(RITA!)HIV Treatment Alerts - February 2001
Shannon Schrader, MD - Southampton Medical Group

At the recent Retrovirus Conference in Chicago, the pendulum continued to swing again regarding a standard way to treat HIV. In the mid 1990s, highly active antiretroviral therapy (HAART) was introduced with much excitement. HAART is commonly called "combination" or "cocktail" therapy. The regular use of HAART regimens led to improvement in the health of HIV-infected patients, but its widespread use also created challenges and dilemmas for clinicians. In 1996, the assumption was that if therapy could completely suppress virus, it could prevent destruction of the immune system, prevent drug resistance, and lead to a possible cure. This strategy resulted in the concept of "hit hard, hit early." Unfortunately, many of the assumptions about this strategy have proven to be incorrect.

One of the big topics at the conference was the question: "When should therapy be started?" The US Health and Human Services Department recently released new HIV treatment guidelines. These guidelines advise physicians to wait before rushing to prescribe drug therapies for HIV-infected individuals. There are 2 reasons to delay treatment: first, concern for the toxicities related to long-term use of anti-HIV drugs, and second, uncertainty as to what drug combinations are best.

The need for new drugs has become very important as patients go through drugs because of viral resistance. Sometimes resistance to one drug can mean resistance to other related drugs—this is called cross-resistance. Missing doses of medication, drug interactions, and short- and long-term toxicities can make a drug less able to fight HIV. New drugs must find ways around resistance to be effective. There are some new drugs in the pipeline, but we must be careful about using the current anti-HIV drugs wisely so that we do not run out of options.

New drugs in the works

FTC, AG1549, DPC 083, calanolide A, BMS 232632, and DMP450 are just a few of the new drugs that comprise the "alphabet soup" of new drug candidates. Each of these products works against the viral enzymes reverse transcriptase and protease, where our current drugs are active. What remains to be seen is whether these compounds will have fewer toxicities or different resistance patterns compared to the currently approved drugs. Some other possible future anti-HIV drugs include TMC 126, a protease inhibitor that may be effective against resistant virus; TMC 120, a non-nucleoside reverse transcriptase inhibitor (NNRTI) that may be effective against resistant virus; and DAPD, a nucleoside reverse transcriptase inhibitor (NRTI) that may be effective against AZT-resistant virus. Tenofovir DF is a nucleotide reverse transcriptase inhibitor that has shown promising results in clinical trials and it has a unique resistance pattern. It is currently in limited expanded access in the US (see page 8).

However, the buzz about new treatments centered on the HIV entry mechanism. For HIV to enter a cell and reproduce itself, it has to bind to the cell surface. At this binding site, there are several possible targets for drugs to act. One such compound that is further along in development is T-20 (pentafuside). T-20 is administered by subcutaneous injection twice a day. It appears to contribute to a substantial viral load reduction when added to a background of anti-HIV drugs. A second such inhibitor, T-1249, is in early studies.

New approaches to treatment

Two other areas of interest were simplifying drug schedules to once a day and intensifying drug strength by adding ritonavir (Norvir) to boost blood levels of drug. As an example of once-daily dosing, lamivudine (Epivir or 3TC) was shown to be effective when given once a day at 300mg. This NRTI is currently given twice a day. For boosting drug levels in the blood, the addition of Norvir to amprenavir (Agenerase), indinavir (Crixivan), or saquinavir (Fortovase) enables these protease inhibitors to be taken with fewer pills. This can help prevent missed doses and possibly allow for once-daily dosing. The addition of Norvir also may enhance the potency of the protease inhibitors.

Finally, the most talked about topic was structured treatment interruptions (STI). This has become the hot topic at most conferences and in most physician offices. The idea behind such a strategy is: 1) to possibly stimulate an anti-HIV immune response, 2) to limit exposure to anti-HIV drugs and hopefully decrease the possibility of side effects, and 3) to conserve possible drug choices in patients with multi-drug resistant HIV.

Without going into a lot of detail, studies of STI were presented on both recently infected and chronically infected patients. In short, the best possible opportunity for STI to work over the long run may be with patients who initiate therapy before seroconversion. Otherwise, the studies have no long-term data on STI being ready for "prime time." If patients and physicians choose to explore STI in practice, the "structured" in STI should change to "supervised" and patients should be monitored closely for any change in immune status. Above all, this should be a decision made with your doctor.

As a physician who treats HIV, I believe that it is imperative to move forward cautiously when treating someone with HIV, to think strategically when recommending treatment, and most importantly, to initiate treatment only when the patient is ready. Treating the individual is more important than just treating the numbers.

DEFINITIONS

Chronically: over a long period of time.

Clinicians: individuals qualified in the practice of medicine or mental health.

Enzymes: complex proteins that carry out specific functions in the body.

Seroconversion: the body's production of antibodies in response to a foreign agent, like HIV.

Subcutaneous: under or into the skin.

Toxicities: poisonous or damaging effects on the body.

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Copyright © 2001 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org

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