Macs and Actg Studies Advance Understanding and Clinical Use of HIV Prognostic Markers
In two of the most definitive studies of prognostic markers for HIV disease published to date, investigators supported by the National Institute of Allergy and Infectious Diseases (NIAID) have found that combining HIV RNA measurements with CD4+ T cell counts provides the most accurate prediction of disease progression in HIV-infected individuals.
FDA has approved 33 products to treat HIV/AIDS. Eleven drugs are to treat HIV infection and 22 are to treat HIV/AIDS-related illnesses:
Zidovudine (AZT) (Retrovir/Glaxo Wellcome) approved March, 1987 for the treatment of AIDS. Approved September 1989, in syrup formulation. Approved February 1990, in intravenous dosage form. Dosage/indication labeling revisions: decreased recommended dose (January 1990), added indication for use in early symptomatic HIV disease and in asymptomatic HIV infection where there is evidence of impaired immunity(March 1990), added indication for use in children 3 months to 12 years (May 1990), added indication for use in preventing transmission of HIV from HIV-infected pregnant women to their babies (August 1994)
Human Interferon alpha (Intron A/Schering-Plough and Roferon-A/Hoffmann-La Roche) licensed November 1988, for the treatment of Kaposi's sarcoma.
Aerosolized pentamidine (NebuPent/Fujisawa) approved June 1989, for the prevention of Pneumocystis carinii pneumonia in immunocompromised patients.
Ganciclovir (intravenous)(Cytovene/Syntex) approved June 1989, for the treatment of cytomegalovirus retinitis. Oral ganciclovir approved December 1994 for the treatment of CMV retinitis in immunocompromised individuals. Oral ganciclovir approved on October 27, 1995 as a prophylactic treatment for the prevention of HIV-related cytomegalovirus (CMV)disease.
Vitrasert (Chiron Vision)sterile intravitreal implant with Cytovene was approved March 1996 for the treatment of cytomegalovirus retinitis.
Fluconazole (oral and injectable) (Diflucan/Pfizer),approved January 1990, for use in the treatment of candidiasis and cryptococcal meningitis. Added indication for treatment of pediatric patients with cryptococcal meningitis and candidal infections (November 1994).
Erythropoietin (Epogen/Amgen and Procrit/Ortho Biotech), licensed December 1990, for the treatment of zidovudine-related anemia.
Foscarnet (Foscavir/Astra Pharmaceutical) approved September 1991, for use in the treatment of cytomegalovirus retinitis. Approved on June 1995 for the treatment of acyclovir-resistant herpes simplex virus.
ddI (didanosine), (Videx/Bristol Myers-Squibb) approved October 1991, for the treatment of adult and pediatric patients (over 6 months of age) with advanced HIV infection who are intolerant of zidovudine therapy or who have demonstrated significant clinical or immunologic deterioration during zidovudine therapy. Dosage recommendations decreased, September 1992.
ddC (zalcitabine), (Hivid/Hoffmann-La Roche) approved June 1992, for use in combination with zidovudine (AZT) as a treatment option for adult patients with advanced HIV infection who show signs of clinical or immunological deterioration. Approved in August 1994 for monotherapy treatment for HIV-infection in adults.
Itraconazole, (Sporanox/Janssen Pharmaceutica) approved September 1992, for the treatment of blastomycosis and histoplasmosis in immunocompromised and non-immunocompromised patients. Approved in March 1994 for a new indication for the treatment of pulmonary and extrapulmonary aspergillosis in patients who are intolerant of or who are refractory to amphotericin B therapy.
Atovaquone, (Mepron/Glaxo Wellcome) approved November 1992, for the treatment of mild to moderate PCP in patients who are intolerant to standard therapy. Approved in February 1995, for the treatment of mild to moderate PCP in patients who are intolerant of trimethoprim-sulfamethoxazole(TMP-SMX).
Dronabinol, (Marinol/Roxane Laboratories) approved December 1992, (new indication) for anorexia and weight loss associated with AIDS.
Rifabutin, (Mycobutin/Adria Laboratories) approved December 1992, for the prophylaxis of Mycobacterium avium complex, a severe infection that often afflicts AIDS patients.
Megestrol acetate, (Megace/Mead Johnson Laboratories) approved September 1993, (new indication), for anorexia, cachexia, or an unexplained weight loss in patients with AIDS.
Trimetrexate glucuronate, (Neutrexin/U.S. Bioscience) approved December 1993, for the treatment of moderate to severe Pneumocystis carinii pneumonia. (Must be administered concurrently with leucovorin [folinic acid]).
Clarithromycin, (Biaxin/Abbott Labs) approved December 1993, (new indication) for the treatment of disseminated mycobacterial infections due to Mycobacterium avium and Mycobacterium intracellular (Mycobacterium avium complex--MAC). Approved on October 1995 for the prevention of Mycobacterium avium complex (MAC).
Immune Globulin Intravenous (Human)/IGIV (Gamimune/Bayer Pharmaceutical Division), licensed December 1993, (new indication) for use in HIV-infected children to decrease the frequency of bacterial infections, increase the time free from serious bacterial infections, and decrease the frequency of hospitalizations.
Trimethoprim/Sulfamethoxazole, (Bactrim/Hoffmann-La Roche and Septra/Glaxo Wellcome) approved January 1994, (new indication) for the prophylaxis against Pneumocystis carinii pneumonia in individuals who are immunosuppressed and considered to be at an increased risk of developing Pneumocystis carinii pneumonia.
Stavudine/d4T (Zerit/Bristol Myers-Squibb) received accelerated approval in June 1994 for treatment of adults with HIV infection who no longer respond to or are intolerant of other anti-viral drugs. Approved in December 1995 for full marketing approval.
Doxorubicin HCL Liposome injection (Doxil/Sequus Pharmaceuticals, Inc) approved November 1995 for the treatment of Kaposi's Sarcoma.
Lamivudine/3TC (Epivir/Glaxo Wellcome) received accelerated approval in November 1995 for use in combination with Retrovir (zidovudine, AZT)in treating AIDS and HIV infection.
Amphotericin B lipid complex (Abelcet/The Liposome Company) approved November 1995 for the treatment of aspergillosis.
Saquinavir (Invirase/Hoffmann-La Roche) received accelerated approval in December 1995 for use in combination with other nucleoside analogue medications for the treatment of advanced HIV disease.
Ritonavir (Norvir/Abbott Laboratories) received full approval in March 1996 for use alone or in combination with nucleoside analogue medications in people with advanced HIV disease. Ritonavir also received accelerated approval for less advanced HIV disease.
Indinavir (Crixivan/Merck & Co. Inc.) received accelerated approval in March 1996 for use alone or in combination with nucleoside analogue medication in people with HIV or AIDS.
Daunorubicin Citrate Liposome injection (DaunoXome/Nexstar, Inc.) received full approval in April 1996 for first line cytotoxic treatment of advanced, HIV-associated Kaposi's sarcoma (KS).
Azithromycin (Zithromax/Pfizer Inc.) received full approval in June 1996 for preventing or delaying the onset of infection with mycobacterium avium complex (MAC).
Nevirapine (Viramune/Boehringer Ingelheim Pharmaceuticals, Inc/Roxane Laboratories Inc) received accelerated approval in June 1996 for the use in combination with nucleoside analogues to treat adults with HIV infection who have experienced clinical and/or immunological deterioration. Nevirapine is the first approval in a new class of drugs called non-nucleoside reverse transcriptase inhibitors.
Cidofovir (Vistide/Gilead Sciences Inc.) received full approval in June 1996 as an intravenous treatment for AIDS-related CMV retinitis, a potentially severe eye infection that can lead to blindness.
Somatropin rDNA origin for injection (Serostim/Serono Laboratories) received accelerated approval in August 1996 for the treatment of AIDS wasting and cachexia.
Nelfinavir (Viracept/Agouron Pharmaceuticals) received accelerated approval in March 1997 for the treatment of HIV infection in both adults and children.
Delavirdine (Rescriptor/Pharmacia & Upjohn) received accelerated approval in April 1997 for use in combnation with appropriate anti-HIV medications to treat patients with HIV infection when treatment is warranted.The studies, one led by John W. Mellors, M.D., of the University of Pittsburgh School of Medicine, and Alvaro Munoz, Ph.D., of the Johns Hopkins School of Public Health, the other by Michael D. Hughes, Ph.D., of the Harvard School of Public Health, and Richard T. D'Aquila, M.D., of Massachusetts General Hospital and Harvard Medical School, appear in the June 15 issue of the Annals of Internal Medicine. An editorial by NIAID grantee Michael D. Saag, M.D., of the University of Alabama at Birmingham, accompanies these reports.
These studies help refine our understanding of prognostic markers for HIV infection and underscore the value of routinely using both viral load measurements and CD4+ T cell counts in the care and management of individuals with HIV/AIDS," says NIAID Director Anthony S. Fauci, M.D.
Last year, Dr. Mellors and his colleagues in NIAID's Multicenter AIDS Cohort Study (MACS) reported that measuring the amount of HIV RNA in the bloodstream, commonly referred to as viral load, is the single best way to predict an HIV- infected person's risk for developing AIDS or dying. The current MACS study confirms and extends those findings.
Our study showed that, while viral load is the most powerful single predictor of outcome in HIV-infected individuals, combining it with CD4+ T cell counts allows a more precise estimation of prognosis," explains Dr. Mellors.
The researchers measured HIV viral load in baseline blood samples obtained from more than 1,600 HIV-infected men who enrolled in the MACS study between March 1984 and April 1985. Physicians measured the participants' CD4+ T cell counts at study entry and monitored the men for signs of HIV disease progression over a 10-year period. Nearly 1,000 participants developed AIDS during this period.
Using a technique known as regression tree analysis, the researchers divided study participants into 12 categories defined by discrete intervals of viral loads and CD4+ T cell counts and determined how many persons in each category had developed AIDS within three, six and nine years of their entry into the study.
The researchers found that CD4+ counts provided important information for discriminating the relative risk for disease progression among individuals with similar viral load levels. For example, only 3.6 percent of study participants with 500 or fewer copies of HIV RNA per milliliter (ml) of blood and more than 750 CD4+ T cells per cubic millimeter (mm3) of blood progressed to AIDS within nine years. By comparison, 22.3 percent of persons with the same viral load but 750 or fewer CD4+ cells/mm3 progressed to AIDS within the same period. At the other end of the risk spectrum, 97.9 percent of persons with baseline viral loads greater than 30,000 copies/ml and less than 200 CD4+T cells/mm3 progressed to AIDS within six years, compared with 66.8 percent who had the same viral load but greater than 500 CD4+ T cells/mm3.
The MACS study was initiated prior to the availability of anti-HIV drugs. Therefore, only 60 percent of the participants were treated with antiretrovirals during the 10-year study period. Those who were treated received monotherapy with AZT or other nucleoside analogue drugs.
"Our results were not confounded by subsequent therapy because there were no baseline differences in the values of the markers between treated and untreated individuals," says Dr. Mellors. "These markers," he adds, "were highly predictive of outcome independent of subsequent treatment with nucleoside monotherapy. The value of this study is that it accurately estimates prognosis for the HIV-infected individual considering therapy."
In a study of the use of these measures during combination antiretroviral therapy, Drs. Hughes, D'Aquila and colleagues in NIAID's AIDS Clinical Trials Group (ACTG) found that prediction of disease progression can be optimized by measuring viral load and CD4+ T cells before, and viral load shortly after, treatment begins. The researchers measured baseline viral load and CD4+ T cell counts in 198 HIV- infected individuals participating in ACTG study 241, which compared treatment with AZT and didanosine (ddI) to treatment with AZT, ddI and nevirapine. These measurements were repeated eight and 48 weeks after treatments started. Over a one-year treatment period, the investigators monitored study participants for signs of disease progression.
A total of 34 individuals developed opportunistic infections, malignancies or died during the treatment period. There was no significant difference in the number of these events between the two treatment groups. The researchers found that low CD4+ T cell counts and high viral loads at baseline independently predicted the risk of disease progression and death. However, they also found that the combined use of these measures improved their predictive value: individuals with high viral loads and low CD4+ T cell counts were more likely to develop AIDS than were those with high viral loads and relatively higher CD4+ T cell counts.
Measuring viral load eight weeks after treatment started provided still more prognostic information -- there was a 52 percent reduction in risk of disease progression for every 10-fold decrease in viral load at this point.
"We also found that a 2.5-fold or greater change in viral load probably indicates a true biological change in an individual patient, rather than a random fluctuation," says Dr. D'Aquila. "Our results, and those of other studies, suggest that clinicians might consider alternate treatments if a patient's viral load is not decreased by at least 2.5- fold within several weeks after a new antiretroviral regimen is initiated."
NIAID, a component of the National Institutes of Health (NIH), supports research on AIDS, tuberculosis and other infectious diseases, as well as allergies and immunology. NIH is an agency of the U.S. Department of Health and Human Services.
NIAID press releases, fact sheets and other materials are available on the Internet via the NIAID home page at http://www.niaid.nih.gov.
Note: MACS investigators measured viral load with a branched DNA assay manufactured by Chiron Corporation (Emeryville, Calif.). In the ACTG study, researchers measured viral load with a quantitative reverse transcription-polymerase chain reaction assay made by Roche Molecular Systems (Alameda, Calif. and Branchburg, N.J.). Supplemental support for viral load testing in ACTG 241 was provided by Boehringer Ingleheim Pharmaceutical, Inc. (Ridgefield, Conn.). Boehringer Ingleheim, Bristol-Myers Squibb Co. (Wallingford, Conn.) and Glaxo Wellcome Co. (Research Triangle Park, N.C.) provided study medications for ACTG 241.