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

April 1998 Table of Contents

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Advocacy

Ronald Baker, PhD

Glaxo Opens Broad Expanded Access Program for Abacavir (Ziagen)

On March 23, 1998, people who are not benefiting from their current combination anti-HIV therapy became eligible to receive the experimental drug abacavir (brand name Ziagen; formerly known as 1592) free from the manufacturer, Glaxo Wellcome. Physicians may call 1-800-501-4672 for instructions on how to enroll patients in the abacavir expanded access program.

Glaxo Wellcome and the Food and Drug Administration (FDA) have established broad inclusion criteria for the program, with no specific CD4 cell count or viral load requirements. This represents a dramatic departure from the entry criteria for most other expanded access programs initiated in the past. Community advocates have been lobbying for more flexible entry criteria as a means of assuring wider access to experimental drugs by individuals who need more effective and/or more tolerable therapies. Community advocates will continue to ask drug manufacturers to adopt broader eligibility requirements for their AIDS drug expanded access programs.

To qualify for the abacavir expanded access program, individuals must be on a failing regimen or unable to tolerate standard therapies. In addition, a physician must verify that the individual cannot construct a viable treatment regimen without abacavir. "Viable regimen" means a drug combination that offers a reasonable chance of successfully suppressing HIV.

When changing 3-drug regimens, U.S. government HIV treatment guidelines strongly urge people to switch to a regimen containing at least 2 new drugs that they have never before used. To facilitate access to new drugs, participants in the abacavir expanded access program will be directed to similar programs for the experimental anti-HIV drugs efavirenz (Sustiva) from Dupont Merck and adefovir dipivoxil (Preveon) from Gilead Sciences. Both of these drugs are also in Phase III testing for the treatment of HIV disease and are expected to receive accelerated approval from FDA before the end of 1998.

FDA is expected to consider Glaxo Wellcome's application for accelerated approval of abacavir sometime this summer. Abacavir is not only a potent inhibitor of HIV, but also penetrates the central nervous system and reaches the brain in high concentrations. Like AZT, d4T, ddI and 3TC, abacavir is a nucleoside analog drug, and it has a somewhat similar resistance profile. This suggests that abacavir likely will prove less beneficial for people who are resistant to other nucleoside analog drugs. In contrast, people who are nucleoside analog-naive or who have not used all other nucleoside analogs may experience substantial benefits from abacavir.

While abacavir may benefit many individuals currently without viable HIV treatment options, use of the drug is not without risk. Common adverse side effects include headache, nausea and vomiting. An estimated 2-5% of patients using abacavir develop a hypersensitivity (allergic) reaction that consists of fever, which may be accompanied by nausea (with or without vomiting), malaise and possibly a rash. These symptoms start several days to 6 weeks after beginning abacavir. Individuals who experience this reaction are advised never to take abacavir again. Restarting the drug after a hypersensitivity reaction has caused life-threatening reactions, and at least 1 person has died as a result.

Safety Alert Issued on Efavirenz (Sustiva)

On March 17, FDA received important new safety information from Dupont Merck, manufacturer of the experimental non- nucleoside reverse transcriptase inhibitor efavirenz (brand name Sustiva; formerly known as DMP-266). It appears that gross abnormalities occurred in 3 of 13 monkeys born to mothers treated with efavirez. Mary Luzar, chief of the Regulatory Affairs Section of FDA, added the following language to the informed consent section of all study protocols using efavirenz:

"Studies using DMP-266 [efavirenz] in pregnant monkeys have shown newborn monkeys with abnormalities at birth. Three out of 13 monkeys were born with birth defects. One monkey had a defect in the roof of the mouth (cleft palate), another had small eyes (microphthalmia), and another was born without a brain (anencephaly) and missing one eye (anophthalmia). The monkeys in this study received doses of DMP-266 similar to those that are being studied in humans. It is not known what this information means or whether this could happpen in humans; therefore, you SHOULD NOT become pregnant while taking DMP-266." Ongoing studies of efavirenz do not allow pregnant women to enroll nor to continue if pregnancy occurs while on a study.

Drugs on Expanded Access

Three experimental anti-HIV drugs are now available free to individuals without viable treatment options through expanded access programs operated by the drugs' manufacturers.

• For information on Glaxo Wellcome's abacavir (Ziagen), call 1-800-501-4672.
• For information on DuPont Merck's efavirenz (Sustiva), call 1-800-998-6854.
• For information on Gilead Science's adefovir dipivoxil (Preveon), call 1-800-GILEAD-5.

Short-Course AZT Reduces HIV Transmission to Infants; Glaxo Cuts AZT Price for Developing Countries

U.S. government researchers announced on February 18 that a short course (4 weeks) of AZT given late in pregnancy reduces the rate of HIV transmission to infants of infected mothers by 50%. The study was conducted by the U.S. Centers for Disease Control and Prevention (CDC) in collaboration with public health officials in Thailand. Many are praising the report because it offers hope that HIV positive, pregnant women in developing countries will have an effective therapy to prevent HIV infection of their newborns. Some critics had called the study unethical because half of the women received placebo pills.

On March 5, 1998, the manufacturer of AZT, Glaxo Wellcome, announced that the company would cut the drug's price by up to 75% to make it accessible in developing countries. With the price cut, a 4-week regimen of AZT costs about $80, and necessary diagnostic tests will add another $20 per person. The cost for medical care by a doctor would add still more to the total price for treatment and care. A longer course of AZT therapy constitutes the standard of care for the treatment of HIV positive, pregnant women in the U.S. The average cost for a year of therapy in the U.S. is $800-$1,000. This longer AZT regimen, which includes treating the newborn with AZT, reduces transmission of the virus to infants born to infected mothers in the U.S. by about 67%, compared to about 50% for the short course regimen given to the women in the Thai study.

Most commentators expressed optimism following reports of the study results and the AZT price cut by Glaxo Wellcome. Others remain skeptical, citing the statistic that most developing nations spend only $10 per individual per year for all their health care, according to The New York Times. The developed nations would need to contribute heavily to any program that hopes to significantly reduce the number of infants who are born HIV-infected each year worldwide through use of short course AZT therapy, even with a 75% price reduction for the drug. Every year about 550,000 infants worldwide are infected at birth, according to the United Nations Program on AIDS (UNAIDS).

Protease Inhibitor Drug Combinations

Several studies are examining the effectiveness of double protease inhibitor combinations with or without 1 or more nucleoside analogs. Different doses and dosing schedules are under study, including the following:

• 400 mg twice-daily ritonavir plus 400 mg twice-daily saquinavir (Invirase or Fortovase). Adding 1 or 2 nucleoside analogs to this double combination results in significant viral load decreases.
  
  
• 1000 mg twice-daily indinavir plus 1,250 mg twice-daily nelfinavir. Using 750 mg or 1,000 mg nelfinavir appears less effective than the higher dose.
  
  
• 800 mg 3-times-daily saquinavir (Fortovase) plus 750 mg 3-times-daily nelfinavir. Adding 2 nucleoside analogs to this double combination significantly increases CD4 cell counts and significantly decreases viral load.
  
  
• 1,000 mg twice-daily saquinavir (Invirase) plus 1,250 mg twice-daily nelfinavir plus 2 nucleoside analogs.
  
  
• 600 mg 3-times-daily saquinavir (Invirase) plus 750 mg 3-times-daily nelfinavir plus 2 nucleoside analogs. At 24 weeks, 80% of both treatment-na•ve and treatment-experienced patients achieved viral loads less than 400 copies/mL.
  
  
• 400 mg twice daily ritonavir plus either 500 mg or 750 mg twice daily nelfinavir. This regimen produces a high incidence of diarrhea (50%), but also potent anti-HIV effects.
  
  
• 800 mg 3 times daily amprenavir plus either 800 mg 3 times daily saquinavir (Fortovase) or 800 mg 3 times daily indinavir or 750 mg 3 times daily nelfinavir. Small, preliminary study results suggest that all 3 of these double combinations are well tolerated and produce significant viral load decreases. The usual dose of amprenavir is 1,200 mg twice daily.

Although there are sufficient data available to warrant safe use of twice-daily dosing of ritonavir/saquinavir, the data on twice-daily dosing of combinations using indinavir, saquinavir and nelfinavir are incomplete and preliminary. Further study results are necessary before twice-daily dosing of these drugs can be recommended for use outside of clinical trials. However, some physicians are already prescribing twice-daily dosing of these drugs for patients who cannot adhere to 3-times-daily dosing.

The 5th Conference on Retroviruses and Opportunistic Infections

About 3,400 researchers, clinicians and treatment advocates attended the 5th annual Conference on Retroviruses and Opportunistic Infections held in Chicago February 1-5, 1998. An article in this issue of BETA covers selected highlights from studies and posters presented at the Chicago meeting. The BETA LIVE! broadcast from Chicago on February 5, 1998 is available on taped playback by calling 800-550-9235. An edited transcript of the broadcast is available at this website. Below are some highlights from the conference.

HAART During Acute Infection

Starting highly active antiretroviral therapy (HAART) within 6 months of initial (acute) HIV infection may greatly benefit an individual's long-term immune response and produce a more favorable long-term outcome than if therapy is started later in the course of infection. Although much remains to be determined in the area of very early therapy for HIV infection, there are now data to support the notion that, if initiated during acute infection (even before antibodies to HIV are detected), continuous HAART may control HIV infection indefinitely.

No Eradication of HIV

Despite the ability of HAART to drive HIV below the levels of detection of available tests for over a year, the virus is not eradicated from the body. Several presenters in Chicago noted that even after treatment with maximally suppressive HAART, an important reservoir of latently-infected CD4 T-cells remains. These cells are not replicating, but they may begin replication at a later time. Several researchers suggested using interleukins (IL-2, IL-12) to stimulate the latently infected cells to replicate. HAART might be used afterwards to eliminate HIV from these cells. Chun calculated that it might take as long as 20 years to eradicate the virus from these reservoirs using this approach.

New Anti-HIV Therapies

Several new agents are approaching the final stages of study prior to marketing, while others are further back in the pipeline. New drugs likely to reach prescription status this year are the nucleoside analog abacavir (see above), the non-nucleoside reverse transcriptase inhibitor efavirenz (see above) and the nucleotide analog adefivir dipivoxil. Second generation protease inhibitors also received attention, including Glaxo Wellcome's amprenavir (141), Abbott's ABT-378 and others.

The double combination of abacavir with indinavir, ritonavir, saquinavir or amprenavir produces potent suppression of HIV and is well tolerated, according to John Mellors, MD. Efavirenz in combination with indinavir or with AZT/3TC also has a potent anti-HIV effect. Some individuals who are treatment-naive may choose to use efavirenz instead of a protease inhibitor in combination with 2 nucleoside analogs as first-line HAART, thereby reserving use of potent protease inhibitor therapy for later.

Hydroxyurea

Reports on the anti-cancer drug hydroxyurea in combination with ddI and d4T received much attention in Chicago, especially a report from France citing 2 patients whose viral loads failed to rebound 12 months after they stopped taking the 3-drug combination of hydroxyurea/ddI/d4T. Other studies show significantly reduced viral load in those on hydroxyurea therapy, but no CD4 cell increases. However, the triple combination of hydroxyurea/ddI/indinavir did lead to increases in CD4 cell counts.

Pre-Treated Individuals

People who have experienced extensive prior anti-HIV therapy face tough challenges in constructing viable new regimens. Because the available protease inhibitors (indinavir, ritonavir, saquinavir and nelfinavir) are cross-resistant, switching from one to another generally does not produce a decrease in HIV to significantly lower levels for a sustained period, even when the nucleoside analogs in a combination regimen are also changed. Some people have done well switching to an indinavir-containing regimen after first failing on nelfinavir plus 2 nucleoside analogs. Others have benefited from changing a 3-drug nelfinavir-containing regimen (after 55 weeks) to the double combination of ritonavir plus saquinavir. Others have benefited from adding the non-nucleoside reverse transcriptase inhibitor delavirdine to a failing indinavir-containing regimen. Perhaps the most common "rescue therapy" following failure on an initial protease inhibitor-containing regimen is use of the double combination of ritonavir/saquinavir. Not surprisingly, this double combination is more effective as an initial regimen than as salvage therapy.

It is important to note that, when switching to a new HAART regimen, the switch should occur as early as possible following a significant increase in viral load. The sooner the switch, the better the outcome with the new regimen. Also noteworthy is the fact that many people on HAART regimens have remained clinically stable thus far despite an increase in HIV viral load.

Viral Load Testing

Standard HIV viral load testing is critically important for monitoring the effects of therapy and for helping to determine the best time to initiate therapy. There is much less agreement about the utility of the the new "ultrasensitive" HIV viral load tests. The standard HIV viral load test has a limit of detection of 400 copies/mL (the Roche PCR test). An "undetectable" result on this assay means that the viral load is below 400 copies/mL. The standard PCR test cannot measure below this threshold. However, new, more sensitive versions of the test can measure HIV viral load as low as 50 copies/mL. The lower the viral load, the better, but how to best use the ultrasensitive tests to guide treatment decisions is uncertain. The clinical significance of driving the viral load from below 400 copies/mL to below 50 copies/mL is not completely understood. In addition, the ultrasensitive PCR tests are expensive and usually not yet reimbursable by third party payers.

Resistance Tests

The results of phenotypic and genotypic testing are not particularly helpful to most HIV patients in guiding treatment decisions. In the future, these tests may become more useful, but for now, most clinicians regard them as expensive, experimental tests that are not yet ready for widespread clinical use.

Unusual Side Effects of Treatment with Protease Inhibitors

Long-term use (greater than 10 months) of any of the 4 available protease inhibitors has been associated with abnormal deposits of fat in the body, particularly in the abdominal area and below the cervical spine. Termed "protease paunch" and "buffalo hump," respectively, these abnormalities do not necessarily resolve when patients switch to a different protease inhibitor regimen. Researchers do not know what causes these effects. A task force has been established to further examine the origin of these effects, and how to manage and prevent them.

Page last updated 5 May 1998