Abstract

HIV epidemic continues to involve researchers and clinicians to unearth new facts about the virus and develop new treatment regimens for patients. The status of anti-HIV treatments is never static but constantly changing due to complicated genetic diversity of the virus and the inability of the body to clear the virus. The development of combination therapy is viewed as an essential step to increase the life span of the HIV positive individuals. Tremendous strides have occurred in the HIV/AIDS arena, yet daunting challenges remain. This article presents a glimpse of recent advances in combination therapy for AIDS.

Introduction

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.[1] Highly Active Anti-Retroviral Therapy (HAART) regimens utilizing protease inhibitors (PIs) are a major factor in reducing the number of AIDS deaths from the mid-1990s to the present. It has been identified a pipeline of 52 drugs for HIV infection and AIDS, including extended release formulations of existing antiretroviral therapies, immune modulators, fusion inhibitors, vaccines, topical microbicides and drugs targeting dementia [2], lipodystrophy [3] and other complications of AIDS.

HAART regimens

The most common initial regimens consist of two nucleoside analogs, combined with either a PI, an NNRTI (Non Nucleoside Reverse Transcriptase Inhibitors) or a third nucleoside analog. The combination of two nukes and a PI is supported by data from randomized studies with clinical endpoints.[4] These regimens, however, often involve a considerable pill burden and relatively frequent side effects, which makes compliance difficulties. They are possibly quite robust with regard to immunological efficacy [5] which has yet to be demonstrated for NNRTIs or nukes. NNRTs with two nucleoside analogs regimen is found to have advantages as they are effective with low pill burden and good tolerability. However, the significantly emerging disadvantage is rapid development of cross resistance. Most explored nucleoside analogs combination is Trizivir [ AZT ( Azidothymidine), 3TC ( Epivir) and abacavir] but studies have shown that in patients with a high viral load, efficacy was inferior to PI combinations.[6]

More recently Bristol-Myers Squibb [7] has submitted an NDA (New Drug Application) for Zerit, [8] an extended-release preparation of stavudine, which is a NRTI (Nucleoside Reverse Rranscriptase Inhibitor). 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, randomized, doubleblind, placebo controlled trial, BMS 099   (a type of studies performed by Bristol-Myers Squibb) 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 the patients in each treatment arm reduced viral load to fewer than 50 copies/mL, and adverse events were similar in both groups.[9]

Coviracil (emtricitabine) is another NRTI for which Triangle Pharmaceuticals [10],[11] has submitted an NDA. This drug has potent selective activity against both (HBV) hepatitis B virus  and HIV. In a 48-week, double-blind, placebo-controlled phase III trial [FTC-301, The FTC 301 study is a randomised, double-blind, double dummy comparative study of FTC (Emtricitabine) vs d4T with a backbone of didanosine and efavirenz in 571 treatment naive individuals] comparing once-a-day Coviracil to immediate-release Zerit given twice daily, each combined with efavirenz and Videx EC (didanosine), interim analysis of safety and efficacy led to unblinding the trial and offering Coviracil to all 571 subjects. Patients with Coviracil in the arm had significant improvements in immunologic function, and 87% had persistent virologic response through six months.[12],[13]

To tackle the emerging problem of antiretroviral resistance, Pfizer [14] is in phase III testing of capravirine, [15] 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-resistant mutations, including K103N.[16] After the unexpected development of vasculitis in animal models, the FDA placed human clinical trials of capravirine on partial clinical hold in January, 2001.[17] Agouron Pharmaceuticals, [18] a Pfizer company slated to market capravirine, believes that it 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. [19] 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 to induce jaundice than nelfinavir.[20]

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 ^[21]has submitted an NDA for fusion inhibitor Fuzeon (enfuvirtide; formerly T-20) [22] 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.[23]

PRO 542, known as CD₄-IgG₂, is a novel fusion protein that incorporates the HIV-binding region of the human cell surface receptor for HIV into a human antibody molecule, [24] from Progenics Pharmaceuticals [25] is a novel fusion protein shown to safely reduce viral load by 60% to 80% in selected patients. Multi-dose phase II studies are under way of PRO 542 as salvage therapy for 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 pause viral spread. These include Celgene’s drug Thalomid (thalidomide) [26]; Chiron’s product IL-2 Proleukin (aldesleukin), [27] a recombinant form of interleukin-2; Alferon N Injection (interferon a-n3), a human leukocyte derived natural interferon treatment, and WF10 (an immuno modulator) designed by Dimethaid Research [28] 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 [29], intended for use as adjunctive treatment, is a chemically stabilized chloride matrix called tetrachlorodecaoxygen (TDCO). Studies to date suggest that WF10, administered intra-venously, is safe in patients with HIV and that it may be especially useful in moderate to advanced AIDS. [30] By promoting phagocytosis and reducing macrophage production of TNF-a (Tumor Necrosis Factor-a), 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) [31] 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.[32],[33]

An alternate approach to prevention is the spermicidal microbicide BufferGel (polyacrylic acid), in phase III development by ReProtect. [34] By increasing the acidity of semen, this product tends to kill sperm and to inactivate pathogens including HIV, HPV, herpes, syphilis and gonorrhea. [35] Data on the anti-HIV activity of BufferGel are expected in two years.

Post treatment issues

Complications of AIDS include lipodystrophy syndrome associated with HAART, for which Ark Therapeutics [36] 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 (4-acetylamino-N-tert-butyl-benzamide) from Centaur Pharmaceuticals [37] and memantine (3,5-dimethyl-adamantan-1-ylamine) from Forest Laboratories.[38]

CPI-1189, prevents apoptosis and reduces glial fibrillary acidic protein immunostaining in a TNF-a infusion model for AIDS dementia complex, [39]  is 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.[40]

Conclusion

Drugs identified in the pipeline may continue to improve the outlook for AIDS patients however significant progress in HAART has reduced the number of AIDS deaths in recent years. New antiretroviral drugs and their combination regimens may improve tolerability and compliance. Emergence of fusion proteins, which prevent HIV entry into the cell may prove as one of the major tools in the management of the disease. Additionally immune modulators work synergistically in order to reduce the viral load as well as immunogens are supposed to improve immunity.

References