Research Initiative Treatment Action (RITA!); Vol 5, No. 2 April 1999
L. Joel Martinez
Since early in the AIDS epidemic immunologists and virologists have been involved in what seemed like a competitive race to find a way to control and perhaps eradicate HIV. With the advent of protease inhibitors and highly active antiretroviral therapy (HAART) it seemed that virologists had gotten an upper hand. After all, it was thought if the virus could be controlled immune reconstitution would follow. With determination and persistence the virus could be held at bay until its remaining embers were completely extinguished. At that point the body would be free of HIV and all pills could be happily flushed down a wide-mouthed toilet.
As with many dreams, this one fell short when it was found that HIV could persist in long-lived, resting CD4 T cells and when the estimates of time to total eradication kept getting longer and longer. Further, side effects possibly related to long term use of HAART have recently begun to be reported in increasing numbers. (See "Body Changes and Blood Abnormalities: The Lipodystrophy and Fat Redistribution Conundrum" on page 20 of this issue.)
In the interim, immunologists kept working on therapeutic approaches involving the immune system. Therapeutic vaccines like Remune and immune modulators like interleukin-2 (Proleukin), (See "Interleukin-2 for the Treatment of HIV Infection," on page 17 of this issue), are but a few of the approaches that are being actively investigated. Knowledge of the workings of the immune system continues to accumulate at a rapid pace. Immunology now seems ready to take center stage, yet its advances rely heavily on the virological advances of the past few years.
An HIV-infected Berliner has become the most famous nonadherent patient as a result of some accidental and unusual circumstances surrounding his case. The gay man was infected with HIV and was treated with a combination of didanosine (Videx), indinavir (Crixivan) and hydroxyurea (Hydrea) approximately 57 days after infection but before complete seroconversion. His viral load fell from approximately 85,000 copies1 to below 500 copies (the lower limit of quantification of the test) after 12 days of treatment. From day 15 to 22 all drugs were suspended due to an episode of epididymitis. During this first drug suspension his viral load rose to 5,356 copies. The drug combination was restarted and again the patient's viral load fell below the level of quantification.
Later a second interruption of treatment occurred as a result of an episode of acute hepatitis A. During this second suspension the patient's viral load remained below the level of quantification. Treatment with the same regimen was commenced but with intermittent adherence for a further 5 weeks. The patient permanently stopped therapy 176 days after its original introduction.
As of the 6th Conference on Retroviruses and Opportunistic Infections (6th CROI), 1999, scientists reported that the Berlin patient had shown no evidence of virological rebound during 551 days following permanent discontinuation of therapy. HIV was still detected in the patient's lymph nodes and in resting CD4 T cells but at low frequency. The CD4/CD8 ratio and the percentage of naïve cells in the patient had normalized.
There was evidence of continuing low level replication of HIV, eliminating the possibility of complete eradication. No neutralizing antibodies were found but strong HIV-specific T helper and CD8 cytotoxic T lymphocyte (CTL) responses were detected (6th CROI, 1999, Abstract 351).
It has been speculated that the Berlin patient has been able to control HIV as a result of low level, intermittent exposure to HIV. The spikes in viremia may have been enough to stimulate an immunological response and the drug therapy may have assured that HIV never overwhelmed the immune system. This type of exposuremdash;enough to prime the immune system, but not enough to cause diseasemdash;is the type of exposure hoped for in a vaccine.
Four patients who had been treated with ritonavir (Norvir), zidovudine (Retrovir) and lamivudine (Epivir) within 90 days of infection with HIV discontinued drug. Two patients whose viral load had reached unquantifiable levels (below 500 copies) had poor adherence to their drug regimen, discontinued drugs with subsequent viral rebound, resumed therapy for variable periods and finally ceased therapy altogether. One patient maintained unquantifiable levels of viral load for 21 months following cessation of therapy; the other patient maintained unquantifiable levels of viral load for 14 months after cessation of therapy. When therapy was suspended both patients had strong CTL responses against HIV.
In contrast the two other patients who had also reached unquantifiable levels of viral load (below 500 copies) on drug therapy, discontinued their regimen more abruptly. One patient maintained low levels of replication for four months but then viral rebound occurred. The second patient had a rapid viral rebound after discontinuation of drug therapy. In both patients rebound of virus correlated with the fading of CTL responses.
The difference in the pattern of discontinuation of these two sets of patients has led scientists to speculate whether the intermittent discontinuation of drug can lead to a boosting of the HIV-specific CTL response and may contribute to prolonged suppression after drug therapy is stopped.
Duplicating the results of the Berlin patient requires an understanding of the key elements that led to the desired result of host control of HIV. Is treatment during acute infection a controlling element? Is intermittent therapy always necessary? Is the use of hydroxyurea, a cancer drug not affected by viral mutation, a critical element to this result?
Franco Lori of the Research Institute of Genetic and Human Therapy (RIGHT) has begun experiments to try to answer these questions. At the 6th CROI, 1999, the preliminary results of Lori's experiments were presented. In one study three SIV-infected macaques were given stavudine, hydroxyurea and PMPA 28 days following exposure to SIV. Protease inhibitors are not active against SIV and thus PMPA was given in their place. The macaques were on therapy for two cycles of 3 weeks followed by treatment interruption. During the first treatment interruption viral load reached a steady state of less than 5,000 copies for 6 weeks. During the second interruption viral load remained below 200 copies and as of the time of the report had remained at that level for 100 days.
In a parallel trial, Lori studied 3 patients who had been treated within one year of primary infection with HAART and hydroxyurea. All had stable viremia (719,000, 22,665 and 33,707 copies). Three weeks of therapy were followed by one week of interruption, allowing viral load to rebound to approximately 5,000 copies. Therapy was reinstituted for another three months before a second interruption, again allowing viral load to rise to 5,000 copies. A third round of therapy was instituted for three months following the rise in viral load.
Following the first interruption it took 1 week for viral load to rise to 5,000 copies. After the second treatment interruption it took a mean of 14 days for viral load to return to the designated level of 5,000 copies and 37 days after the third interruption.
This is an ongoing trial with the continuous pulsing of therapy. The hope is that the time from interruption of therapy to viral rebound continues to increase so that perhaps at some point patients will be able to go off therapy altogether or only receive therapy in short pulses with long intervening periods without drugs. These trials will help decide if this is a viable treatment option for chronically infected individuals and whether this form of "self-inoculation" with viral spikes is an effective way of controlling HIV.
One of the primary problems in attempting to eradicate HIV has been the persistence of the virus in resting, latently infected CD4 T cells. These cells are long-lived and it is believed that drug therapy could not be sustained for periods long enough to exhaust these reservoirs. Is there was a way to quicken the turnover of these cells?
At the 36th Meeting of the Infectious Diseases Society of America, 1998 and at the 6th CROI, 1999, researchers from the National Institutes of Allergy and Infectious Diseases reported on the effects of IL-2 on the pool of latently infected, resting CD4 T cells. One group of patients was treated with IL-2 and HAART. Another group received only HAART. The patients receiving IL-2 and HAART had much lower levels of resting CD4 T cells carrying replication-competent HIV than patients receiving HAART alone.
Three patients studied showed no evidence of resting CD4 T cells infected with replication competent HIV despite the activation of up to 360 million cells. (See "Interleukin-2 for the Treatment of HIV Infection" on page17 of this issue.) Biopsies failed to find any HIV in the lymph nodes of two of these patients.
Despite the apparent success of the IL-2/HAART regimen in the study noted above there is evidence in other studies suggesting reservoirs are not cleared by the regimen. In a study published in The Lancet (353:9147, p.119, 1999) scientists reported HIV activity continued in patients with successful viral suppression whether or not they received IL-2.
The question of whether IL-2 clears latent reservoirs of infected, resting CD4 T cells remains unanswered. However, Anthony Fauci and his group at the National Institutes of Health have begun a trial to see whether persons with profound viral suppression as a result of HAART and IL-2 therapy may be able to suppress HIV without drugs. Participants are required to have viral loads of less than 500 copies for a minimum of one year, less than 50 copies for 30 days prior to enrollment and CD4 T cell counts above 350 cells/mm3. Fifty participants will be recruited to either stay on their drug regimen or to stop drugs. Therapy will be restarted if viral load reaches 5,000 copies or if there is a 25% drop in CD4 T cell count. As of this writing there is no report of any participant having a viral rebound.
Bruce Walker of Massachusetts General Hospital has been at the forefront of this type of drug termination trial, having been one of the first researchers to take a patient off drug therapy in a controlled setting. While he has been willing to conduct these experiments with careful controls, he and other scientists strongly warn patients that stopping therapy outside a research setting can be dangerous. Others have warned that this termination strategy may be overplayed before any real proof of efficacy can be established.
Small, intermittent spikes in viral load may provide the type of stimulation to the immune system to provoke its protective action. Whether these same spikes could result in damage to the immune system is unknown. One possible alternative is to provide a similar type of antigenic stimulation with a nonpathogenic therapeutic vaccine like the HIV-1 immunogen (Remune). The HIV-1 immunogen is widely known as the "Salk vaccine."
At the 6th CROI, 1999, a study by Fred Valentine of the New York University Medical Center and others reported that after 32 weeks a group of patients receiving HIV-1 immunogen and HAART had significant increases in functional immune responses as compared to a group of patients receiving only HAART and an adjuvant.
Ninety-four percent of patients receiving HIV-1 immunogen and HAART had viral load levels under 40 copies as compared to 75% of the control group. In addition, 87% of participants in the HIV-1 immunogen group had less than "1 copy" as compared to 50% in the control group.
All the experiments mentioned above are exciting and hold promise for the future. They are, however, preliminary results that are in the first stages of testing. Self-vaccination through intermittent therapy may turn out to be the Holy Grail of HIV control, but for the moment it must be approached with a degree of skepticism and care. Many other promising options have ended in disappointment. With some luck this may be a step in the right direction.
1 Throughout this newsletter "copies" represent "copies/mL."
Adjuvant: in vaccines, a substance added to increase the immune response to the inoculant.
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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
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