American Foundation for AIDS Research, May 2003
Dave Gilden

Michel Foucault once said, "There are no relations of power without resistance." Today, the same could be said about the relationship between HIV and the forces that try to suppress it, be they natural immune responses or drug therapy. The Conference on Retroviruses and Opportunistic Infections held in Boston on February 10 to 14 marked a decade of these annual overviews of the latest in HIV research. After ten conferences, researchers keep returning to the same issue: whatever we throw at HIV, this simple, but highly mutable virus finds a way to dodge it.

John Coffin, Director of the HIV Drug Resistance Program at the National Cancer Institute and a professor at Tufts University School of Medicine, started off the conference by declaring, "If you don’t get resistance, the drug is no good."

That dictum was borne out even in the case of new drug classes, which promise effective salvage therapy for those with growing resistance to the current standard treatments — drugs that inhibit HIV’s reverse transcriptase and protease enzymes.

For nearly the entire past decade, researchers searched for ways to create suitable integrase inhibitors. These drugs would add a major new line of attack by stopping HIV from inserting its genes into the cell’s own genome. Both Merck and GlaxoSmithKline at last have integrase inhibitors in human trials, but they have the resistance issues that parallel those of the standard drugs, according to Daria Hazuda, who directed the Merck integrase inhibitor drug discovery program.

Hazuda described a series of viral culture experiments that attempted to breed integrase inhibitor-resistant HIV. Researchers found a number of mutations that appear in the HIV integrase enzyme after exposure to the Merck, Glaxo and other anti-integrase compounds. Although the Merck and Glaxo products differ structurally, several common resistance-conferring mutations appeared. These mutations occur with other integrase inhibitors as well. This raises the possibility that HIV can become cross-resistant to the integrase inhibitors under development.

T-20 (Fuzeon, enfuvirtide) is a new drug from Roche and Trimeris that blocks HIV entry into uninfected cells. At the Treatment Insider’s press time, T-20’s FDA approval was expected momentarily. As the first agent to attack HIV outside the cell, T-20 should have no resistance problems, at least initially. Alas, that honeymoon is all too brief. Michael Greenberg, Director of Molecular Biology at Trimeris, gave a presentation in which he charted the evolution of HIV resistance to T-20. Greenberg and his colleagues analyzed the genetic makeup of the HIV in 661 participants in phase III T-20 trials, all of whom had a long history of treatment failure before starting T-20 plus an optimized background regimen. Within 24 weeks on T-20, 301 of these participants had again experienced treatment failure.

Earlier studies in this trial cohort found that the likelihood of treatment failure inversely correlated with the number of truly active drugs that supported T-20 in the salvage regimen. When doing genetic analyses on participants’ HIV, Greenberg and his colleagues found mutations in a nine-unit sequence in the gp41 envelope protein to which T-20 binds. A single mutation in that region could result in up to 249-fold resistance.

The HIV in some of these trial participants turned out to have as much as 21-fold T-20 resistance even before the trial began. This initial resistance is associated with how HIV attaches itself to cell membranes, reported Eric Hunter of the University of Alabama. That is a sobering thought, since more rapid attachment may lead to a more virulent as well as more resistant virus.

Resistance promotes counter-resistance, as that ultimate dialectician Karl Marx might have said. Many of the new drugs described at the conference are designed to remain active against HIV impervious to present agents. Among these was a new integrase inhibitor from the Rega Institute in Leuven, Belgium. Belonging to a new structural class, V-165 is at least partially active against the HIV that resists other integrase inhibitors, though this particular molecule may yet turn out to be too toxic for human use.

Also, Roche unveiled the first human results for T-1249, a successor to T-20. The trial was a dose-ranging ten-day monotherapy trial in persons who had failed T-20. A median viral load drop of 1.12 logs (92%) occurred. However, the longer that people had been on T-20, the weaker was their response to T-1249.

Many studies at the Retrovirus Conference found that drug resistance paradoxically has some benefits. The mutations that protect against the drugs seem to compromise the ability of HIV to cause disease, at least until compensatory mutations restore viral virulence.

The PLATO collaboration, which pooled 13 observational cohorts, found that persons on therapy could tolerate viral loads of up to 10,000 copies/mL (or up to 10% of their pretreatment viral load setpoints) without declines in CD4 counts. Moreover, the rate of CD4 loss at any particular viral load was higher in treated than untreated patients.

Duke University investigators presented a partial explanation for this observation from their study of patients with "discordant" responses — patients under treatment who had had measurable viral loads but normal CD4 counts for a number of years. If such persons were taking protease inhibitors, their HIV had a highly impaired capacity to replicate. But this impairment was not as apparent in discordant patients taking NNRTIs (efavirenz or nevirapine) instead of protease inhibitors. Discordant responders also had a decreased level of immune cell activation compared with outright treatment failures. This is another sign of reduced viral virulence.

At the end of the conference, Steve Deeks of the University of California at San Francisco described how he tried to take advantage of this reduced replication capacity through "partial treatment interruptions." He followed 20 patients with low, stable viral loads during treatment (median viral load of around 10,000 copies/mL) who stopped either their protease inhibitor or their nucleoside analogs, but not both.

The five that stopped their nucleoside analogs experienced an immediate three- to tenfold increase in their viral loads, whereas the 15 who went off protease inhibitors were stable for 16 weeks. Two of these latter patients have had viral breakthroughs around week 24, though. In these two, viral load rebound occurred as a strain of HIV appeared that lacked the protease inhibitor resistance mutations and possessed improved replication capacity.

Deeks’ results indicate that the residual potency of the nucleoside analogs is mainly responsible for the good results in discordant responders with drug-resistant HIV. They may stop their protease inhibitors for a while and experience improvements in quality of life and blood lipids. But the two people in the nucleoside analog arm who now have rebounding viral loads indicate that once again, HIV’s evolutionary abilities can overcome any quick fix.

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