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July 30 - August 1, 1999 Published January 31, 2000 Workshop Summary II. STI Research Needs
Appendix I: Current & Planned STI Studies STRUCTURED TREATMENT INTERRUPTIONS WORKSHOP From 30 July to 1 August 1999, a diverse, international group of biomedical researchers, statisticians, clinicians, research administrators and community treatment advocates met to discuss and develop plans for research on structured treatment interruptions (STIs) in the context of highly active antiretroviral therapy (HAART). Participants reviewed observations to date, currently available virologic, immunologic and clinical hypotheses, and reviewed studies now underway or in the planning stages. They evaluated STI research in the context of fully-virally suppressed patients with primary or chronic HIV infection, and multi-drug resistant (MDR) patients who are failing to achieve full viral suppression. In a series of intradisciplinary and interdisciplinary breakout-groups, participants identified gaps in current STI research and developed several proposals and mechanisms to address these gaps, and to coordinate and expedite the overall STI research effort. Among the conclusions and follow-up steps to emerge by consensus from the STI Workshop were the following:
Workshop participants discussed these and other objectives. The following report summarizes the workshop proceedings and the discussions that led to the workshop conclusions and follow-up recommendations. The STI Steering Committee will undertake to facilitate their implementation. Preliminary Results: New Collaborations, New Data In late 1999 the STI Workshop steering committee solicited brief, one-paragraph summaries from workshop participants of new partnerships and research results which occurred as a result of the STI Workshop. The results are given below. Additional work has been submitted to the Seventh Conference on Retroviruses & Opportunistic Infections, and to peer-reviewed journals. We have recently completed a randomized study of structured treatment interruptions among patients experiencing long-term virologic failure with a protease inhibitor-based regimen. The objective of this clinical trial was to determine the effect of treatment interruption on the evolution of viral resistance and replication capacity ("fitness"), and to determine if changes in viral fitness predicted changes in viral replication and/or CD4 T cell turnover. Our primary hypothesis was that long-term CD4 T cell gains in the setting of virologic failure are associated with reduced viral fitness and prolonged CD4 T cell survival, and that discontinuation of therapy is associated with increased viral fitness, increased viral replication and reduced CD4 T cell production. Our secondary hypothesis was that drug discontinuation leads to loss detectable drug resistance and a durable response to subsequent salvage therapy. The primary outcomes of the study included: change in HIV RNA and CD4 T cell levels; change in viral resistance using both phenotypic and genotypic resistance assays, change in CD4 T cell turnover, change in spontaneous CD4 T cell apoptosis and change in viral fitness. Secondary outcomes included change in the quality of life. This study had both a randomized and non-randomized component. To be eligible for the randomized part of this study, patients must have met the following criteria: (1) long-term therapy with a protease inhibitor based regimen (&t;g 18 months), (2) documented evidence of virologic failure (HIV RNA > 5000 copies/mL) for the preceding 6 months, and (3) CD4 T cell count at least 100 cells/mm3 above pre-therapy nadir. Patients experiencing virologic failure but who had not had a sustained CD4 T cell count were entered into a single arm non-randomized observational study, and followed off therapy in an identical manner. Sixteen subjects with a sustained CD4 increase were randomized in a 2:1 manner to discontinue all antiretroviral therapy or to continue their stable regimen; 8 subjects who had not had a sustained CD4 increase were enrolled in the non-randomized arm. All subjects were seen weekly for 12 weeks and then every 4 weeks. Using a deuterated glucose/mass spectrometry method, CD4 and CD8 T cell turnover was measured at baseline and at week 12 (sooner in subjects restarted therapy). Viral fitness was measured using recombinant HIV-1 vectors expressing patient derived protease and reverse transcriptase genes and containing a luciferase indicator gene (this assay is similar to the PhenoSense drug susceptibility assay except that read-out is normalized for viral inoculum, and no anti-retroviral drugs are used). This study is now fully enrolled (24 adults; all male; 3 African Americans; 3 Latino). Results from drug susceptibility, viral fitness and T cell turnover assays are expected first quarter 2000. We have developed a large specimen bank (PBMCs, virus stock and plasma) and would be willing to collaborate with other participants from the STI workshop. - Steven Deeks, San Francisco General Hospital There's been plenty of attention focused on STIs at DAIDS. Immediately following the STI Workshop last August, we held the Therapeutic Vaccines meeting, in which STIs were discussed both as a vaccination strategy, either alone or in combination with a vaccine, and also as a means of testing the efficacy of a vaccine or other immune-based therapy, by interrupting antiretroviral therapy at the end of the clinical trial and seeing if the immune-based therapy enhanced the host's immunologic containment of the virus. These issues will be addressed again in May, at the 2000 Immune Reconstitution and Surrogate Markers in HIV/AIDS Meeting, which we've been developing through the sponsorship of the Institute of Human Virology. I've continued to talk with colleagues at the FDA, who will probably be convening an advisory panel meeting in June, to address endpoints in clinical trials and will doubtless include a discussion of how to regard surrogate marker changes that may arise as a result of STI. I've assisted Bob Redfield in designing a therapeutic tat vaccine study that employs an STI at the conclusion. We are now in the process of designing a concept to bring to the ACTG for further development of tat vaccines, and the final protocol design is likely to employ an STI, once safety, immunogenicity, and biological activity have been demonstrated. Three ACTG protocols are in the final stages of development, that employ STI in subjects with chronic HIV disease, good viral suppression on HAART and CD4 counts >500. ACTG 5063 will look at the effects of cycles of STI in such a population, ACTG 5068 will look at a therapeutic vaccine plus cycles of STI, and ACTG 5024 will explore the effects of therapeutic vaccine or IL-2 or both, using an STI at the conclusion. I am the medical officer for those three protocols. A protocol is under development in the ACTG looking at the effect of STI for patients in need of salvage antiviral therapy. The CPCRA protocol for STI+salvage therapy that was discussed both at the STI workshop and at the Immune Restoration Think Tank is in the final stage of development. The final modifications that are being worked on in the CPCRA protocol are safety checks to make sure the trial is halted if we see the pattern of CD4 fall following STI without return to baseline when therapy is resumed, that was seen in the Frankfort study presented at the summer workshop. A trial is planned by the intramural division of the NIAID, comparing continuous HAART to cycles of HAART and STI, looking at whether the two strategies might simply be equivalent in terms of disease progression. Thanks for the opportunity to participate in the very valuable workshop. - Larry Fox, Division of AIDS, NIAID, NIH STIs in already responding patients are a strategy to boost the immune system. In our hands, after two cycles of interruption, four out of nine patients developed a spontaneous drop of plasma viral load coincidentally with the recovery of proliferative and cytotoxic activity against HIV antigens. For the moment, this should be considered exclusively a research activity not applicable for routine clinical practice. Moreover, STIs in already responding patients should be clearly differentiated from drug holidays in failing patients. - José M. Gatell, Universidad de Barcelona The STI Workshop reinforced the enthusiasm of the ACTG [Adult AIDS Clinical Trials Group] A5063 protocol team (chair: Ian Frank, MD/University of Pennsylvania; co-chairs, Joe Eron, MD/University of North Carolina; and Trip Gulick, MD, Cornell University). A5063 is a study of STIs in a group of chronically HIV-infected subjects taking antiretrovirals with maximal virologic suppression. Subjects will undergo four repeated cycles of treatment interruption and reinitiation. In addition, enthusiasm was generated for development of the ACTG A5086 study (chair: Connie Benson, MD/University of Colorado; co-chairs: John Mellors, MD/Pittsburgh; and Diane Havlir, MD/University of California at San Diego). A5086 is a study of STIs in a group of HIV-infected subjects experiencing virologic breakthrough. Subjects will be randomized to initiate a "salvage" regimen based on resistance testing either immediately or after an eight-week STI. The primary endpoint will be virologic suppression at 24 weeks after starting treatment. - Roy "Trip" Gulick, Cornell University Medical Center The meeting was successful in bringing investigators from around the world and from multiple disciplines to the same table, to discuss a wide range of issues related to structured treatment interruption. Although considerable and growing excitement surrounds this concept, very little has been published to date about the immunologic, virologic, and clinical effects (not to mention the risks) of such a maneuver. The discussion thus seemed to fill a void, to focus attention on multiple layers of interrelated issues and - perhaps most importantly - to highlight areas of potential collaboration. Given the complexity of the problem and the urgency with which it needs to be addressed, I can think of no more efficient way to move forward. - J. Michael McCune, The Gladstone Institute, UCSF It is a tribute to the organizers, the speed and the effective manner in which they have captured the emergence of a field of study in AIDS therapy. The discussion the workshop facilitated will have great impact on how all attendees will design and execute studies in this area by addressing consensus views on goals, safety and quality of life issues that otherwise may have been undefined (or highly varied among prospective studies). In summary, the workshop did great service to researchers and people infected with HIV-1 by facilitating a coordinated and "peer-reviewed" approach to what may be the hopeful approach to AIDS therapy to date. We have completed the analysis of a detailed observational study in five chronic infected/suppressed persons who interrupted therapy as compared to five untreated controls. Although data continue to be gathered, analysis to date supports that CD4 and CD8 T cell HIV-1 specific responses can be boosted in this subset of patients in association with viral rebound. Planned studies are centered on applying the results from the observational data into a prospective clinical trial to test safety and the immune and viral outcomes of HIV-1 therapy interruption following sequential STIs of varying duration. A single center, randomized, non-blinded study is planned as a collaborative team effort by Drs. L.J. Montaner (Wistar Institute), R. Gross (University of Pennsylvania), J. Kostman (Jonathan Lax Treatment Center), D. Nixon (Aaron Diamond AIDS Research Center), M. McCune and R. Grant (both from UCSF's Gladstone Institute). - Luis Montaner, The Wistar Institute The main new area concerning use of STIs that I've been working on since June is on the re-design of the Quest study. This is a Glaxo-Wellcome study of primary infection patients that was originally designed to try to document viral eradication. All patients are given all 4 GW drugs. They were originally going to be randomized to drop amprenavir or not at 18 months. Then at 2 years anyone with no evidence of active infection would stop therapy to assess if there is viral rebound. We now have assays of course which mean we always know there is replication competent virus around. The adapted design will drop the 4 vs 3 comparison and instead randomize to adding a vaccine or not. The endpoint will be assessed by looking at the time to viral rebound above some cut-off (perhaps 1000 copies). The idea is to see whether use of vaccines in PHI-treated patients can affect the viral "set-point". On a separate note, I have discussed with Mike Youle doing a study of patients virologically failing on a regimen. Resistance testing is done then they are taken off all drugs and then restarted on the same regimen, to see whether re-suppression with the same regimen is ever possible... He's done this for a few patients, one of whom who has just restarted. I guess the overall impression from the July meeting was to make us slightly more wary about stopping, especially in those with low CD4 nadir. I was also involved in a discussion with MRC and know that they are now planning jointly with the Canadian HIV Trials network a comparison of STI vs. no STI before starting salvage regimen, along the lines I was suggesting in Boston. This is a 2x2 factorial, also comparing "mega" and "mini" HAART. - Andrew Phillips, Royal Free Hospital STRUCTURED TREATMENT INTERRUPTIONS WORKSHOP I. INTRODUCTORY PRESENTATIONS Introductory presentations focused on:
Subsequent discussions focused on:
Finally, the workshop identified four working groups to carry out five specific tasks which emerged:
A. PRELIMINARY OBSERVATIONS
Researchers from the Aaron Diamond AIDS Research Center (ADARC) have shown that slower decay rates in the latently infected cell compartment (L cell) occur in people who have intermittent episodes of plasma viremia (>50 but <500 copies/ml) while on HAART. Those with more than two episodes of intermittent viremia per year had non-decaying L cell slopes. Treatment interruptions have been studied in several settings:
These patients were later challenged with mega-HAART regimens. Patients who had experienced an STI seemed to have an independently elevated chance of going beneath the limit of quantitation when resuming therapy. There were important differences in the Frankfurt patients between those whose virus shifted to wild-type (WT) and those whose virus did not shift. CD4 T cell Count Changes in Frankfurt
Those who experienced a treatment interruption and had a viral shift back towards wild-type had a five-fold greater chance of having their viral load go beneath the limit of quantitation (500 copies/ml) than those who did not revert to wild-type during the interruption. However, there is a major unresolved risk/benefit equation in the disconnect between rising viral load and persistently elevated CD4 T cell counts in patients experiencing partial suppression. The immunologic benefit may persist, but at the cost of the further evolution of multi-drug resistance. The disconnect between viral load and CD4 T cells in partial suppression - disconnect vs. further evolution of MDR. How far will those viruses evolve? B. VIROLOGIC ISSUES Several observational studies have observed temporary containment of HIV replication during treatment interruptions. The HIV-specific CD4 T cell response seen in Franco Lori's Berlin patient increased despite a lack of significant viral outgrowth. Why is viral load contained (for variable periods) in some individuals who interrupt treatment?
We know that in most PHI patients there is a quick rebound in virus levels, but in some individuals there is a delayed rebound. Usually the subsequent response to therapy has been good with no evidence of drug resistance.
The results have been similar to the PHI patients.
Before treatment, the HIV/CD4 T cell interaction typically leads to advanced disease (AIDS). When intervening with HAART, suppressing HIV replication reduces the HIV/CD4 interaction and reverses disease. When measurable plasma viremia returns, disease progression eventually resumes (although possibly in different forms). So the question of stopping therapy immediately raises the danger that the patient will experience an immediate recurrence of the HIV/CD4 interaction that could once again lead to progression. It is unclear whether the timing and pace of progression, however, follow the same patterns as seen in natural history data. C. IMMUNOLOGIC ISSUES
What is the effect of suppressive HAART on HIV-specific immune responses?
What is the effect of drug discontinuation on viral load and HIV-specific immune responses?
II. STI RESEARCH NEEDS
Several practical study design considerations were raised:
Baseline data to be gathered:
Longitudinal data to be gathered:
Virologic data to be collected during the studies (some variation due to varying hypotheses): Virologic Data of Interest in STI Clinical Trials
What are the differences between primary HIV infection (PHI) and early disease? PHI patients have very high viral loads - often in the millions. They haven't established a viral setpoint yet, or even necessarily seroconverted. By contrast, "early" patients have seroconverted and have established a setpoint. To distinguish between the two, use the "detuned ELISA" from Busch (Irwin Memorial Blood Bank, San Francisco). Whether differences exist between the two groups, and how significant they are, is unknown. We don't know, so both should be studied. Both groups, especially PHI, are difficult to identify and study. It might be helpful to quantitate the level of antigen exposure and give therapy (or restart therapy) only after people have seen "enough" antigen. The trial design and endpoints were left unresolved. There was no consensus on whether the primary endpoint should be where the viral setpoint would land, or time to relapse, or preservation of CD4 T cell cells. But there was general consent on the need for a comparison group and a control group who are not treated during PHI. There should be multiple rounds of STIs over one to two years in a group treated during PHI, cycling on and off therapy, comparing the viral load setpoint in that group to a continually treated group and an untreated group. Both treated groups would come off therapy at a later timepoint and see where the setpoint lands, or compare time to relapse. C. Studies in People Chronically Infected / SuppressedThere is a need for two studies, one for those with viral load below 50 copies/ml (profoundly suppressed) and those with 50-5,000 copies (partial suppression). In both populations, individuals would be randomized to continual vs. intermittent HAART, or HAART with one (or more) STIs. Therapy would be resumed in people in the STI group when the CD4 T cell count dropped below 300. The endpoints would be 1) the proportion of people who respond to HAART after re-initiation of therapy, or 2) both viral load declines and CD4 T cell rebounds post re-challenge. The studies should be stratified by pre-treatment and baseline viral load. The studies also need to incorporate an evaluation of the impact of hydroxyurea, which blunts CD4 T cell responses. There needs to be an evaluation of whether the studies are doing patients harm. D. Studies for Chronically Infected / Unsuppressed (viral load detectable)There are profound differences between people with unsuppressed viral load and high CD4 counts and those with similar viral load but falling CD4 counts, for whom the drugs may be providing no benefit at all. While return to wild type virus may increase the chances of future response to therapy, if it fails to result in renewed ability to suppress virus, it may do harm. Wild type is the pathogenic virus which originally led to immune depletion and the decision to initiate therapy. It's quite possible that the drug-resistant, but possibly less fit, virus is less pathogenic and hence more desirable. Some researchers would prefer to understand pathogenesis better in this subgroup before generating new hypotheses.
Observational Database There needs to be an observational database to:
Prospective Observational STI Cohort Study
The laboratory tools involved in assessing STIs are complex and not universally accessible. A Laboratory Working Group was set up to help ensure that researchers have access to relevant technologies, including viral resistance assays, HIV reservoir samples, and immune activation markers. STI Laboratory Working Group Volunteers
It is important to develop and promulgate a statement about what is known and issues to consider for researchers, clinicians and people with HIV when considering an STI. The Guideline would:
STI Clinical Practice Guideline Working Group
The issue of STIs for people taking drugs with long half-lives such as efavirenz and nevirapine is complicated by the fact that patients may have to stop their NNRTIs before stopping their nucleoside analogues and/or protease inhibitors. Based on these basic principles:
Several researchers indicated an interest in coordinating work on patients who are heavily pre- treated, not fully suppressed, and have few treatment options. This will be particularly useful for sharing information relating to protection of patient safety. Salvage / MDR Working Group Volunteers Steven Deeks APPENDIX I -- CURRENT & PLANNED STI STUDIES - I
APPENDIX II -- STI WORKSHOP PARTICIPANTS
APPENDIX III -- REFERENCES Acosta EP. The promise of therapeutic drug monitoring in HIV infection. Medscape HIV/AIDS 5(4), 1999. Alcorn K. Brussels and Barcelona patients join Berlin patient in lack of viral rebound after treatment break. AIDSmap.com, 1999. André P, Groettrup M, Klenerman P, et al. An inhibitor of HIV-1 protease modulates proteasome activity, antigen presentation, and T cell responses. Proc Natl Acad Sci USA 95(22), 13120-13124, 27 October 1998. Balter M. Can immune systems be trained to fight HIV? Science 286, 19 November 1999, 1470-1. Blanchard P. The effects of planned treatment breaks prior to multidrug rescue therapy regimens (MDRT). AIDS Treatment Project Doctor Fax 69, 4 June 1999. Brown D. HIV respite is brief: Subjects relapse after halting treatment. Washington Post, 9 May 1999, A1. Cimons M. Patients welcome experimental halt in AIDS drugs - but virus returns: Scientists were not surprised that undetectable HIV rebounded in test but results are expected to benefit research. Los Angeles Times, 15 May 1999. Cohen J. Exploring how to get at and eradicate hidden HIV. Science 279(5358):1854, 20 March 1998. Dalod et al. Evolution of cytotoxic T lymphocyte responses to human immunodeficiency virus type 1 in patients with symptomatic primary infection receiving antiretroviral therapy. J Infect Dis 1998 178:61-9. D'Aquila R. Replicative fitness of protease inhibitor-resistant mutants of HIV-1. HIV/AIDS Treatment Update, Medscape 1999. Davey RT. Structured withdrawal of HAART in HIV-1 infected patients. Medscape HIV/AIDS 5(5), 1999. Davey, RT, Bhat N, Yoder C, et al. The NoHRT trial: a prospective study of cessation of HAART in HIV- infected patients after prolonged viral suppression. Abstract I-269, 39th ICAAC, San Francisco, 1999. Deeks S. Second International Workshop on Salvage Therapy for HIV Infection. Medscape HIV/AIDS 5(3), 1999. Deeks S, Barbour J, Swanson M, et al. Sustained CD4 T cell response after virologic failure of protease inhibitor based regimens: Correlation between CD4 and viral load response after two years of therapy. Abstract 494, Sixth Retrovirus Conference, Chicago 1999. Delaney M. Research for the new millennium: A five-point plan that HIVers can live with. POZ, January 1999. Delaney M. Happy holidays. POZ, December 1999, 78-81. Devereux HL, Youle M, Johnson MA, Loveday C. Rate of decline of resistant viruses. AIDS 1999, 13:123-7. DeWit S. Kabeya K, Hermans P, Clumeck N. Discontinuation of therapy after treatment for primary HIV infection (PHI). Abstract 413, Seventh European Conference on Clinical Aspects and Treatment of HIV Infection, Lisbon, 1999. Garcia F, Plana M, Vidal C, et al. Dynamics of viral load rebound and immunological changes after stopping effective antiretroviral therapy. AIDS 1999 13:F79-86. Gilden D. Absence makes the HAART grow fonder. GMHC Treatment Issues, 13(2), February 1999. Gray CM et al. Frequency of class I HLA-restricted anti-HIV CD8+ T cells in individuals receiving highly active antiretroviral therapy (HAART). J Immunol 1999 162:1780-8. Harrigan RP, Whaley M, Montaner JSG. Rate of HIV-1 RNA rebound upon stopping antiretroviral therapy. AIDS 13(8), F59, 28 May 1999. Harrington M. Slouching towards a cure? HIV Plus 1(2), December 1998/January 1999 Harrington M. New approaches to structured treatment interruption & pulsed-dosing therapy in HIV infection. Unpublished manuscript, May 1999. Hel Z, Poudyal M, Tsai W-P, et al. Therapeutic immunization with NYVAC-SIV controls viremia following antiretroviral therapy suspension in SIV251-infected macaques. Cent Gardes Symposium Program & Abstracts, 1999. Ho D. Personal communication, 19 January 1999. Jubault V, Burgard M, Le Corfec E, et al. High rebound of plasma and cellular HIV load after discontinuation of triple combination therapy. AIDS 1998 12:2358-9. Kalams SA, Goulder PJ, Shea AK, et al. Levels of human immunodeficiency virus type 1-specific cytotoxic T- lymphocyte effector and memory responses decline after suppression of viremia with highly active antiretroviral therapy. J Virol 1999 73:6721-8. Knox RA. Some patients controlling HIV after stopping drug cocktail. Boston Globe, 26 January 1999. Lisziewicz J, et al. HIV-1 suppression by early treatment with hydroxyurea, didanosine, and a protease inhibitor. Lancet 1998 352:199-200. Lisziewicz J, Rosenberg E, Lieberman J, et al. Immune control of HIV after suspension of therapy. Abstract 351, Sixth Retrovirus Conference, Chicago, 1999. Lisciewicz J, Rosenberg E., Lieberman J, et al. Control of HIV despite the discontinuation of antiretroviral therapy. N Engl J Med 340(21):1683-4, 27 May 1999. Lori F, Zinn D, Varga G, et al. Intermittent drug therapy increases the time to viral rebound in humans and induces the control of SIV after treatment interruption in monkeys. Abstract LB5, Sixth Retrovirus Conference, Chicago 1999. Lucas GM. Mending a broken HAART: A report from the 2nd International Workshop on Salvage Therapy. The Hopkins HIV Report, Baltimore, July 1999. Miller V, Gute P, Carlebach A, et al. Baseline resistance and virological response to mega-HAART salvage therapies. Abstract 130, Sixth Retrovirus Conference, Chicago 1999. Miller V, Rottman C, Hertogs K, et al. Mega-HAART, resistance and drug holidays. Abstract 030, Second International Workshop on Salvage Therapy of HIV Infection, Toronto, 1999. Morris L, Binley JM, Clas BA, et al. HIV-1-antigen-specific and -nonspecific B cell responses are sensitive to combination antiretroviral therapy. J Exp Med 1998 188:233-45. Neumann AU, Tubiana R, Calvez V, et al. HIV-1 rebound during interruption of highly active antiretroviral therapy has no deleterious effect on reinitiated treatment. AIDS 1999;13:677-683. Ogg GS, Jin X, Bonhoeffer S, et al. Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 1998 279:2103-6. Ogg GS, Jin X, Bonhoeffer S, et al. Decay kinetics of human immunodeficiency virus-specific effector cytotoxic T lymphocytes after combination antiretroviral therapy. J Virol 1999 73:797-800. Ortiz GM, Jin X, Demoitie MA, et al. Containment of breakthrough HIV plasma viremia in the absence of antiretroviral therapy is associated with a broad and vigorous HIV specific cytotoxic T lymphocyte (CTL) response. Abstract 256, Sixth Retrovirus Conference, Chicago 1999. Ortiz GM, Nixon DF, Trkola A, et al. HIV-1 specific immune responses in subjects hwo temporarily contain virus replication after discontinuation of highly active antiretroviral therapy. J Clin Invest, September 1999, 104(6), R13-R18. Piscitelli SC, The limited value of therapeutic drug monitoring in HIV infection. Medscape HIV/AIDS 5(4), 1999. Pitcher CJ, Quittner C, Peterson DM, et al. HIV-1-specific CD4 T cells are detectable in most individuals with active HIV-1 infection but decline with prolonged viral suppression. Nature Medicine 5(5):518, May 1999. Richman D. The challenge of immune control of immmunodeficiency virus. J Clin Invest, September 1999, 104(6), 677-8. Rosenberg ES, Billingsley JM, Caliendo AM, et al. Vigorous HIV-1 specific CD4+ T cell responses associated with control of viremia. Science 1997 278:1447-50. Ruiz L, Martinez-Picado, J, Romeu J, et al. Structured treatment interruption in chronically HIV-1 infected patients after long-term viral suppression. Abstract 1224, Seventh European Conference on Clinical Aspects and Treatment of HIV Infection, Lisbon, 1999. Siliciano R. HAART for life. The Hopkins HIV Report, Baltimore, July 1999. Smart T. Going wild (type) with structured treatment interruptions (STIs). GMHC Treatment Issues 13(9/10), September/October 1999, 3-4. Spiegel HML, DeFalcon E, Ogg GS, et al. Changes in frequency of HIV-1-specific cytotoxic T cell precursors and circulating effectors after combination antiretroviral therapy in children. J Infect Dis 1999 180:349-68. Staszewski S, Miller V, Sabin C, et al. Rebound of HIV-1 viral load after suppression to very low levels. AIDS 1998 12:2360-1. Vila J. Absence of viral rebound after treatment of HIV-infected patients with didanosine and hydroxycarbamide. Lancet 1997 350:635-6. Waldholz M, Tanouye E. Studies will see if drug holidays for HIV patients can lead to vaccine. Wall Street Journal, 16 February 1999, A1. Woodward WC, Yozviak JL, Doerfler RE. Intermittent antiretroviral therapy (ART) can induce reduction of viral rebound during ART interruption. Abstract 236, Seventh European Conference on Clinical Aspects and Treatment of HIV Infection, Lisbon, 1999. 1 ADARC's John Moore explained the importance of measuring coreceptor expression patterns during STIs. When "a small burst of viremia is associated with a much greater decline in CD4 T cell count... during the period of limited viremia, the population of circulating CD4+ CCR5+ activated T cells increases, and these are excellent targets for HIV-1 infection. A small blip in viremia could easily take out a disproportionately large fraction of the circulating T-cell pool under these conditions. Normally, CCR5+ cells are only a minor fraction of the total, and this fraction is diminished during active infection... The differential susceptibility to ... infection and the different virus production capacity of different subsets needs to be taken into account." (John Moore, personal communication). * * * |
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