(Laurie Barclay, MD, Oct. 7, 2002)

The human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), which is characterized by immunosuppression, cachexia, fatigue, other systemic symptoms, and susceptibility to opportunistic infections, Kaposi's sarcoma, and hematologic cancers.

Worldwide, 40 million people are living with HIV/AIDS, and 3.3 million died from AIDS during 2001, including 1.1 million women and 580,000 children under age 15. According to the Centers for Disease Control and Prevention (CDC), the cumulative number of AIDS cases reported through December 2001 is 816,149, including 141,048 in females and 9,074 in children under age 13. Total deaths in persons with AIDS are 467,910, including 5,257 in children under age 15.

Approximately one-fourth of HIV-infected Americans do not know that they are infected, and estimated new infections are 40,000 annually. African-Americans and Hispanics make up over 70% of new HIV infections. Although gay and bisexual men continue to have high rates of infection, nearly a third of new HIV infections in the US are now in women, with minority women accounting for more than 80% of that increase.

HIV is spread by sexual contact, by sharing needles or syringes, and rarely by blood transfusion, now that blood is screened for HIV antibodies. Babies born to HIV-infected women may become infected before or during birth or through breastfeeding. The HIV virus compromises immunity by destroying CD4+ T cells (helper cells).

Since the AIDS epidemic began, the FDA has approved 47 drugs for the treatment of HIV/AIDS, including 19 antiretroviral drugs for use singly or in combination therapy. Highly active antiretroviral therapy (HAART) regimens utilizing protease inhibitors are a major factor in reducing the number of AIDS deaths from the mid-1990s to the present. However, none of the currently available therapies completely stops HIV replication.

CenterWatch has identified a pipeline of 52 drugs in development for HIV infection and AIDS, including extended-release formulations of existing antiretroviral therapies, immune modulators, fusion inhibitors, vaccines, topical microbicides, and drugs targeting dementia, lipodystrophy, and other complications of AIDS.

Bristol-Myers Squibb (BMS) has submitted an NDA for Zerit, an extended release preparation of stavudine, which is a nucleoside reverse transcriptase inhibitor (NRTI). The one-capsule, once-daily formulation should improve quality of life and compliance relative to the FDA-approved immediate release formulation of Zerit, with similar virologic activity. In a recent Phase III multinational, prospective, randomized, double-blind, placebo-controlled trial (BMS 099) combining Zerit with efavirenz and lamivudine, 80% of the 392 patients in the treatment arm containing Zerit extended release achieved viral load suppression below 400 copies/mL after 48 weeks of treatment, compared with 75% of the 391 patients in the arm containing Zerit immediate release. More than half of patients in each treatment arm reduced viral load to less than 50 copies/mL, and adverse events were similar in both groups.

Coviracil (emtricitabine) is another NRTI for which Triangle Pharmaceuticals has submitted an NDA. This drug has potent selective activity against both hepatitis B virus (HBV) and HIV. In a 48-week, double-blind, placebo-controlled Phase III trial (FTC-301) comparing once-a-day Coviracil to Zerit given twice daily, each combined with efavirenz and Videx EC, interim analysis of safety and efficacy led to unblinding the trial and offering Coviracil to all 571 subjects. Patients in the Coviracil arm had significant improvements in immunologic function, and 87% had persistent virologic response through six months.

To tackle the emerging problem of antiretroviral resistance, Pfizer is in phase III testing of capravirine, a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) which has been shown in several studies to retain activity against HIV that has developed some NNRTI resistance mutations, including K103N. After the unexpected development of vasculitis in animal models, the FDA placed human clinical trials of capravirine on partial clinical hold in January, 2001. Agouron Pharmaceuticals believes that capravirine may offer unique benefits to HIV-infected patients and therefore remains committed to its clinical development and to additional toxicology studies.

One of the problems with available protease inhibitors (PI) is their tendency to increase blood lipid concentrations. In hopes of circumventing this problem, Bristol-Myers Squibb has begun phase III testing of atazanavir, an experimental PI formerly called BMS-232632. A randomized trial in 467 patients at 51 sites suggests that concentrations of total cholesterol, LDL cholesterol, and triglycerides do not increase significantly in treatment-naive patients taking a HAART regimen including atazanavir, and that the drug is effective, safe and well tolerated compared to nelfinavir. Other advantages include once-daily dosing and fewer gastrointestinal effects, but the drug is more likely than nelfinavir to induce jaundice.

Unlike currently approved antiretroviral drugs which target viral enzymes involved in replication, the fusion inhibitors are designed to block HIV from fusing with a host cell before the virus begins replication within the cell. Trimeris has submitted an NDA for fusion inhibitor Fuzeon (enfuvirtide; formerly T-20) and has received fast track designation from the FDA.

Physician enrollment for the U.S. Early Access Program for Fuzeon began August 19, 2002 for a limited number of patients with advanced HIV disease. Data from two large, international Phase III trials suggest that patients on combination therapy with Fuzeon are twice as likely to achieve undetectable blood levels of HIV and a significant increase in immune cells at 24 weeks compared with patients who received combination therapy without Fuzeon.

PRO 542 from Progenics Pharmaceuticals is a novel fusion protein shown to safely reduce viral load by 60-80% in selected patients. Multi-dose Phase II studies are underway of PRO 542 as salvage therapy of HIV-infected patients refractory to currently available antiretroviral medications.

Rather than targeting the HIV virus directly, immune system modulators boost the ability of the immune system to halt its spread. These include Celgene's drug Thalomid (thalidomide); Chiron's product IL-2 Proleukin (aldesleukin), a recombinant form of interleukin-2; Alferon N Injection (interferon alfa-n3), a human leukocyte-derived natural interferon treatment; and WF10, designed by Dimethaid Research to enhance macrophage function and to thereby eliminate reservoirs of HIV-infected CD4 cells and macrophages. All these drugs are in phase III development.

WF10, intended for use as adjunctive treatment, is a chemically stabilized chloride matrix called tetrachlorodecaoxygen (TDCO). Studies to date suggest that WF10, administered intravenously, is safe in patients with HIV and that it may be especially useful in moderate to advanced AIDS. By promoting phagocytosis and reducing macrophage production of TNF-alpha, WF10 may slow AIDS progression and reduce the likelihood of opportunistic infections.

Based on phase II trials by Immune Response Corporation, Remune (HIV-1 immunogen) is a promising adjunctive therapy using inactivated virus to restore HIV-specific immune responses, with positive effects on viral load and on counts of CD4 helper T lymphocytes.

Vaccines designed to prevent AIDS rather than to slow its progression are AIDSVAX B/B and AIDSVAX B/E, both in phase III development by VaxGen. An alternate approach to prevention is the spermicidal microbicide BufferGel (polyacrylic acid), in phase III development by ReProtect.
By reducing the alkalinity of semen, this product tends to kill sperm and to inactivate pathogens including HIV, HPV, herpes, syphilis and gonorrhea. Data on the anti-HIV activity of BufferGel are expected in 2005.

Complications of AIDS include lipodystrophy syndrome associated with HAART, for which Ark Therapeutics is in phase II testing of EG005, a drug that reduces cellular levels of Angiotensin II and thereby increases mitochondrial efficiency. Drugs targeting AIDS-related dementia for which phase II testing is completed include CPI-1189 from Centaur Pharmaceuticals and memantine from Forest Laboratories.

CPI-1189, an oral drug that potentially inhibits neuroinflammation, has safely produced statistically and clinically significant cognitive improvements in AIDS dementia in double-blind, placebo-controlled clinical studies lasting five months. Memantine, which modulates N-methyl-D-aspartate (NMDA) receptor activity, has been used to treat other types of dementia, with rapid and lasting improvement in cognitive, psychological, social and motor impairments. Animal models including transgenic mice suggest the applicability of this drug to AIDS dementia, for which clinical trials are ongoing.

Although significant progress in available antiretroviral therapy has reduced the number of AIDS deaths, drugs identified in this pipeline should continue to improve the outlook for AIDS patients. New antiretroviral drugs may improve tolerability and compliance while reducing HIV resistance; fusion proteins prevent HIV entry into the cell; and immune modulators work synergistically to reduce viral load. For patients with chronic infection, drugs in development may reduce chronic complications such as lipodystrophy and dementia. The ultimate goal is prevention, whether through vaccination or topical microbicide, for those individuals at high risk.