As All the World Drools Over Triple HAART Hype, Low Key Dual Combo Appears First to Achieve the Unimaginable
The first cure?
In a recent issue of Nature Medicine, a group of immunologists make two obvious but rarely discussed observations about the limitations of current triple drug cocktails for HIV infection: First: If, upon cessation (or failure) of treatment the level of virus in the blood rebounds to the same level as before treatment, then the immune system clearly hasn’t “learned” anything new about controlling the infection during this treatment-induced temporary cease-fire. Secondly, If, after being “undetectable” for a couple of years (blood, lymph nodes, the whole gamut), viral load still surges back within 2-4 weeks of stopping therapy, then there must be cells in the body that current therapies are not reaching.
A couple of months ago, Aaron Diamond’s first eradication candidate was scheduled to stop his therapy. After some two years on a triple combination (AZT+3TC+ ritonavir), the Aaron Diamond team could find no detectable HIV RNA in his body. Neither could they culture virus from any of his cells. “Dodge,” as the patient was called, was featured on a special Friday Nightline segment. “Just one name,” the reporter explained, “like Madonna or Prince.” The show was called “The First Cure.” But the first cure was not to be. Just as they were about to take Dodge off his unpalatable potion to test whether or not the ‘cure’ had worked, scientists at Johns Hopkins called with disappointing news. After artificially stimulating some of Dodge’s cells in the lab, they were able to make his cells grow HIV anew. If it could happen in a petri dish, they argued, it could happen in Dodge’s body. Withdrawal of Dodge’s treatment would have to be postponed.
What the Nightline program didn’t tell its riveted audience (didn’t know) was that a similar experiment had already been conducted in France — and with much more stunning results. As part of an on-going study with the combination of ddI and the 30-year old cancer chemotherapy drug hydroxyurea, an Argentinean physician based in Lyon (Dr. Jorge Vila) had identified 2 patients who, after 12 months of treatment with ddI and hydroxyurea, had no detectable HIV-RNA in their lymph nodes or blood. Low levels of proviral DNA, however, (believed to be incapable of producing new virus) were detected in some of the cells of each patient. Although the quantitation tests in these 2 patients might have been less rigorous (or less thorough) than those in the Aaron Diamond case, the patients agreed to stop therapy. That was in 1995. One year later, Vila and his colleagues report no rebound of HIV. Neither can they detect infectious virus after in vitro cell activation. The study was published as a letter to The Lancet at the end of August (vol. 350:635-6).
Although clearly very interesting, what this all means is still unclear. The fact that there was no viral rebound for an entire year after only one year of treatment with this dual combination is remarkable. (Recent revisions of earlier mathematical models estimate that fully suppressive therapy would need to be given for a minimum of 6 years – and perhaps for life.) The authors propose that hydroxyurea’s success is due to its ability to permeate into the viral reservoirs of HIV infection: so-called “resting” T-cells and macrophages where the popular triple combos can’t reach. Others posit the moderate immunosuppressive activity of hydroxyurea as a possible explanation for its unique effect in the setting of HIV infection. (Remember Jean-Marie Andrieu’s prednilisone paper and Fauci’s cyclosporin-A experiments?)
Rather than targeting HIV directly, hydroxyurea is said to inhibit HIV replication by acting upon the cellular enzyme ribonucleotide reductase, which HIV needs to assure a continual supply of nucleotides in order to successfully assemble a DNA chain from its viral RNA. A drug from the same pharmaceutical house that brought us ddI and d4T, hydroxyurea is little promoted for one very simple reason: Bristol Myers’ patent on it expired in 1995. So no one’s gonna get rich on this. Bristol Myers said it has no interest in financing further research with hydroxyurea, and recently pulled out of an on-going study of the drug within AmFAR’s community-based clinical trials network (CBCT).
Exciting as all this is, it would be inaccurate to say that HIV has been eradicated from these two patients. Both still harbor cells with fully integrated HIV-DNA. No one can be certain that these cells, upon bumping into their assigned antigen months or years from now, won’t become activated and begin again to pump out millions and millions of copies of new HIV. The authors of the study propose that this HIV DNA is defective and incapable of producing infectious virus, and that is a plausible hypothesis. It’s less clear, at least for the time being, that the results achieved in these 2 patients can be reproduced in larger numbers of patients.
To begin with, both patients were recently infected. No one has yet done this hydroxyurea experiment with individuals with chronic HIV infection. Secondly, Dr. Vila’s patients had not been treated with any other HIV medicines prior to going on the ddI+hydroxyurea combination. Will the same results be achievable in drug-experienced patients? Thirdly, both patients had extremely low viral loads (676 and 1,120 copies/mL) even before therapy. (Some critics question whether the individuals were even productively infected, although HIV-antibody seropositivity was confirmed by ELISA and Western blot.) Various other experiments with ddI+ hydroxyurea have shown that at most 30-40% of patients become “undetectable” on this combination. Patients with relatively high viral loads will almost certainly not. Will hydroxyurea perform as well in combination with, for example, 3TC, nevirapine or the protease inhibitors? Lastly, it’s entirely possible that these two individuals might have cleared their HIV infection on their own. Maybe there was something special about their immune responses.
A third intriguing anecdote was delivered by Franco Lori (Research Institute for Genetic and Human Therapy, Pavia, Italy) at the Gallo meeting in Baltimore, MD on September 16th. An HIV-infected German man with baseline HIV-RNA viral load of some 85,000 copies is reported to have driven the virus down to “undetectable” levels with the combination of indinavir+ddI+hydroxyurea. After 144 days on the treatment, an acute case of hepatitis A caused him to stop his medications for 3 weeks. Before restarting them, his physicians checked the amount of virus in his blood. It was still undetectable — and has remained so for 9 months.