PROVIDING HIV/AIDS CARE IN A CHANGING ENVIRONMENT — FEBRUARY 2003
Since the introduction of antiretroviral therapy, 16 discrete compounds have been approved by the Food and Drug Administration (FDA) and are available in a variety of formulations. More new drugs are expected soon. Some will work similarly to those available today but will offer new benefits, such as simpler dosing requirements, greater potency, and fewer side effects. Others will work in new ways and offer renewed hope to those for whom the current reservoir of treatment options is nearing depletion.
For example, Viread, the most recently approved antiretroviral agent, helps meet what Timothy Price, M.D., a Washington, DC, physician who is board certified in both internal medicine and infectious disease, identifies as the relatively new goal of completely suppressing “the virus to achieve undetectable levels.” Price, who treats many people living with HIV disease, has seen that “any detectable level of virus [while on drug treatment] is likely to lead to viral resistance.”
Viread represents a new class of drugs, the nucleotide analogue reverse transcriptase inhibitors, although it works similarly to an older class, the nucleoside reverse transcriptase inhibitors. Studies have shown that it is capable of reducing viral load to undetectable levels, especially among people with already low levels of detectable virus.1 No medication is free of side effects, but Viread appears to have a relatively favorable toxicity profile.
In his practice, Dr. Price has found that Viread is valuable both for patients who never have been treated and for those who have treatment experience because it has a “unique resistance pattern” and “minimal side effects.” It is especially useful because it is taken as one pill daily, whereas some antiretrovirals require more than a dozen pills each day.
Larry D’Angelo, M.D., who heads the adolescent medicine department at Children’s Hospital in Washington, DC, underlines the importance of minimal dosing requirements. Clinicians at the department’s Burgess Clinic, which treats nearly 150 teens with HIV and receives funds through the Ryan White Comprehensive AIDS Resources Emergency (CARE) Act, try to prescribe extended release Videx, Viread and Kaletra, each of which may be taken only once or twice a day.
Ongoing research is soon likely to yield a new class of effective drugs: fusion inhibitors. Sometimes called entry inhibitors, these agents block the virus from fusing with the membrane found on the outside of the human cell. If HIV cannot fuse with the cellular membrane, it cannot enter the cell, continue its cycle of replication, and spread throughout the body. Fusion inhibitors are the first class of drugs that attack HIV before it enters the cell.
Although the National Institutes of Health (NIH) has catalogued several potentially effective fusion inhibitors, the first likely to be available on the market is called T-20, or Fuzeon. The FDA has granted priority-review status for T-20, and a decision concerning its approval should be made by the spring of this year.
When a human cell is approached and signaled by HIV, a protein on the cell membrane surface called gp41 changes its shape, something cell biologists call a conformational change. Without that change, the virus cannot fuse with the membrane. Fuzeon is believed to work by inhibiting the gp41 protein from changing its shape, thereby preventing HIV from gaining access to the cell.2
Generally, it is much more difficult to lower the viral load and increase the number of CD4 cells in people who have already been on antiretroviral drugs than to do so in those who are “treatment naive.”
The FDA application concerning Fuzeon is based on the results of two 24-week international clinical studies among adults with HIV disease who had previously been on combination therapy but still had detectable viral loads. The data showed that patients taking Fuzeon as part of combination antiretroviral therapy had a significantly larger drop in viral load and a greater improvement in their immune function, as represented by an increase in their CD4 cell count, than did those whose therapy did not include Fuzeon.3 That the volunteers had been on combination therapy prior to the study is encouraging because, generally, it is much more difficult to lower the viral load and increase the number of CD4 cells in people who have already been on antiretroviral drugs than to do so in those who are “treatment naive.”4 In addition to the studies with adults, a small clinical trial looked at the effects of Fuzeon in HIV-infected children ages 4 to 12 who had detectable virus in their bloodstream. The study found that the drug was well tolerated and associated with viral suppression.5
Two of Dr. Price’s patients have tried Fuzeon regimens. Prior to treatment with the experimental therapy, both patients had virus that had become resistant to multiple antiretroviral drugs as well as CD4 immune cell counts below 50 and viral load levels well above 100,000, suggesting that their treatment regimens were failing. According to Dr. Price, both patients experienced a “dramatic drop” in viral load to undetectable levels within a few weeks of starting Fuzeon. Nevertheless, both patients rebounded to detectable levels of virus, even with continued use of the drug. From this experience, Dr. Price believes that Fuzeon “probably is an excellent drug, but there is a problem adding only one drug to a failing regimen. Patients need combination therapy with more than one active drug,” he says.
Once Fuzeon is approved, demand for it may exceed the supply. A press release issued late last year by Trimeris and Hoffmann-La Roche, the drug’s producers, called Fuzeon “one of the most complex and challenging molecules ever chemically manufactured on a large scale by the pharmaceutical industry.”6 The companies already have begun producing the drug in anticipation of FDA approval and expect to have enough to treat 12,000 – 15,000 people by the end of 2003 and up to 39,000 in 2005.
Because demand for Fuzeon is expected to exceed supply, at least initially, Roche and Trimeris will manage its allocation. The companies are working with HIV physician and patient groups to develop an allocation plan, which has yet to be announced.
Information on another fusion inhibitor, T-1249, was presented at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy in September 2002. Although only Phase I and Phase II trials* have been conducted so far, the data seem to show that T-1249 may be effective against virus mutations that are resistant to Fuzeon.7
One important difference between Fuzeon and T-1249 and other antiretroviral medications is that the fusion inhibitors cannot be given orally. Fuzeon and T-1249 are peptides, or short proteins. If taken orally, they would be degraded by the acid and other chemicals in the stomach and intestines, as are other proteins. In clinical trials, the fusion inhibitors have been self-administered by injection or administered by a parent or other caregiver, and it is expected that they would be administered by injection if approved for market. Although local reactions at the injection site have occurred, a manufacturers’ survey of people using Fuzeon found that most people were able to give themselves the medications easily and that the injections did not have a significant negative impact on patients’ daily lives.8 The study also indicated that the vast majority of study volunteers would choose to continue the drug if they needed it.
Several other classes of potential drugs are under investigation, including virucidal agents, immune modulators, and inhibitors of various HIV proteins.9 In fact, scores of compounds, representing both traditional and new approaches to HIV eradication, are in various stages of testing through the NIH.10 The following drugs show promise and may be among the next to be approved:
The excitement over potential new therapeutic options is tempered by concerns about whether high prices will keep them out of reach for many people, even in wealthy countries like the United States. Fuzeon, specifically, is of concern because it is produced through a complicated and expensive manufacturing process.15 Although its price has not yet been announced, speculation has been that the drug will cost patients $10,000 to $15,000 per year, much more than any AIDS drug now on the market and equal to the cost of an entire multidrug antiretroviral regimen today.16
Many of Dr. Price’s patients have health insurance with prescription coverage, and the AIDS Drug Assistance Program (ADAP) and other programs in Washington, DC, are relatively generous, so most of his patients with HIV have been able to afford the drugs he prescribes. Price worries about patients without access to one of those programs, however, because a month’s supply of drugs already may cost $2,500, a high price for most middle-class patients and out of reach for those who are poor. Most of Dr. D’Angelo’s patients are covered by Medicaid. Even so, all of the ADAP funds allocated to Dr. D’Angelo’s clinic were exhausted 3 months before the new funding cycle began.
Many people with AIDS around the Nation have difficulty obtaining the medications they need because of restricted access to drugs. Even without the introduction of new drugs, the pressures on ADAP have grown as the cost of antiretroviral medications has increased.17 The demand for funds also is rising because the drugs have resulted in decreased mortality; thus, people receive ADAP benefits for longer periods of time than in the past. Finally, as the disease has spread, it has affected more and more Americans without health insurance, adding to the number who seek support.
Last year, at least 12 States exhausted their ADAP funds well before the end of the fiscal year.18 As a result, those States established waiting lists or expenditure caps or otherwise restricted patient access. Other States routinely limit their programs by restricting their formularies, establishing income ceilings, or imposing a variety of other criteria that restrict the number of clients who are eligible for the program.19
“We are seeing a number of them develop ‘medication fatigue’—they are just tired of taking drugs.”
—Larry D’Angelo, M.D.
Children’s Hospital
Washington, DC
In addition to the pressures on public programs, some private insurers have made moves to reduce their costs by cutting back on prescription drug benefits. In California, for example, one HMO tried to limit some policy holders to $500 per year for prescription coverage, much less than the cost of even one month’s supply of drugs for most people with HIV/AIDS.20 The move was rejected by the State’s department of managed care, which has the authority to regulate prescription benefits in some cases. However, the incident reflects skyrocketing cost pressures felt by all payers, both public and private, and no simple solution exists.
The greatest difficulty for his patients, Dr. Price says, is “balancing the efficacies of the medications with their toxicities.” He notes that it is daunting for patients who are 20 or 30 years old—and who could live to age 80—to face 50 or 60 years of complicated therapy with toxic drugs. Faithful adherence to a medical regimen is critical—”the most important factor in how a person does in the long run,” says Price—and must be maintained at greater than 95 percent, day in and day out, even though the medications may produce dangerous and uncomfortable side effects.
Dr. D’Angelo has a similar perspective, saying that “adherence, adherence, adherence” is the most serious challenge his teen patients face. “We are seeing a number of them develop ‘medication fatigue’—they are just tired of taking drugs,” he says. Despite close monitoring, two or three patients die each year “because they are unwilling or unable to take their medications,” he adds. In hopes of keeping its patients healthy, the clinic is participating in a Centers for Disease Control and Prevention (CDC) research project to study the effectiveness of a support group program to improve adherence and reduce high-risk behavior among HIV- positive adolescents.
The excitement over potential new therapeutic options is tempered by concerns about whether high prices will keep them out of reach.
The science of AIDS is changing quickly. New drugs that offer hope to people with HIV soon will be on the market. At the same time, however, the drugs will present many challenges. For scientists and clinicians, the question will be how to use the drugs most effectively. For people with HIV disease, the problem of adherence will not go away. For the Nation, the challenge will be how to pay for the drugs and how to bring treatment to those facing daunting barriers to care. All of us—scientists and clinicians, people with HIV and their allies, and ordinary citizens—must work together to confront these issues if we are to keep the epidemic in check and avoid a resurgence of AIDS morbidity and mortality.
—Eric Rosenthal, M.D.
* Phase I trials are the first tests of a new drug in humans; they take place after laboratory and animal data suggest efficacy and generally include just a few dozen healthy subjects, rather than people with the disease under investigation. The objectives are to determine the safety and tolerability of the drug at various doses, understand how the body processes it and, if possible, collect preliminary data on the drug’s potential usefulness. Phase II trials include a larger number of subjects, this time patients with the disease, and study dosing and toxicity to determine the optimal regimen to assess in Phase III trials. Phase III trials evaluate the safety and effectiveness of the drug in the intended population. They generally involve several hundred to several thousand patients in multiple settings. Data from the trials serve as the basis for a drug approval application to the FDA. Finally, Phase IV studies are conducted after the drug has been approved and marketed in order to optimize its use. They study, for example, interactions with other drugs or long-term drug safety.
Source: U.S Food and Drug Administration. General considerations for clinical trials. Federal Register. 1997;62(242):6613-6619. Available at: http://www.fda.gov/cder/guidance/1857fnl.pdf. (PDF 68KB) Accessed January 14, 2003. [back]
| Brand Name | Generic Name | Class | FDA Approval Date |
|---|---|---|---|
| Retrovir | zidovudine, AZT | nucleoside reverse transcriptase inhibitor | March 1987 |
| Videx | didanosine, ddI | nucleoside reverse transcriptase inhibitor | October 1991 |
| Hivid | zalcitabine, ddC | nucleoside reverse transcriptase inhibitor | June 1992 |
| Zerit | stavudine, d4T | nucleoside reverse transcriptase inhibitor | June 1994 |
| Epivir | lamivudine, 3TC | nucleoside reverse transcriptase inhibitor | November 1995 |
| Invirase | saquinavir | protease inhibitor | December 1995 |
| Norvir | ritonavir | protease inhibitor | March 1996 |
| Crixivan | indinavir | protease inhibitor | March 1996 |
| Viramune | nevirapine | non-nucleoside reverse transcriptase inhibitor | June 1996 |
| Viracept | nelfinavir | protease inhibitor | March 1997 |
| Rescriptor | delavirdine | non-nucleoside reverse transcriptase inhibitor | April 1997 |
| Combivir | zidovudine and lamivudine | non-nucleoside reverse transcriptase inhibitor | September 1997 |
| Fortovase (soft gelatin capsule) | saquinavir | protease inhibitor | November 1997 |
| Sustiva | efavirenz | non-nucleoside reverse transcriptase inhibitor | September 1998 |
| Ziagen | abacavir | nucleoside reverse transcriptase inhibitor | December 1998 |
| Agenerase | amprenavir | protease inhibitor | April 1999 |
| Norvir (soft gelatin capsule) | ritonavir | protease inhibitor | June 1999 |
| Videx EC (enteric coated capsule) | didanosine | nucleoside reverse transcriptase inhibitor | October 2000 |
| Kaletra | lopinavir and ritonavir | protease inhibitor | September 2000 |
| Trizivir | abacavir, zidovudine, and lamivudine | nucleoside reverse transcriptase inhibitor | November 2000 |
| Viread | tenofovir disoproxil fumarate | nucleotide analogue reverse transcriptase inhibitor | October 2001 |
| Source: U.S. Food and Drug Administration Web site (http://www.fda.gov/oashi/aids/virals.html). |
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Note: Restrictions on ADAP programs are fluid and vary from month to month. Source: Aldridge C, et al. National ADAP Monitoring Project Annual Report. Menlo Park, CA: Henry J. Kaiser Family Foundation; 2002. p. 11. Available at: http://www.atdn.org/access/adap/adap2002.pdf. (PDF 1.6MB)
Data-reporting packages for submitting 2002 CARE Act Data Report (CADR) data have been mailed to all CARE Act grantees of record. Grantees who have not received their package should call the technical assistance helpline at (888) 640-9356, ext. 206, to request one. The package contains the final version of the CADR form and instructions, which can also be downloaded from the HAB Web site. Note: Grantees who downloaded a CADR form and instructions prior to December 18, 2002, received a version that differs slightly from the final one. The final version, which is now on the HAB Web site, should be used for reporting purposes this year. To download forms, go to http://hab.hrsa.gov/tools/data/datareporting.htm.
In addition, HAB is encouraging all grantees to submit their CADR reports online this year. The online data entry version of the CADR will be available as of January 22, 2003, on the HAB Web site. For technical help in accessing the online CADR, please call the HRSA Call Center at (877) GO4-HRSA. To enter data online, go to http://hab.hrsa.gov/performance.
Step 1 The HIV virus enters a human body.
Step 2 Virus circulates in the bloodstream.
Step 3 HIV fuses with a human cell.
Step 4 HIV infects the cell by injecting its contents, including its genetic code (RNA), into the cell.
Step 5 The HIV RNA is used as a template, assisted by the virus’ reverse transcriptase enzyme, to manufacture viral DNA.
Step 6 The newly created HIV DNA is incorporated into the human DNA by the integrase enzyme.
Step 7 When the infected human cell reproduces, it activates the HIV DNA (now part of the human cell DNA), which makes the raw material for new HIV virus copies that can spread the infection throughout the body.
Step 8 The raw ingredients for new virus copies, including proteins and RNA, come together, re-form themselves, and push out of the infected cell in a process called “budding.”
Step 9 The immature virus breaks free of the infected cell.
Step 10 The new virus matures: Raw materials are cut by the protease enzyme and assembled into a functioning virus.
Step 11 The process repeats.
Researchers approach HIV drug development according to the current understanding of the virus’ life cycle. Each step along the way provides an opportunity to combat the virus.21 One of the foundations of combination therapy—taking more than one antiretroviral drug—is that the virus is more vulnerable if it is attacked in multiple ways and at multiple points.
The drugs used to suppress the virus are grouped according to their mechanism of action; each class of drugs is designed to attack HIV at a specific critical point in its lifecycle. The currently available classes are nucleoside analog reverse transcriptase inhibitors; non-nucleoside reverse transcriptase inhibitors; protease inhibitors; and the newest class, nucleotide analogue reverse transcriptase inhibitors. The reverse transcriptase inhibitors affect the manufacture of viral DNA (Step 5) by hindering the reverse transcriptase enzyme. Protease inhibitors affect the assembly of proteins on their way to becoming new virus copies (Step 8) by interfering with the protease enzyme.
1Peiperl L. Probability and durability of achieving <50 copies/mL of HIV RNA by treatment intensification with tenofovir. HIV InSite’s Coverage of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Accessed January 9, 2003.
2Database for anti-HIV compounds. National Institute of Allergy and Infectious Diseases Web site. Available at: http://www.niaid.nih.gov/daids/dtpdb/clasdrug.htm. Accessed January 9, 2003.
3Stephenson J. At international HIV/AIDS conference, daunting challenges mixed with hope. JAMA. 2002;288(6):683-5.
4Palella FJ, Chmiel JS, Moorman AC, et al. Durability and predictors of success of highly active antiretroviral therapy for ambulatory HIV-infected patients. AIDS. 2002;16(12):1617-26.
5Church JA, Cunningham C, Hughes M. Safety and antiretroviral activity of chronic subcutaneous administration of T-20 in human immunodeficiency virus1-infected children. Pediatr Infect Dis J. 2002;21(7):653-9.
6Trimeris. Update on the Manufacture of Investigational HIV Drug Fuzeon [press release]. December 18, 2002. Available at: http://www.trimeris.com/, Accessed January 14, 2003.
7O’Brian WA. The continuing promise of fusion inhibitors: more data on T-20 and T-1249. Medscape Report on the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. Available at: http://www.medscape.com/viewarticle/442225. Accessed January 9, 2003.
8Cohen CJ, Dusek A, Green J, et al. Long-term treatment with subcutaneous T-20, a fusion inhibitor, in HIV-infected patients: patient satisfaction and impact on activities of daily living. AIDS Patient Care STDs. 2002;16(7):327-35.
9For information about many of these compounds, see the National Institute of Allergy and Infectious Diseases; database for anti-HIV compounds, available at: http://www.niaid.nih.gov/daids/dtpdb/clasdrug.htm.
10Additional information on clinical trials may be found at http://clinicaltrials.gov and http://www.niaid.nih.gov/daids/therapeutics/geninfo/niaidres.htm.
11Gallant JE. New drugs in clinical development and treatment of naïve patients. Hopkins AIDS Report [serial online]. 2002a;14(2):10-2. Accessed January 9, 2003.
12Gallant JE. Report from ICAAC: new drugs and antiretroviral therapy for treatment naïve patients. Hopkins AIDS Report [serial online]. 2002b;14(6):1-3,7. Available at: http://hopkins-aids.edu/. Accessed January 9, 2003.
13Gallant 2002a.
14Cheonis N. The HIV/AIDS drug pipeline: a status report. The Body [serial online]. Summer/autumn 2002. Available at: http://www.thebody.com/sfaf/summer02/ aids_drugs.html. Accessed January 9, 2003.
15Krauss K. Thousands face loss of treatment in ADAP money crisis. AIDS Treatment News. June 28, 2002.
16Excitement over pending approval of novel AIDS drug Fuzeon (T-20) tempered by worries over cost. August 23, 2002. Available at: http://www.hivandhepatitis.com/recent/resistance/ 082302a.html.
17For more information on the ADAP program, see the Health Resources and Services Administration HIV/AIDS Bureau Web site at http://hab.hrsa.gov/programs/factsheets/ adap1.htm.
18Krauss 2002.
19AIDS Treatment Data Network, Henry J. Kaiser Family Foundation, and National Alliance of State and Territorial AIDS Directors. National ADAP Monitoring Project Annual Report. Washington, DC: authors; April 2002. Available at: http://www.atdn.org/access/adap/.
20Ornstein C. Kaiser’s bid for $500 cap on drug coverage rejected. Los Angeles Times. October 11, 2002.
21See the Johns Hopkins HIV Service Web site for a useful animation depicting the HIV life cycle and associated drug targets . The National Institute of Allergy and Infectious Diseases provides a detailed description of the HIV life cycle at http://www.niaid.nih.gov/daids/dtpdb/virpage1.htm.
In this Issue
Publisher
U.S. Department of Health and
Human Services
Health Resources and Services
Administration
HIV/AIDS Bureau
Editor
Richard Seaton
Impact Marketing and
Communications
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