Prevention of HIV transmission now possible in many cases

Post-exposure treatment proves successful

A cure for HIV infections will elude scientists well into the next century, says a leading AIDS researcher. But John Mellors, MD, of the University of Pittsburgh, says there’s encouraging news for some patients exposed to the virus — most especially neonates born to infected mothers and health care workers who accidentally stick themselves with infected needles.

In these situations, prophylaxis using zidovudine is quite effective, with transmission-prevention rates approaching 80% in accidental needlesticks, and about 65% in neonates, Mellors reported at the 10th International Conference on Antiviral Research held in Atlanta.

Still, the news overall is less encouraging. While viral researchers have found ways to outsmart the AIDS virus, using drugs like reverse transcriptase and protease inhibitors, the bug learns to work its way around these compounds with astonishing speed. In that regard, stingy regimens of anti-HIV drugs may pose the greatest risk for the emergence of stubborn infections.

Mellors says the AIDS virus is so hardy — that is, it replicates so rapidly — that numerous mutants are produced every day. Even after a single week of drug therapy, resistant mutants can dominate HIV infections, he says. Raising the pharmacological barrier to escape is one way to prevent the rapid emergence of mutants. In other words, give higher doses of anti-HIV drugs. "Therapies that partially suppress HIV replication are doomed to failure because of resistance," Mellors says.

Another barrier to a cure for chronically infected adults: the possibility that the virus can "hide" in some cells of the body, eluding both detection and eradication. While mathematical models suggest a triple-drug regimen should wipe out an HIV infection in about three years, Mellors says there’s some evidence the virus can retreat to sanctuary sites in the body. And, he points out, it only takes one viral cell to start the infection all over again.

Clearly, new drugs are needed, and researchers have found a slew of chemicals that have in vitro, and in some cases, in vivo activity against HIV. Protease inhibitors continue to come on line. The latest entrant, nelfinavir (Viracept), appears to have a couple of advantages over earlier agents. It can be used in children, and its resistance pattern differs from that of other protease inhibitors, meaning it can be used as a first-line treatment. Drawbacks include significant drug interactions with rifampin and rifabutin, and the development of diarrhea in up to a third of patients who use the drug.

Beyond protease inhibitors

There’s no reason to believe that resistance to nelfinavir won’t develop quickly, however, as it has to the other available protease inhibi-tors. Little wonder, then, that pharmaceutical researchers are looking elsewhere for new drugs. Japanese scientists have identified a quinoline molecule that suppresses HIV replication. In vitro tests show that a compound code-named K-12 completely suppressed replication spurred on by tumor necrosis factor alpha, and — good news for the development of resistance — it took very little drug to accomplish the task.

Another antibiotic class may find its way into the antiviral arsenal. Belgian researchers have found that macrolides containing a disulfide bridge inhibit replication of HIV-1, HIV-2 and simian immunodeficiency virus. The compounds appear to inhibit replication of virus at a late stage, much like protease inhibitors — but work even when protease inhibitors don’t, for example when resistance has cropped up.

In vitro, at least, resistance to the macrolide drugs seems to develop slowly. Even after 82 days of constant exposure, the virus remained sensitive to the compounds.

The so-called "fusion inhibitors" represent another area of interest for drug researchers. While the exact mechanism of these compounds is unknown, they are thought to prevent binding (or fusing) of the virus to normal cells. AR177 or Zintevir is one of the leading candidates in this class slated for future development. Another is the synthetic peptide pentafuside.

Wreaking havoc on HIV

One big advantage to adefovir dipivoxil, another new drug, is its persistence in infected cells. Still in clinical trials, the drug has an intracellular half-life of about 15 hours — giving it plenty of time to wreak havoc on HIV, which it does by inhibiting viral polymerases. Early studies have shown adefovir active not only against HIV, but cytomegalovirus (CMV) and hepatitis B. At this point, mutations appear slow to develop. A twelve-week trial involving 30 patients led to mutations in just one subject.

Compound 1592 represents the first carbo-cyclic nucleoside to be administered to humans. The drug, about to enter phase III clinical trials, inhibits RNA transcriptase. Its sponsor, Glaxo-Wellcome in Research Triangle Park, NC, says the drug may prove especially useful in AIDS-related dementia, because it crosses the blood-brain barrier. Thus far, study subjects have tolerated the drug well, and it’s proven effective. According to Glaxo, viral loads have dropped 1.5 to 1.8 logs in patients taking the drug, while CD4 counts have risen an aver-age of 80 to 100 cells.

Researchers at the antiviral conference also discussed two new treatments for a common complication of AIDS: CMV retinitis. Studies on fomivirsen sodium show that it may work where other drugs for CMV retinitis don’t. Patients who failed to respond to ocular implants — ganciclovir, for instance — responded to fomivirsen. Drawbacks to the ew drug include a nearly 20% incidence of increased intraocular pressure, manageable with antiglaucoma medications, the drug manufacturer says.

GEM 132, another future CMV drug, appears to undergo limited metabolism in the eye, giving it a long duration of action. Tests on rabbit eyes found that the drug settles from the vitreous humor and partitions into the retina. In rabbits, the drug was measured in eye tissue even months after it was instilled. "If this works and it’s safe we can give very infrequent doses," says R. Russell Martin, MD, of Hybridon, makers of the drug.

Some troubling news about HIV therapies surfaced at the antiviral conference, including the revelation that some popular AIDS drugs may prove highly toxic in the long term. A team of German doctors has found in vitro evidence that ganciclovir not only disrupts viral cells, but possibly normal cells as well.

The researchers say the active metabolite of ganciclovir, GCV-TP, passes on to normal cells in a host’s body and may induce damage and death similar to that which occurs in viral cells. While the scientists were unwilling to state the carcinogenic potential of ganciclovir, they did say the drug could pose a genetic risk in some patients.

Foscarnet, another drug used for CMV retinitis, also carries a long-term risk, say researchers at Emory University in Atlanta. An in vitro test on rat osteoblasts confirmed that the drug interfered with both osteoblast differentiation and bone mineralization — even at therapeutic doses. The research team concluded that AIDS patients treated with foscarnet may develop damage to bone tissue in the long run.

CDC’s annual AIDS ranking

With all the good news about HIV remissions, it’s possible to forget there’s still an epidemic going on. The Centers for Disease Control and Prevention (CDC) in Atlanta gave us a reminder last month, as it released its yearly ranking of the AIDS rate in the United States.

The highest rates are in the New York City area. New York City itself ranks first, with Jersey City and Newark, NJ, close behind at numbers three and seven, respectively. Florida is another AIDS trouble spot, with Miami ranked second and West Palm Beach and Ft. Lauderdale ranked fifth and sixth. San Francisco ranked fourth.

The biggest surprise: Wilmington, DE. That city, which has a population of less than 100,000, ranks 15th in the rate of AIDS cases, just behind the much larger cities of Washington, DC, Atlanta, and Houston.