At the Keystone HIV Pathogenesis symposium in January 1999, the Aaron Diamond AIDS Research Center’s Douglas F. Nixon presented a paper entitled “Temporary Containment of Viral Replication After Cessation of Antiretroviral Drug Therapy.” He reported on 4 individuals from one of the ADARC’s primary HIV infection (PHI) HAART studies. They had been only intermittently (about 50%) adherent, but viral load and immune responses were measured throughout their drug holidays as well as their on-treatment periods. Each time they stopped taking therapy, their viral load spiked up, but immune cells — HIV-specific CD4+ T-cells and cytotoxic T-lymphocytes (CTLs) — moved in to contain the virus. Eventually, after several such cycles on and off treatment, 2 of the 4 stopped therapy altogether. Their viral load rebounded but was, once again, quickly contained by the immune response. One remains off therapy with a viral load beneath the limit of quantification (<50 cells/ml) after a year off HAART, and one is 4-6 months out. There were no reporters at Keystone, so it took a few weeks for this story — surely one of the most important developments of late — to percolate out; it was ultimately broken by Mike Waldholz of The Wall Street Journal on January 25, with the appetizing title “Cocktail Break.”
Seeking to pursue these findings further, the ADARC researchers opened an IRB-approved study in which people who have maintained viral load below 50 copies/ml for over 2 years, and who have both HIV-specific CD4+ and CD8+ CTL cells, can elect to go off HAART and be followed closely for viral and immunological responses. So far, 2 additional individuals — each treated during PHI — have been able to maintain viral control after stopping therapy. Their viral rebound was slower than in natural infection, with a doubling time of four days rather than one, but it eventually rose to baseline before a vigorous immune response reduced it once again to beneath the limit of quantification. Five more individuals, some acutely and some chronically infected, are now being followed in this “Stop HAART” study. Unlike Bruce Walker, the ADARC researchers have been able to identify HIV-specific CD4+ cells in both acute and chronic infection, suggesting that they may be recoverable if immune reconstitution is sufficient. (France’s Brigitte Autran still stands fast at 6-8 years for sufficient immune recovery.)
Intriguingly, “Patients with a little virus [rather than none] have the best [CD4+] proliferative response [to HIV],” commented Ho. It appears that these individuals may have successfully immunized themselves against HIV, at least in the short-term, under cover of HAART. Their CD4+ cells still harbor substantial HIV provirus, but it appears that whenever the virus is turned on the immune system is able to control it — for the time being. They will have to be followed for life, however, as any immune stimulus, whether it be an immunization, an infection, or the immune deterioration associated with age, could be sufficient to overcome this temporary immune control of HIV.
About one year ago during the jointly co-sponsored TAG/AmFAR “reservoirs” meeting at MIT, Donald Mosier, a mouse researcher at The Scripps Research Institute (La Jolla, CA) first proposed in public the then heretical proposition of cycling patients on and off antiretroviral therapy (see “Reservoirs Dog,” in the 5/98 TAGline). Over the summer, San Francisco’s Steve Deeks had also recently begun to privately embrace the prospect of pulsed therapy. The idea last winter was that, in the face of waning immune responses due to the absence of sufficient antigen to maintain effector cell functions, antigenic stimulation was needed. Where ADARC researchers and others suggested periodic immunization with various synthetic HIV vaccine products, Mosier lambasted Ho and Markowitz’s unnecessarily complicated approach, challenging his colleagues thusly, “It surprises me that you’re actually thinking about vaccines [to boost immunity] when you’ve got the natural infection of immunized people to begin with.” Tufts’ John Coffin also found the vaccination proposition preposterous.
In the meantime Italy’s controversial Franco Lori, after perhaps stumbling onto a winning treatment schedule in his (and Berlin’s Heiko Jessen’s) clinical practice, has been experimenting with the idea of periodically suspending antiretroviral treatment for increasing intervals of time — after an (as yet undefined) sufficiently recuperative initial period of viral suppression. The goal: to eventually “teach” the immune system to control the virus on its own. Lori’s (still entirely experimental) renegade approach has been dubbed, “Start, Stop.” As of the Chicago retrovirus meeting, the number of reports of patients successfully stopping therapy still totaled fewer than a dozen — and this was almost exclusively among individuals treated during primary infection. The ratio of success to failure appeared to hover around 1:1.