VIRUSMYTH HOMEPAGE

THE BIG QUESTION NOW IN
ANTI-HIV THERAPY - WHEN?

By Jay A. Levy

San Francisco Chronicle 23 February 2001

ANTI-HIV therapies that dramatically reduce AIDS deaths were the center of controversy at the eighth annual Retrovirus Conference this month in Chicago.

New federal guidelines recommend a delay before starting antiviral therapy. At the same time, researchers from the University of California at San Diego announced that strains resistant to the anti-HIV drugs were being found in 14 percent of individuals newly infected with the virus.

A heightened sense of caution in starting treatment with these potent therapies is now apparent. But has this question really been answered? Time will tell. In the meantime, we have three reasons to question the administration of combination therapy (also known as highly activated antiviral therapy, or HAART:

-- The drugs do not eliminate virus-infected cells and thus cannot "cure."

-- Long-term use of antiviral therapy, which can be toxic, may also lead to the emergence of resistant viruses.

-- There is no evidence that early treatment has made a difference in overall disease progression.

The new recommendations consider evidence that delay does not compromise the patient's health. On the contrary, delay could improve the long-term quality of life -- and keep treatment options open.

My concern is not about treatment within the first weeks of infection. Some studies suggest that antiviral therapy, received before antibodies develop, delivers some long-term benefits. Unfortunately, few individuals are aware so quickly that they are infected.

My concern is about treatment months to years after infection. With other infectious diseases, the microbe either replicates outside a host cell, or enters the cell, destroying it in the process. Therefore, treatment is beneficial once the infection is detected.

HIV infection is not like other infectious diseases. HIV incorporates its genetic material into the chromosome of cells and remains there, able to reproduce itself and spread to other cells in the body.

The virus creates cellular reservoirs in the immune system and in organs such as the kidney, heart, testes and brain.

Thus, while some of my colleagues initially thought HIV could be eradicated with these powerful anti-HIV drugs, the basic biology of HIV says no. Since this virus becomes part of the cell it infects, without necessarily killing the cell, the virus can be eradicated only if all infected cells are eliminated.

While antiviral therapy prevents the spread of HIV to new cells, none of the current anti-HIV drugs kills previously infected cells. HIV remains in infected people even after four to five years of antiviral therapy.

Unfortunately, with long-term treatment needed to contain HIV, drug toxicity and/or viral resistance defeats the effectiveness of the therapy.

One reason for early treatment had been to stop HIV from irreversibly destroying the immune system. This concern does not take into account the immune systems' flexibility. Even when the essential disease-fighting cells attacked by HIV are reduced by 25 percent, and immune system structures such as lymph nodes are completely disrupted, the immune system can recover with antiviral therapy.

A physician treating an HIV-infected individual must consider the options. The persistence of HIV in cells argues for a delay in initiating antiviral treatments. Unless the infected person is sick, the very real problems of long- term treatment must be considered: toxicity which may lead to damage of the pancreas, heart, kidney or brain), emergence of resistant viruses and suppression of the body's natural anti-HIV immune responses.

The increased prevalence of resistant viruses in newly infected people reflects the widespread use of HAART (highly activated viral therapy), and the misconception that this treatment will prevent HIV transmission. Antiviral therapies are powerful, but their use must be saved for the most effective moment.

Perhaps in the future, therapies will be discovered that will (1) have some direct effect on HIV-infected cells and (2) can be given long-term without toxicity. We can hope for development of innovative approaches that restore and augment the body's natural ability to resist HIV. This would reduce the need for toxic drugs.

Until then, clinicians should heed the new recommendations and save antivirals for the time when they can be of best use. I foresee, in fact, future recommendations that will raise the threshold even higher before beginning current anti-HIV therapies.

Jay A. Levy is Director of the Laboratory for Tumor and AIDS Virus Research at the University of California at San Francisco.

VIRUSMYTH HOMEPAGE