Important note: Information in this article was accurate in November 2000. The state of the art may have changed since the publication date.
The present highly active antiretroviral therapy (HAART) is very effective against HIV. Still, it has not proven able to tame HIV so that the immune system can take over controlling this virus as it does with others. There is always a small amount of residual HIV that can flare up if treatment is interrupted – even after years of suppressing plasma HIV to below detectable levels (50 copies/mL).
One exception may be people who were successfully treated from the onset of their HIV infection. Immediate treatment protects the capabilities of their immune systems, leaving them basically intact. At the same time, their short pre-therapy exposure to HIV is analogous to a vaccine. The immune defenses of early-treated patients are a step ahead of the virus, and these people may be able to stop therapy at some point. The September 29 issue of Nature magazine carried a report from Eric Rosenberg and Bruce Walker of Massachusetts General Hospital (MGH) describing the first study of intentional treatment interruptions in a small group of patients treated almost immediately after their HIV diagnosis.
The article's introductory paragraph states, "At present, five out of eight subjects remain off therapy with viral loads of less than 500 RNA copies per ml plasma after a median 6.5 months..." A step forward in understanding how to control HIV may have occurred, but the experience of the 12 study volunteers described in the paper is not as optimistic as this statement makes it appear. (Another seven study participants were at too early a stage in the study for inclusion in the Nature report.)
The study cohort began treatment within the month (mostly within the week) following diagnosis with early HIV infection. Ten of the 12 were in the acute or primary stage of HIV, a mononucleosis-like syndrome that arises after contracting HIV. It usually lasts for about three weeks. The other two study participants were diagnosed with early HIV infection of less than six months' duration. All 12 received triple-drug, protease-inhibitor regimens. In nine of the 12, this treatment reduced their HIV to below 50 copies/mL for one to three years before their first treatment interruption.
Treatment was not successful in the other three members of this group because they had become infected with drug-resistant HIV. Unlike the others, these three did not develop sustained anti-HIV T-helper cell activity, which is critical to immune defenses against the virus. These study participants did not proceed to the treatment interruption phase of the study.
Six of the nine successfully treated individuals have managed to maintain viral loads below 5,000 copies/mL – not 500 – after stopping their antiretroviral medications. Time off treatment so far has ranged from five to nine months.
Two persons maintained this level of viral suppression on their first treatment interruption and have not resumed treatment. After a brief initial viral load rebound to above 5,000 copies/mL, their viral loads have bounced from below 50 to over 1,000 copies/mL. At the time of the report, this fluctuating low viral load has continued for seven months in one study participant and nine months in the other.
Another seven study participants experienced enduring viral load rebounds within 50 days of stopping treatment the first time. Their viral loads ranged from 5,000 to over 50,000 copies/mL. They all restarted their anti-HIV medications and commenced a second treatment interruption about 100 days later. The one with the lowest rebound – who plateaued at 5,000 copies/mL during days 50 to 100 of the first interruption – did very well the second time around. This volunteer's viral load has since hovered around 500 for five and a half months. Two others have remained off drugs for five and six months, with viral loads fluctuating largely from below 500 to 5,000 copies/mL. (During this period, each has had one brief viral load blip to over 25,000 copies/mL.)
The four remaining study participants were not as successful with their second treatment interruption. After the second treatment halt, their fluctuating viral loads settled down in the 500 to 5,000+ range. Viral loads tended upward during the next several months. All four restarted therapy within two to six months. (At the time of restart, their viral loads were 4,600, 7,000, 11,000 and 17,000 copies/mL.)
The person who restarted therapy with a viral load of 7,000 (after an unplanned two-month treatment interruption due to hepatitis A-induced liver dysfunction) had a third interruption, with no better results. He restarted therapy after three months of viral loads mostly hovering around 5,000 copies/mL.
In sum, six of the 12 persons described in the Nature article have continued their treatment interruption while maintaining low viral loads. These viral loads fluctuate, and in one case viral load blips could be associated with intercurrent infections. At almost no time were viral loads while off drugs as low as they were before halting treatment. Until longer follow-up is available, Walker himself is unsure of the eventual outcome of the MGH cohort. He warns against "over-interpreting" the data.
Primary HIV usually appears as a nonspecific collection of symptoms that can include fever, swollen glands, sore throat, a short-lived spotty skin rash that can extend into the mouth and esophagus, muscle and joint pain, diarrhea, headache, nausea and vomiting. This initial syndrome of infection commonly goes unrecognized, and it would be a public health challenge to detect a substantial number of persons whose HIV infection is early enough that they can follow the Massachusetts General Hospital strategy. And even if early detection were possible, this strategy appears unworkable in many patients.
Preserving the healthy characteristics of those who successfully halt therapy will require very careful monitoring. One would have to be ready to resume therapy soon after HIV rebounds. Keeping track of the patients is another medical challenge raised by this early start-early stop strategy.
These challenges make wide public application of the early treat-early stop approach very difficult. They underlie researchers' desire to tease out the correlation between immune response and control of HIV in the MGH cohort. Walker said, "Over 30 more persons are lined up for this study and related ones. These studies will help tell us what part of the immune response is key to controlling HIV."
The Massachusetts General researchers associated control of HIV when off therapy with heightened activity by CD8+ cytotoxic lymphocytes (CTLs), which kill virus-infected cells. A promising sign was that the number of different epitopes (amino acid sequences extracted from HIV proteins) recognized by CTL clones in the volunteers' blood increased with each of the two treatment interruptions. Most importantly, lab assays indicated that the five successful study participants tended to have higher anti-HIV CD4+ T-helper proliferation during the periods off therapy in which viral loads went down. These T-helper cells modulate he CTL activity, greatly enhancing its duration and effectiveness.
These data on immune activity are as yet incomplete and preliminary. Still, they suggest comparisons with long-term nonprogressors (LTNPs). LTNPs keep viral loads low without drugs. They evince much greater anti-HIV T-helper activity than the average person with chronic HIV. Both their T-helper and CTL populations also detect and respond to a relatively broad range of HIV epitopes. Through the luck of genetics and environment, LTNPs' immune systems overwhelm HIV for long periods, if not for life. They have created a defense that HIV cannot escape by means of a few mutations that render it undetectable.
In the Massachusetts General Hospital patients, immunity was protected from the outset by antiretroviral therapy. These persons maintain whatever immune response the average person initially produces against HIV, and even after successive treatment interruptions, their responses usually do not equal the range or strength of those in LTNPs.
When off drugs, there is – so far – substantial replication, including viral load blips that reach into the thousands and tens of thousands. Escape mutants could well emerge after months and years without treatment. Runaway viral load would then suppress the CD4+ T-helper cell component of anti-HIV immunity. Of course, those with breakthrough HIV could go back on drugs. What happens after that is an open question since their immune systems have lost the struggle to erect an adequate and sustainable barrier against HIV. Viral diversity is greater than before, with the various HIV strains in the body built from an evolving and diverging set of protein sequences. It will be more difficult to create a second-line immune defense that is broad enough to recognize and act against all the HIV now in the body.
For Walker and others like Jay Levy of the University of California San Francisco, elucidating the protective elements of the immune response will allow creation of a much more controlled strategy applicable to larger numbers of people. Jay Levy said, "Walker's study shows that the immune system can control HIV, but a better approach would be to create a vaccine for use in people on therapy. Then you could create immune control of HIV without letting the virus replicate and infect more cells."
Walker is experimenting with several vaccine constructs, including the Remune killed HIV vaccine and a canary pox virus altered to produce HIV proteins. His group is administering these to persons with chronic HIV and plans eventually to try stopping antiretroviral drug therapy in some of the volunteers. These attempts may fail because the vaccines do not elicit the proper immune responses.
Even if a vaccine contains the best collection of antigens to trigger effective immunity, other problems may render it ineffective. Levy notes that vaccines like Remune "may not have the right delivery system." Attempts to promote antigen presentation have become a popular alternative to the current crop of vaccine candidates. Levy, Juliana Lisziewicz at the RIGHT Institute in Washington and Melissa Pope of the Aaron Diamond Research Center in New York, among others, all report early work on similar approaches involving genetically engineering patients' dendritic cells to produce HIV antigens. Dendritic cells are highly efficient at displaying foreign antigen on their cell surface to evoke specific T-helper cells' activation and proliferation.
The immune responses in the successful Massachusetts General Hospital cohort members will serve as a guide in improving the design of these vaccines. It will be worthwhile emulating those responses through a vaccine, although viral evolution as well as HIV's direct suppression of immune cell proliferation (see sidebar) may render those responses useless. A more in-depth and long-term analysis of this cohort's experience will yield a more realistic evaluation of the HIV-infected immune system's potential for controlling the virus and the extent to which medical assistance can help create a durable immune defense.
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