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Being Alive
Life Beyond the Big Three
Tom Baholyodhin, MD
September 5, 1996
Being Alive 1996 Sep 5: 6

Although good news from the International AIDS Conference in Vancouver has inspired renewed hope within the hiv/aids arena, there is a growing concern that prevention efforts may begin to wane once people believe that a "cure" is at hand.

A vital question demands further exploration: What are the options for the growing population of hiv+ people who are unable to tolerate currently available protease inhibitors? Even among individuals who can tolerate the side effects of protease inhibitors, a significant percentage will still fail therapy due to non-compliance (leading to viral drug resistance), or from rare "breakthroughs" despite strict adherence to the prescribed three-drug combination. Preliminary data from the "Crixivan plus Two Nucleosides Study" suggest that, after 60 weeks of treatment, a persistent, "undetectable" viral load exists among 80-p;90% of study participants; 10-p;20% of study participants have detectable levels of hiv in circulation. The significance of this finding is still unclear.

If the goal of triple combination anti-retroviral therapy is to achieve long term viral clearing, the idea of a safety net is very attractive. It has been estimated that 12 anti-retroviral drugs will be available for general use by the end of 1996, thus broadening treatment options. The next generation of anti-hiv agents approaching Phase III trials may be categorized as follows: Improvement of Existing Classes of Drugs Nucleoside Analogues: 1592U89 from Glaxo-Wellcome is a nucleoside analogue with potent in vitro (test-tube) activity against hiv-1. Like other agents in this class, 1592U89 inhibits the enzyme reverse transcriptase, thus preventing viral replication. The valuable features of this drug are: good absorption when taken orally (the drug may be taken with food); capability of reducing viral load by two log-fold when used by itself; ability to increase (on average) CD4 cell count by 100 cells/mm^3 after four weeks; no rapid resistance seen in vitro; excellent central nervous system penetration.

Lobucavir (BMS) is another promising nucleoside analogue currently in development. In addition to good oral absorption and potency against hiv, Lobuvacir is active along a "broad spectrum" (i.e., it is active against CMV, Herpes simplex and Herpes zoster, Hepatitis B virus, and Epstein-Barr virus).

Protease Inhibitors: Nelfinavir (Viracept) from Agouron Pharmaceuticals appears to be one of the most potent protease inhibitors available. One study examining the relationship between nelfinavir in combination with AZT and 3TC showed an average decrease in hiv-RNA by 3.6 log. Interestingly, the development of resistance to nelfinavir still allows susceptibility to indinavir, ritonavir, saquinavir and VX-478 (a new and highly potent protease inhibitor compound from Glaxo-Wellcome), thus potentially making nelfinavir the first line protease inhibitor.

New Classes of Antiretroviral Drugs Nucleotide Analogues: Adefovir dipivoxil (Gilead Sciences, Inc.) is one of the first nucleotide-class drugs being developed for the treatment of hiv. Unlike nucleoside analogues which only penetrate uninfected cells, adefovir dipivoxil is capable of penetrating both infected and uninfected cells, and a principal benefit is its ability to stay inside a cell for a long period of time. Adefovir dipivoxil is a broad spectrum antiretroviral agent, active against CMV, Herpes viruses, Hepatitis B virus, and HIV.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI's): Nevirapine is the first drug within the NNRTI classification to be approved by the Food and Drug Administration (FDA) for use in combination therapy. Nevirapine acts by directly inhibiting the enzyme reverse transcriptase, unlike nucleoside-class drugs which act upon the same enzyme via a different mechanism (i.e., prevention of hiv-DNA chain growth).

DMP-266 (Dupont Merck) is a new NNRTI with good oral absorption. DMP-266 has a high specificity for hiv-1 reverse transcriptase and is effective on AZT-resistant viral strains, making it a very potent agent. In vitro (i.e., test tube) studies with DMP-266 show resilience against the development of drug resistance.

Biological Immune Modulators Interleukin-2 is a natural cytokine released by T-cells and has powerful effects on the growth and differentiation of immune cells (including T-cells, B-cells, and natural killer cells). Preliminary data indicate that Interleukin-2 is capable of stimulating dramatic increases in CD4 cell counts in people with early hiv infection. Although Interleukin-2 is generally well-tolerated, some people develop a flu-like illness with each infusion. This form of infusion approaches the reality of "immune reconstitution" (i.e., the ability to restore a damaged immune system to normal function).

HBYO97, mentioned at the Vancouver conference, is an intriguing compound designed to prompt hiv-1 genetic mutation and cause the virus to be less virulent. Other novel cytokines, e.g. "C-C chemokines" (a substance produced by CD4 cells, CD8 cells, T-cells, and macrophages), can stop hiv replication in vitro and prevent HIV from entering into human cells.

(Tom Baholyodhin, MD is an HIV specialist who is actively involved in clinical research at Kraus Medical Partners. For additional information, contact the KMP Research Hotline at 800.860.0700).