation 680.

Adefovir Dipivoxil

• HIV resistance to 3TC led to increased sensitivity to adefovir dipivoxil (Preveon)

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