HIV Persists Despite HAART
This possibility is especially distinct given that maintaining optimum therapy and maximal viral suppression becomes more and more difficult as the years go by. Adherence to the complex dosing schedules is increasingly fatiguing, and, in any case, the difficulty in managing the drugs' long-term side effects makes continuing them for years problematic. Therefore, Dr. Lange hypothesized, it might be better to put off initiating therapy until people are at risk for serious health problems.
Behind Dr. Lange's concession has been a series of disappointing studies in the recent past. Chief among these unhappy results has been the discovery that residual (ongoing) HIV replication occurs despite drug therapy. In his ICAAC lecture, David Ho, M.D., of the Aaron Diamond AIDS Research Center (ADARC) in New York at one point flashed a slide displaying a cell harboring such replication. The cell came from a person with HIV whose viral load had been suppressed for almost three years below the limit of detection using the most sensitive assays.
The existence of residual replication had previously been inferred from reports like the one published by Johns Hopkins University researchers a year ago. The Johns Hopkins group found virtually no decrease in the pool of cells latently infected by HIV even with 3.5 years of successful HAART. The latent pool is considered HIV's final redoubt. Current drugs cannot touch HIV that is not biologically active. The immune system itself has no way of finding and eliminating cells with completely quiescent, or latent, HIV. (Research is underway to facilitate purging of that reservoir, as discussed later.)
The implication was that the latent pool was slowly being replenished with fresh infected cells as its older constituents died. The researchers did propose a best-case scenario in which replenishment did not quite reach 100% and HIV petered out in the end, after about six decades of successful treatment. The extent of residual replication was incorporated into a mathematical model published by William Paul, M.D., former director of the National Institutes of Health (NIH) Office of AIDS Research, Dr. Lange, and others in the October 1999 issue of Nature Medicine.
According to Dr. Paul, HIV replication occurs in localized bursts as virus-producing cells send a wave of virions (complete virus particles) at their uninfected neighbors. So much virus is present that it becomes probable that some will pass through the wall of protection presented by the drugs. There are also differences in drug levels from tissue to tissue and from cell to cell. Besides, different HIV particles have varying degrees of vulnerability to treatment.
"The present drugs are not potent enough to kill off all the virus. That's also true in other diseases, but there, the immune system cleans up the residual infection. Here, close is not good enough," commented lead author Roger Pomerantz, M.D., of Thomas Jefferson University. The report was published in the November 3, 1999 issue of the Journal of the American Medical Association.
Probably not everyone receiving therapy that was thought to be suppressive (before the advent of more sophisticated testing methods) has some actively replicating HIV, but most seem to. Reports similar to the Philadelphia one have since cropped up in medical journals and at the 7th Conference on Retroviruses and Opportunistic Infections (CROI) held in San Francisco this past winter.
Dr. Ho's group at the Aaron Diamond AIDS Research Center reported in January that the slow decline in the numbers of cells containing quiescent HIV is related to the frequency of transient "blips" (very low but detectable levels of HIV RNA) in viral load. The group looked at 33 people who had been on HAART for 13 to 36 months and generally kept their viral loads below 50 copies/mL. All but 12 had occasional transient peaks above the 50-copies/mL limit. The average number of these blips ranged from 0.4 to 5.8 per year. Those with the highest number of blips showed increases in the number of latently infected cells.
A poster at the 7th CROI by R.P. Bucy and colleagues described testing 28 people for the existence of the HIV RNA genome within their immune cells, a marker of virus in the process of reproducing. This RNA was found in every specimen from every individual, regardless of whether he or she experienced viral blips or not. The level of RNA, detected at an average of 277 copies per million white blood cells, was also independent of the length of time on HAART, even in those with no blips. The actual number of virus-producing cells was low, as each such cell contained about 1,000 copies of HIV RNA.
Those who are treated very early, during primary infection just after contracting HIV, also showed residual replication. A study done by S. Yearly and colleagues from Switzerland and presented at the 7th CROI found low levels of HIV-producing cells for at least two years after extreme viral suppression (plasma viral load below 3 copies/mL) in a cohort of 12 persons treated during primary infection.
This residual virus that exists despite HAART might only represent a single "round" of replication. Most likely, this replication originates in latently infected cells that become activated and produce HIV, which is then largely blocked by the antiviral drugs in a person's system. Yet that hopeful possibility was undermined by a study done by Tae-Wook Chun, M.D., who works with Anthony Fauci, M.D., at the National Institute of Allergy and Infectious Diseases (NIAID). Dr. Chun and his associates examined nine persons who temporarily went off therapy, only to see their HIV population reach pretreatment levels within one to two months. When the researchers examined the genetic makeup of this new population, they found that in seven out of nine cases, it exhibited marked differences from that found in latently infected cells.
If not from the latently infected cells, then where does this replication come from? Currently, the answer is unknown. Another small study described at the 7th CROI sought to unravel that mystery. T. Zhu and colleagues studied the genetic variations in the HIV of 12 individuals. The newly formed virus arose in activated CD4 cells and monocytes and, again, differed genetically from that found in the resting, latently infected CD4 cells. The latently infected cells contained HIV that genetically looked like variants formed by activated cells in an earlier time period. The residual ongoing replication then contributes to the pool of latently infected cells to a much greater degree than the latently infected cells feed residual replication.
The reality of this danger was underscored at the 7th CROI by Richard D'Aquila, M.D., of Harvard Medical School, who described an intensive genetic analysis of HIV clones isolated from people with viral loads consistently below 50 copies/mL. Five people were on their second drug combination and were experiencing occasional viral load blips in the course of two years of therapy. All five had prior resistance-associated mutations, but all five also bore evidence of additional mutations in at least some of the isolated HIV. In contrast, no new mutations could be detected in seven without viral load blips.
Detection of drug resistance arising during successful HAART is everyone's great fear because it would indicate that HAART-induced suppression of HIV is inevitably limited in duration. Before any conclusions can be reached, however, many issues in this study require resolution. For one thing, most of the mutations may have appeared in the early weeks of HAART, before HIV was maximally suppressed. The development of drug mutations might be due to a slower viral replication decline in certain people.
Dr. D'Aquila's study is ultimately limited by the sensitivity of his research assays, which makes it difficult to pinpoint when mutations associated with drug resistance first appear. It might simply take longer for the people without viral load blips to produce mutated HIV in detectable quantities. The appearance of additional drug resistance was charted in one subject after a mere one-week blip, but that mutation may have already existed for some time, its origin occurring as some point between blips.
Dr. D'Aquila commented, "The take-home message is that there is still drug selection pressure on whatever little virus is still replicating. It is not the case that there is virus [in the body] with absolutely no exposure to the drugs." Again, HAART's wall of protection is not quite high enough. Dr. D'Aquila's subjects, meanwhile, continue to do as well as before; their viral load remains undetectable without changing therapy. The current mutations confer only slight resistance. The need for a preemptive alteration of the subjects' regimens, before further resistance evolves, is another of this study's open questions.
Structured Treatment Interruption" in this issue).
Interest redoubled when it was realized that successful HAART treatment brought HIV levels so low that not enough was left to stimulate an anti-HIV immune response. What remained of that response in untreated people with HIV declined after they commenced therapy.
The 7th CROI featured reports of no fewer than 20 STI studies, all in very preliminary stages. It was difficult to tell from this initial data whether the treatment pauses did any good. A common observation in these studies was that anti-HIV immune response increased during STI. These responses were measured by tests of cell proliferation (replication) or interferon-gamma production among cells removed from subjects and cultured in the lab in the presence of HIV proteins.
The group led by Bruce Walker, M.D., at Boston's Massachusetts General Hospital has been conducting a highly publicized STI study in seven individuals whose treatment began during primary HIV infection. According to a poster at the 7th CROI by M. Altfeld and colleagues, cytotoxic (cell-killing) T-lymphocyte, or CTL, responses to HIV greatly broadened and increased in frequency during STI. Three persons who have gone through two or three STIs maintained their viral loads around 5,000 copies/mL for 8-17 weeks after an initial peak in HIV levels. All three decided to go back on therapy and try another STI later on, in an effort to reach a lower viral equilibrium.
Viral loads in the 1,000-10,000 copies/mL range are not exceptional in persons with chronic HIV infection, and the Massachusetts General study subjects may have been properly cautious when they decided to recommence therapy. It is not certain that the observed increases in anti-HIV immunity will have any long-term protective effect. After all, such immune responses frequently arise early in HIV infection, but eventually fail to control HIV, as the infection annihilates the CD4 cells that orchestrate them.
Indeed, the improvements in HIV immunity observed during STI may not be newly created, just newly detected. The cells involved may have always been there. In treated people, there may not be enough HIV to activate them. In those who are untreated, the CD4 cells are unable to proliferate and defend the body in the face of chronically high levels of HIV. If they did manage to survive (as shown in a monkey model) and control HIV, the virus would have mutated to escape the protective immune cells the way it manages to escape effective medication.
The most successful of the 7th CROI STI studies involved an unconventional therapy -- just ddI plus hydroxyurea for a period of over three years. This combination of a single nucleoside analog and an inhibitor of host (human) cell metabolism kept viral loads stable at an average 549 copies/mL among nine persons, only one of whom had a viral load below 50 copies/mL. The nine (known as the PANDA cohort) were matched with eight people on HAART for two years, six of whom had viral loads below 50 copies/mL (the other two were below 400 copies/mL). All 17 were taken off therapy for eight weeks. Treatment was to resume earlier if viral loads rose above 10,000 copies/mL or CD4 cell counts dropped below 200 cells/mm3.
After eight weeks, six of the eight HAART recipients had restarted therapy, but none of the hydroxyurea cohort had. As Franco Lori, M.D., and the other authors of this report have noted before, many of those in the hydroxyurea group had comparatively high anti-HIV immunity during their years of partially suppressed HIV. This may have made the difference.
But beware of accounts of small numbers of people who can stop therapy without viral rebound. It appears that there have always been such people and that a given individual's ultimate equilibrium viral load after stopping therapy is close to what he or she had before therapy began (the original "set-point"). Two recent studies argue for this conclusion.
A research group in Southeast Asia and the U.S. has found 13 people on double nucleoside analog (NRTI) combinations who kept their viral loads below 500 copies/mL for more than 90 days after stopping treatment. Pretherapy viral loads (available for seven) were very low (ranging from below 500 copies/mL to 9,000 copies/mL).
At the 2nd Frankfurt Symposium on the Clinical Implications of HIV Resistance, held February 25-27, 2000, in Frankfurt, Germany, Richard Harrigan, M.D., presented results from a survey of the cohort from the BC Centre for Excellence in HIV/AIDS in Vancouver. His study compared pre- and post-therapy viral load in 238 individuals who stopped therapy for at least 90 days.
Final viral loads after stopping therapy were, on average, very close to the pretherapy equilibrium, or set-point. (Eight of the 15 had no pretherapy data available.) The individuals who kept their viral loads below 400 copies/mL after stopping therapy all had very low set-points to begin with. Their median pretreatment viral load was less than 1,500 copies/mL, although one person had a pretreatment viral load of 10,000 copies/mL.
Dr. Harrigan later commented, "Personally, I think that most of the people who keep their HIV largely suppressed during an STI or upon complete discontinuation of therapy are those who had low pretreatment set-points. There might be some people who had a high pretherapy viral load -- for example, those treated during primary infection before they reached a viral load equilibrium. But the simplest assumption might be that there are no lingering effects of treatment in most cases."
One study did find an unfortunate side effect of treatment interruptions. Researcher J.M. Orenstein and colleagues monitored five volunteers and found that after treatment ceased, lymph nodes quickly showed signs of excess cell activation (within one to two months) and started to degenerate in the manner typical of HIV infection. Previous reports had shown that lymph node architecture can recover during viral suppression, but an STI appears to reverse this trend. There also was reseeding of the latently infected cell pool after therapy stopped. The five subjects had been off therapy for one to two months and had seen their viral loads leap from under 50 copies/mL to 3.2 million copies/mL. Before treatment was interrupted, their lymph nodes (examined by biopsy) had been nearly quiescent and close to normal in structure.
There ought to be safer strategies for attacking residual HIV than STIs. Indeed, several attempts have been made to marshal the immune system against HIV that involve immune response modifiers administered while suppressive antiretroviral therapy continues.
First among these is interleukin 2 (IL-2; aldesleukin, Proleukin) a substance released by CD4 cells to stimulate CTLs. IL-2 also increases the proliferation and maturation of the CD4 cells themselves. IL-2 has been tested since the early 1990s as a means of countering the depletion of CD4 cells caused by the infection. This research began in the laboratory of H. Clifford Lane, M.D., of NIAID.
"IL-2 is just CD4 lymphocyte growth factor," Dr. Lane has argued. "When you give it to people and their CD4 counts go up, they don't get sick." The clinical benefit that Dr. Lane claims remains largely unproven. The CD4 cell changes seen with IL-2 administration may represent changes in quantity but not the quality of immune responses. IL-2 is currently the subject of two large six-year trials to definitively document to what extent IL-2 delays HIV disease progression.
Whether or not persons receiving IL-2 become ill, they do suffer from a range of severe flu-like side effects from IL-2, which is usually administered as subcutaneous injections twice a day for five days every one to two months. These cycles last at least until CD4 cell counts reach a normal level, at which point administering IL-2 can become more intermittent. The daily dose of IL-2 ranges up to 15 million international units (MIU) but is usually reduced to 9 MIU or less due to the severity of the side effects while still achieving therapeutic increases in CD4 cell count.
With the advent of HAART, IL-2 has found a new proposed use: to stimulate CD4 cells in blanket fashion so that those cells harboring latent HIV will start producing the virus. HAART drugs might then block this HIV from infecting other cells while the cells with newly activated infection quickly die off. In this way, IL-2 could have a purging effect on the hidden reservoir of HIV and rid the body of remaining virus. In this case, people might then be able to stop therapy without experiencing viral rebounds.
Several studies have addressed this possibility. Unfortunately, IL-2's promise has not been confirmed. In one STI trial, Hans-Jürgen Stellbrink, M.D., of the Universitätsklinikum Hamburg-Eppendorf and colleagues tested HAART (consisting of d4T [Zerit], 3TC [Epivir], nelfinavir [Viracept], and saquinavir [Fortovase]) with and without IL-2 in 56 treatment-naive volunteers with CD4 cell counts above 350 cells/mm3.
There was no difference between the two study arms in terms of change in viral load, either during treatment or after it was halted. Lymph nodes, checked by biopsy, took somewhat longer to reach undetectable virus levels among those on IL-2 (a mean of 377 days on HAART alone and 422 days on HAART plus IL-2). Nor was the rate of decrease in HIV-infected cells affected appreciably by administering IL-2. The most dramatic difference was that after one year on treatment, all those on IL-2 had normal CD4 cell counts, compared with only half of those on HAART alone.
Two additional studies have failed to observe any benefit to adding IL-2 to HAART before a treatment interruption. At the 7th CROI, NIAID researchers reported on 14 persons who stopped treatment for a period of 26 to 168 days. All had viral loads less than 500 copies/mL (for two months to three years), and 11 were receiving IL-2 in addition to HAART. Regardless of the IL-2 or how long their HIV had been suppressed, the subjects' final viral load set-point during the treatment interruption was, once again, close to what it had been before starting HAART, with a median lapse of six years.
L. Ruiz and colleagues from the University Hospital Germans Trias i Pujol in Barcelona reported at the 7th CROI on 12 volunteers undergoing repeated 30-day treatment interruptions every three months. Five of the 12 received two IL-2 cycles (dosed at 3 MIU twice daily) before the first interruption. All had had viral loads below 50 copies/mL for more than two years. After two interruptions, IL-2 had made no difference in either viral load rebound or CD4 cell response to HIV p24 core antigen.
If IL-2 alone is not enough to activate and purge the latently infected reservoir, perhaps adding additional immune modulators might help. A. Lafeuillade and colleagues from France tried combining HAART, IL-2, and interferon-gamma, which should stimulate macrophages in addition to CD4 cells. Macrophages are a major reservoir for HIV and can sustain slow chronic virus production for long periods of time.
In this case, the experiment was not successful: ten volunteers without previous treatment received five drugs (AZT [Retrovir], ddI, 3TC, saquinavir, and ritonavir) plus intermittent IL-2 and interferon-gamma. By month 18, viral load had dropped below 20 copies/mL in all ten subjects, but HIV-infected cells were still detectable and the virus could be cultured from these cells in all cases. Two study participants who halted treatment at this point experienced rapid viral rebound.
The French results follow a negative experience using HAART and IL-2 plus OKT3. OKT3 is a monoclonal antibody that attaches to the T-cell receptor and together with IL-2 causes rapid T-cell activation -- before triggering their death. In a recent study using this technique performed by J.M. Prins and colleagues from the Netherlands, three persons on HAART with viral loads below 5 copies/mL for at least 26 weeks were given a five-day course of OKT3 plus IL-2. HIV levels did rise modestly at first in the blood (in one person) or lymph nodes (in the other two), but there was no evident permanent change in the number of infected cells. Meanwhile, the three suffered from severe adverse side effects, including kidney failure and seizures in one.
IL-2 would be more likely to have a significant, durable impact if it promoted the rise of anti-HIV immunity that would detect and eliminate HIV-producing cells. This possibility is not so far-fetched: since IL-2 causes generalized proliferation of CD4 cells, it should boost the number and activity of any cells in this population that react to HIV antigens. As mentioned above, several studies have indicated that such CD4 cells exist, both in untreated persons and in those on successful HAART. They remain quiescent even as other immune defenses return during successful HAART. IL-2 might be just the thing to switch on these T-helper cells. They could then prompt other immune cells, in particular CTLs, to mop up the residual HIV infection.
In practice, IL-2 does not seem to have that effect, though the various studies have come to contradictory conclusions. At best, administering IL-2 seems to lead to only a modest increase in CD4 cell proliferation, which also occurs when people's cells are exposed to HIV antigens in the laboratory.
In the latest study to investigate this subject, G.P. Rizzardi and colleagues from Switzerland selected 34 people starting on abacavir (Ziagen) plus two PIs. At week 16, they randomized those with viral load under 400 copies/mL to either continue without change, add IL-2 (at a dose of about 10 MIU twice daily for five days every six weeks), or take the Remune therapeutic vaccine (injected every 12 weeks). Remune consists of killed HIV with its envelope proteins removed. The remaining viral core is coated with a mineral oil-based adjuvant (enhancing agent) that helps trigger immune cell recognition and response to the HIV proteins present in the vaccine. The participants in this study were subject to intensive immunologic monitoring, including lymph node biopsies at study entry and at week 63.
Nineteen of the participants have continued beyond week 63. None of the six on HAART alone showed any increase in immune response to HIV and only one of the five on IL-2 plus HAART did so. In contrast, five of the seven persons on HAART plus Remune had moderate increases. At the same time, IL-2 led to heightened responses to other disease antigens and to more rapid and profound increases in overall CD4 cell counts.
Vaccines have not always been effective at inducing immunity. One trial presented at the 7th CROI by Xia Jin, Ph.D., of ADARC used a vaccine consisting of a canarypox/HIV hybrid virus plus free gp160 (HIV envelope protein) as a therapeutic vaccine in people first treated with HAART within 90 days of developing primary HIV infection. Trial participants had viral loads below 50 copies/mL for more than two years and were taken off therapy completely after a course of four vaccinations over six months. Of the four volunteers described so far, only two developed strong new responses to HIV proteins. Though not proving much in itself due to the small sample size, these two also displayed much slower HIV rebound than the other two. They had viral doubling times (amount of time until the virus doubles in quantity) of 3.2 and 4.5 days, compared with a doubling time of 1.4 days in the two persons with weaker HIV immune responses.
The degree and durability of protection afforded by the vaccine-induced immunity is in any case subject to the same controversy as that surrounding STI-induced immunity. It might be that achieving effective immunity requires combining several immune-based approaches in a manner analogous to the way HAART blocks HIV growth (i.e., using several drugs at once).
One 40-person trial presented at the 7th CROI studied HAART plus IL-2 plus Remune after 16 weeks of successful HIV suppression. G. Hardy of the Imperial College School of Medicine in London and colleagues found that HAART alone did not lead to new immune responses to HIV or a decline in HIV-infected cells beyond a certain point. HAART plus IL-2 at least accelerated that decline, and HAART plus Remune triggered the appearance of new anti-HIV CD4 T-helper cells. In persons receiving all three, there was a tendency for this new anti-HIV immune response to appear after fewer immunizations with Remune.
While it represents a tentative but real beginning, the concept of adding combined immune therapy to anti-HIV drug regimens clearly needs refining with better immune modulators and vaccine products. But even if that effort is successful, will people be able to bear the physical and financial burdens of what might be called HIVES (high intensity viral eradication strategy)?
Dave Gilden is Director of Treatment Information Services at amfAR.
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Ghanekar, S. and others. Flow cytometric analysis of HIV-1 antigen-specific CD4+ T-cell proliferation in HIV-infected long-term survivors. 7th CROI. Abstract and poster presentation 582.
Gougeon, M.L. and others. Immunological and virological efficacy of long-term IL-2 therapy in HIV-infected patients. 7th CROI. Abstract and poster presentation 383.
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Lori, F. and others. Control of viremia after structured treatment interruptions. 7th CROI. Abstract and poster presentation 352.
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Martinez, J. and others. Selection of antiretroviral resistance in the latent reservoir of human immunodeficiency virus type 1 during successful therapy. 7th CROI. Abstract and oral presentation 238.
McNeil, A.C. and others. HIV-specific CD4+ T cells are maintained in untreated patients with or without proliferative response to HIV antigens. 7th CROI. Abstract and oral presentation 186.
Mittler, J.E. and Perelson, A.S. Mathematical model for the decay of the replication-competent latent reservoir: effect of treatment interruptions and IL-2 stimulation. 7th CROI. Abstract and poster presentation 349.
Orenstein, J.M. and others. Rapid activation of lymph nodes upon interrupting HAART in HIV-infected patients after prolonged viral suppression. 7th CROI. Abstract and poster presentation 358.
Prins, J.M. and others. Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy. AIDS 13(17): 2405-2410. December 3, 1999.
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Rizzardi, G. and others. Effect of HAART and immune-based strategies in HIV-1-infected antiretroviral-naive adults. 7th CROI. Abstract and poster presentation 545.
Ruiz, L. Structured treatment interruption in chronically HIV-1 infected patients after long-term viral suppression. 7th CROI. Abstract and poster presentation 354.
Sherer, R. and others. No detectable HIV RNA in thirteen individuals months after stopping antiretroviral therapy. 7th CROI. Abstract and poster presentation 351.
Stellbrink, H.J. and others. Influence of interleukin-2 (IL-2) on productive and latent HIV infection and on viral rebound. 7th CROI. Abstract and oral presentation 240.
Yearly, S. and others. Decay rates of cell-associated HIV-1 DNA correlate with residual viral replication in patients treated during primary HIV-1 infection. 7th CROI. Abstract and oral presentation 210.
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This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.