Bay Area Reporter - March 23, 2001
Matt Sharp, Survive AIDS Writers Pool

The recent Retrovirus and Opportunistic Infections conference in Chicago presented no big breakthroughs like the International AIDS Conference in Vancouver in 1996, where protease inhibitors hit the radar screen.

However, despite the lack of earth-shattering news there are several drugs in the pipeline, and important new fields of discovery in order to develop better drugs. The research in AIDS is at a point where scientists are able to avail computer technologies and learn from past mistakes so that unique discoveries can now be made.

The 14 drugs used today to fight HIV are clearly inadequate at completely controlling HIV reproduction. Used in combination, HIV chemotherapy also has its toxic side effects and if drugs are not taken correctly they will become less effective over time. New candidates for HIV need to be developed that will be less toxic, easier to take, and obviously more effective.

At the conference in a closing lecture by Dr. Roy Gulick, from Cornell University, a very complete and comprehensive picture of where we stand with HIV therapy was presented. Gulick spoke of the challenges and needs of HIV research with respect to antiviral therapy. Adherence, toxicity, activity, and resistance are the challenges in current treatment of HIV.

Each challenge presents a need for better therapies to be developed for people who have never been treated, those who need to maintain treatment, and those who need to construct salvage regimens. Existing drugs need to be improved, and newly developed drugs must be made better. Drugs need to be more convenient and easier to take with fewer side effects and improved activity against both wild type and resistant forms of HIV. Research needs to focus on viral reservoirs where HIV can hide out, and new targets for stopping HIV must be discovered.

It is encouraging that several older drugs are improving in convenience and dosing, thus lowering side effects without jeopardizing effectiveness or causing resistance. Starting with the nucleoside analogs, AZT will be made as a time-released drug in a twice-daily dose. AZT has been combined with 3TC and now the two are combined with Abacavir, cutting down on the overall number of pills. ddI is now a once a day pill, enteric coated for better absorption. The drug d4T also will be available in a time-released 100 mg. pill to be taken once a day.

Protease inhibitors, perhaps the most burdensome to people with AIDS in terms of toxicity and the number of pills taken, have made some improvements. Saquinavir was made into a soft cell capsule (Fortavase) several years ago, making it more absorbable. Nelfinavir (Viracept) is now a twice a day dosing in 625 mg. pills. Ritonavir (Norvir) is now proven to enhance the levels of Saquinavir, Nelfinavir, and Amprenavir (Angenerase) and is made into a co-formulation with the newly released Lopinavir (Kaletra). New protease inhibitors such as Tipranivir, BMS-232, and mozenavir seem to be effective against PI resistant virus; a real issue with the current protease inhibitors.

Probably the biggest issue with developing new non-nucleoside drugs is cross resistance with current available drugs. This means that people who take an older drug usually becomes resistant to other drugs in the same class. Since this is the biggest obstacle with non-nucleosides, all new drugs in development appear to not be cross resistant with the older drugs such as nevirapine and Sustiva.

One nucleoside guanine drug, DAPD, effective against AZT and 3TC resistant virus, is in early human testing. In an early study of patients who have used AZT and 3TC, 500 mg. of DAPD twice a day decreased virus two logs from baseline levels. Capravirine, an NNRTI has also been shown to be effective against NNRTI resistant virus, but development is on hold due to a severe toxic problem seen in dogs. TMC-120 has been shown to be effective against the common NNRTI mutation, K103. These drugs are exclusively made to work against NNRTI mutated virus. They are in early Phase I/II development and larger human studies need to be completed before we will know how effective they will be.

New targets to stop virus replication are producing new generations of HIV drugs. Tenofovir, a drug written about previously in this column, has recently opened in an expanded access program. The nucleotide drug is active against many nucleoside resistant viruses and may enable a "resensitization" to a crucial 184 mutation. The drug, administered once a day, may turn out to be more potent than its cousin adefovir that was denied approval by the Food and Drug Administration, and may be an important addition to a new combination for salvage patients.

A veritable new field of research and development has opened up with the HIV entry inhibitor drugs. The compounds prevent entry, attachment or fusion of HIV to the host cell. People are most familiar with the fusion inhibitor T-20 because it is furthest along in development. There is also second-generation fusion inhibitor T-1249 that will not be cross resistant to T-20 and appears to be 2-100 times more active.

Other promising entry inhibitor candidates are attachment inhibitors and co-receptor inhibitors (possibly useful against the CXCR4 and CCR5 co-receptors) that are much earlier in development. There is also talk about using these drugs in combination since they may have a synergistic effect. These strategies offer great hope but unfortunately most, but not all of them must be administered by a needle. As exciting as the new attachment inhibitor field is for new strategies especially for people who have tried all the existing drugs, caution must be used as the drugs are all in early stages of development.

Gulick listed several other classes of HIV drugs being researched. DC-sign inhibitors, regulatory protein inhibitors, uncoating inhibitors, assembly inhibitors, capsid protein polymerization inhibitors, RNAase H inhibitors, and even integrase and zinc finger inhibitors, drugs thought to be useless, are back in development. And there are adjunctive therapies that aid in the effectiveness of certain antivirals. The good news is that there are dozens of new drugs in development for HIV. Unfortunately new drug candidates have a high rate of failure for one reason or another, so the more possibilities, the more hope there is.

At the retrovirus conference it was encouraging to see so many drugs in the pipeline, despite the research lag during the last few years as protease inhibitors seemed to provide a false sense that the cure for AIDS had arrived. Drug research is a lengthy trial and error process that is very expensive and until more human studies are completed, we won't know how toxic or effective the pipeline drugs may turn out to be. But, as we learn more about HIV, the drugs, effects on the cell and the body, there will be new hope for better treatments for all people with HIV and AIDS.
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