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The End of Opportunism?

William G. Powderly, MD; Alan Landay, PhD; Michael M. Lederman, MD

JAMA. 1998;280:72-77.

ABSTRACT
Objective.— Clinical care of people infected with human immunodeficiency virus (HIV) has been substantially affected by the introduction of potent antiretroviral therapy. Changes in the immune system after such therapy and the clinical consequences are important issues for clinicians treating patients with HIV.

Data Sources.— A systematic review of MEDLINE, 1993 to January 1998, of peer-reviewed publications, abstracts from national and international conferences, and product registration information through January 1998.

Study Selection and Data Extraction.— Criteria used to select studies include relevance to immune reconstitution with potent antiretroviral therapy and having been published in the English language. Assessment of data quality and validity included consideration of venue of the publication and relevance to practice.

Data Synthesis.— Suppression of viral replication after administration of potent antiretroviral therapy that includes inhibitors of the HIV-1 protease is associated with quantitative and qualitative changes in the immune system. In patients with relatively advanced disease, there is a first-phase rise (during the initial 3 months) in both naive and memory CD4⁺ and CD8⁺ T lymphocytes and B lymphocytes. This is followed by a slower second-phase increase (after 3 months) in cells primarily of the naive CD4⁺ and CD8⁺ phenotypes. These quantitative changes are associated with qualitative improvements in host immune responses, best characterized by dramatically reduced risk of opportunistic infection. Restoration of the immune system during the first year of potent antiretroviral therapy is partial at best.

Conclusions.— Potent antiretroviral therapy has become the standard of care for people with HIV infection, and its use has led to significant reductions in the incidence of the acquired immunodeficiency syndrome (AIDS) and in mortality from HIV infection. Although incomplete, considerable immune recovery occurs, sufficient, in most cases, to provide adequate protection against most AIDS-associated opportunistic infections.

INTRODUCTION

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TREATMENT of patients infected with human immunodeficiency virus (HIV) has changed enormously in the last 2 years. In 1996, for the first time, new acquired immunodeficiency syndrome (AIDS) cases and deaths declined in incidence in the United States.¹ Although this is not entirely explained by better antiretroviral therapy, the advent of more potent agents, particularly availability of inhibitors of HIV-1 protease, has been a major contributor to this new era. Use of potent combination therapy (also known as highly active antiretroviral therapy or HAART) has been associated with dramatic decreases in incidence of new opportunistic events. Clinicians have reported reductions in hospitalizations for AIDS-related events.^2-3 New cases of opportunistic infections such as cytomegalovirus (CMV) retinitis and disseminated mycobacterial infections are much less common, with incidences reduced by as much as 75% to 80%.^4-5 Prospective clinical trials indicate that potent antiretroviral therapy reduces opportunistic infection incidence. In a trial comparing addition of lamivudine to zidovudine-containing regimens,⁶ patients with more potent lamivudine-containing regimens were much less likely to progress to AIDS (ie, develop an opportunistic event) or die than controls. Addition of a protease inhibitor to this regimen is even more effective—in another trial,⁷ addition of lamivudine and indinavir to zidovudine was associated with an even greater benefit in terms of survival and fewer opportunistic events vs zidovudine and lamivudine alone. Thus, several groups now recommend combinations including reverse transcriptase inhibitors plus a protease inhibitor as standard of care.^8-10

Opportunistic infections occur in HIV disease due to immunodeficiency caused principally by progressive loss of CD4⁺ T lymphocytes. It is thus reasonable to assume that reduced incidence of opportunistic infections with potent antiretroviral therapy results because virus-induced immunologic damage is halted. CD4⁺ cell counts stop falling when potent antiretroviral therapy is instituted, and, in general, a potent regimen of 2 nucleoside reverse transcriptase inhibitors and a protease inhibitor can be expected to raise the CD4⁺ cell count by an average of 0.150x10⁹/L (150/µL) over 12 months.^{7, 11} There are also clear indications that improved immunologic competence is occurring as well. Anecdotal reports suggest that potent antiretroviral therapy can lead to resolution of infections previously believed impossible to treat such as cryptosporidiosis, microsporidiosis, azole-resistant thrush, and progressive multifocal leukoencephalopathy.^12-15 Long-term remission can be achieved with infections such as CMV retinitis and disseminated Mycobacterium avium complex infection when such therapy is initiated, leading some physicians to discontinue specific antimicrobial treatment in patients receiving potent antiretroviral treatment.^16-18 Prior to availability of potent therapy, such infections were usually associated with almost inevitable progression. Furthermore, when opportunistic infections do occur, some patients may mount at least a partial host response not seen previously. Localization of M avium infection to lymph nodes with evidence of granuloma formation on biopsy¹⁹ or presence of vitritis in patients with CMV retinitis²⁰ has been attributed to a newly present host inflammatory response.

This evidence prompts important questions that we attempt to address herein via a systematic review of peer-reviewed publications using MEDLINE, 1993 to January 1998, and conference abstracts and product registration information through January 1998. These questions are as follows. How complete is the host immunologic response to such therapy and can the virus-induced damage be mended? How quickly does the host recover and is recovery durable? What are the clinical implications of such responses, both in terms of antiretroviral treatment and antimicrobial prophylaxis? It is important first to understand the effect of HIV infection on the immune system.

EFFECT OF HIV INFECTION ON IMMUNE RESPONSES

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The cardinal feature of progressive HIV infection is progressive depletion of CD4⁺ cells from the circulation and from lymphoid tissue.²¹ Functional defects in remaining cells are also demonstrable and include failure of proliferation and cytokine production in response to commonly encountered antigens and anergy to delayed-type hypersensitivity skin testing.^22-23 Thus, quantitative and qualitative defects in immune responses are seen. Despite profound immune deficiency, HIV infection also induces a state of chronic immune activation in CD4⁺ cells, CD8⁺ cells, and circulating monocytes.^24-25 This may limit ability of the host to provide defense against opportunistic pathogens and may enhance HIV propagation as activated CD4⁺ cells are more permissive for HIV replication.

Immune Phenotypic Changes

The importance of CD4⁺ cell depletion in immune deficiency was recognized in the earliest days of the AIDS epidemic.^26-28 The CD4⁺ cell count has been critical in early epidemiologic studies for predicting HIV disease progression risk and as an AIDS diagnostic criterion. Current recommendations for opportunistic infection prophylaxis are almost completely based on CD4⁺ cell counts.²⁹ The mechanism(s) responsible for CD4⁺ cell depletion in HIV disease remains under investigation. Proposed mechanisms include direct killing by HIV, immune-mediated killing, or indirect effects such as induction of programmed cell death (apoptosis).³⁰ Although early HIV infection is characterized by decrease in circulating CD4⁺ cells and expansion in numbers of circulating CD8⁺ cells, in advanced HIV infection, all circulating lymphoid populations, including CD8⁺ cells, B lymphocytes, and lymphocytes with natural killer cell phenotype, eventually decrease.^31-32

The CD4⁺ cell compartment consists of 2 functional subsets separated on the basis of expression of other cell surface markers. Naive cells express CD45RA and CD62L. Memory cells express CD45RO and lack expression of the CD45RA isoform. In principle, naive cells are newly generated through selection in the thymus for cells bearing an appropriately diverse repertoire of T-cell receptors that have some (but not too much) affinity for the person's major histocompatibility (MHC) antigens. Naive cells represent the potential for generating immune responses to newly encountered antigens but are not particularly capable of cytokine expression or of effector cell activity. After exposure to antigenic peptides expressed on cell surface class I MHC molecules (in the instance of CD8⁺ cells) or those on cell surface class II MHC molecules (in the instance of CD4⁺ cells), naive cells evolve into cells that express the memory phenotype. Memory cells are capable of cytokine expression and effector cytolytic activity. After antigenic exposure, some cells will die and others may revert to a less activated memory state where they are capable of rapid responses to previously encountered antigens, providing the classic secondary or anamnestic response characteristic of the immune response to previously encountered antigens. In healthy adults about half of circulating cells are of the naive phenotype and half are memory cells. In HIV infection, there is a selective loss of naive CD4⁺ cells early in the disease.³³ Functional studies, however, show losses in antigen-specific responses that are mediated by memory cells.³⁴ Although memory cells may be preferentially susceptible to productive infection with HIV,³⁵ only a small minority of these cells are infected in vivo. Thus, both the preferential depletion from circulation of naive cells in HIV disease and the apparent loss of responses to antigens, including antigens that are infrequently encountered, are not readily explained by models that attribute cell loss and immune dysfunction to direct infection of immune cells by HIV and subsequent cytolysis.

Immune Function Changes

As mentioned, HIV infection is associated with profound defects in CD4⁺ cell–dependent antigen responsiveness measured as impaired lymphocyte proliferation, impaired production of helper T-cell cytokines, or impaired response to delayed-type hypersensitivity skin testing.^{23, 36-41} Mechanisms underlying these defects are not well understood. A leading paradigm for functional change in CD4⁺ cell function has been proposed,^{22, 37} in which a sequential loss of antigen, alloantigen, and mitogen reactivity as HIV disease progressed was identified. As antigen-responsive cells are the least frequent in circulation and mitogen-reactive cells the most frequent, these observations led some to suggest that progressive loss of CD4⁺ cells resulted in depletion of reactive cell clones resulting in holes in the repertoire of responsiveness and failure of host defenses.^42-43

CD8⁺ cells are major effectors of cell-mediated cytotoxicity; their receptors can recognize foreign peptides expressed on the cell surface in the context of class I MHC antigens. Recognition and binding result in triggering cytolytic mechanisms that can result in destruction of cells serving as the factory for continued production of intracellular pathogens such as viruses. CD8⁺ cells also are an important source of -chemokines and other soluble factors that also may prevent HIV propagation through inhibition of virus binding to cellular coreceptors and other mechanisms.^44-46 Development of a CD8⁺ cytolytic response is associated with down-regulation of HIV propagation in early infection^47-48 and thought to be a critical mediator of host defense against HIV. Maintenance of a strong cytolytic response also depends on expression of helper cytokines by CD4⁺ cells, and CD4⁺ cell responses to HIV are profoundly altered in HIV disease, more so than responses to other antigens. Recent studies indicate that CD4⁺ cell response to HIV antigens is preserved in those in whom HIV replication is controlled and can be retained when viral replication is suppressed during primary (acute) HIV infection by potent antiretroviral therapy.⁴⁹ Very early loss of (or failure to mount) these responses suggests that HIV-reactive CD4⁺ cell clones are rapidly depleted at sites of viral replication, either directly through virus-induced cytolysis or indirectly though induction of programmed cell death. Accumulating information suggests that preservation of interdependent CD4⁺ and CD8⁺ cell responses to HIV is associated with and possibly responsible for a better outcome of HIV infection.

Immune Activation in HIV Disease

Despite clinical and laboratory evidence of immune deficiency, HIV infection is also characterized by immune activation. Both CD4⁺ and CD8⁺ cells express on their surface molecules such as CD38 and class II major histocompatibility antigens (HLA-DR) that are consequences of lymphocyte activation. In the CD4⁺ cell population it is mostly memory (CD45RO⁺) cells that express these activation markers.²⁴ Inappropriate activation of memory cells might contribute to observed loss of functional activity. CD8⁺ cells also bear activation markers in HIV disease. Recent studies have shown that high-level expression of CD38 on CD8⁺ cells is a powerful predictor of HIV disease progression independent of CD4⁺ cell numbers and, though related to plasma HIV RNA levels, more predictive of outcome than these levels.²⁵ This suggests that immune activation as reflected by CD38 expression on CD8⁺ cells may reflect effects of HIV replication on immune deterioration.⁵⁰ In this regard, CD38 expression correlates well with lymphocyte susceptibility to programmed cell death.

There is also evidence of monocyte activation in HIV disease as levels of proinflammatory monocyte–derived cytokines such as tumor necrosis factor (TNF-) and interleukin 6 (IL-6) are often elevated in HIV disease and are correlated with plasma HIV RNA levels.⁵¹ As HIV infection induces TNF- and IL-6 expression and each of these cytokines can activate HIV expression, they may drive HIV production in vivo or their elevated levels may be a product of HIV replication or the relationship may be bidirectional.

Thus, HIV infection is associated with profound disturbances in immune homeostasis. Progressive depletion of circulating CD4⁺ cells, impaired function of remaining cells, and evidence of inappropriate immune activation are hallmarks of the immune dysregulation of HIV infection. A key question is whether these abnormalities can be corrected after potent antiretroviral therapy use.

IMMUNOLOGIC CHANGES AFTER ADMINISTRATION OF ANTIVIRAL THERAPIES

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Early trials with single-agent antiviral therapies now recognized to have modest antiviral activity resulted in minor immunologic improvements. In certain trials, these therapies resulted in decreased opportunistic infection risk^52-53 and modest increases in circulating CD4⁺ cells and lymphocyte functions such as proliferation, natural killer activity, and delayed-type hypersensitivity.^{52, 54-55} Unfortunately, the clinical and laboratory benefits were short-lived.

As mentioned, use of powerful combinations of potent antiretroviral therapy producing more sustained decreases in HIV circulating levels has been associated with more dramatic and durable clinical benefits. Careful studies of immune function in these patients has allowed detailed characterization of immunologic changes associated with potent therapy. The most detailed studies have been done in recipients of regimens including nucleoside analogue reverse transcriptase inhibitors and a protease inhibitor^56-60 in which treatment was associated with at least 2 phases of change in numbers of circulating lymphoid cells. The first phase takes place in the first few months of therapy, characterized by rapid increase in circulating naive and memory CD4⁺ and CD8⁺ cells. Numbers of B lymphocytes are also increased, but numbers of natural killer cells are unaffected.^58-59 The only lymphoid population not experiencing an increase during this time is that of phenotypically defined natural killer cells (CD16⁺ or CD56⁺), generally not found in lymphoid tissue.

Mechanisms underlying first-phase cellular increases are not well understood. Preliminary analysis of lymphoid tissue reveals an increased frequency of cells undergoing apoptosis^61-62 and an increased expression of Ki69 antigen by proliferating cells. With potent antiretroviral therapy, tonsillar biopsy specimens show decreases in total lymphocyte apoptosis,⁶¹ but not CD4⁺ cell apoptosis.⁶² Whereas modest increases in tonsillar CD4⁺ cell numbers during this first phase were shown,⁶² preliminary studies elsewhere found decreased CD4⁺ cell numbers in lymph nodes.⁶³ Cell-labeling studies in macaques have indicated an apparent increase in cellular turnover in simian immunodeficiency virus infection,⁶⁴ while preliminary labeling studies using nonradioactive isotopes in humans suggest that the cellular increases seen with potent antiretroviral therapy are associated with increases in production.⁶⁵ Nonetheless, we suspect that the first-phase cellular increases after potent therapy are too large and rapid to be primarily attributable to new production and release of cells. We favor a model where viral replication cessation in lymphoid tissue results in a decrease in cellular activation, and activation-induced apoptosis and adhesion, resulting in rapid increase in circulating T and B cells.

First-phase increases in circulating CD8⁺ cells have not been recognized in patients treated with nucleoside analogue antiretrovirals⁶⁶ or a combination of zidovudine and didanosine and the nonnucleoside reverse transcriptase inhibitor nevirapine⁶⁷ (Julio S. G. Montaner, MD, written communication, April 15, 1998). A first-phase rise in CD8⁺ cells is also not observed in persons with less advanced HIV infection receiving the combination of zidovudine, lamivudine, and indinavir (A.L., unpublished observation, February 16, 1998). To know whether this is a function of the magnitude of viral replication suppression or stage of disease will require further study.

The second phase of cellular changes persists at least as long as the first year of therapy and is characterized by a slower slope increase in circulating naive CD4⁺ and CD8⁺ cells and a decrease in circulating memory CD8⁺ cells.^{56, 58, 68} The significance of the memory CD8⁺ cell decrease is not clear. Recent data suggest that some if not all of the decrease may be related to the decrease in HIV-reactive CD8⁺ cell clones.⁶⁹

The slow and apparently selective increase in naive CD4⁺ and CD8⁺ cells seen during this period provides some optimism that T-cell development and maturation are taking place. However, it is not clear whether these naive cells have matured through a thymic pathway, nor has it been proven definitively that these naive cells are newly developed from more primitive precursors. Available data suggest that during the early first phase of cellular restoration, perturbations in the T-cell receptor repertoire are not corrected.^{59, 70} During the second phase of cellular recovery, however, there are indications that the diversity of the CD4⁺ cell receptor repertoire may be improving.⁵⁷ Taken together, these observations suggest that the early first-phase cellular restoration seen after potent antiretroviral therapy use is primarily a redistribution of cells originally present in lymphoid tissues and that generation of new cells is not a major contributor to the increase. The second-phase increase on the other hand may represent a maturation of newly generated T cells, and this is supported by evidence for diversification of the CD4⁺ cell repertoire. How much diversification is possible in adults and how active the thymus is in this setting remain to be determined. Ongoing studies that involve longer follow-up of patients receiving suppressive antiretroviral therapies are critical to confirm the origin, diversity, and potential of these slowly appearing naive cells. If the experience after intensive chemotherapy serves as a guide, full recovery of CD4⁺ cell numbers may take years.⁷¹ The features of T-cell regeneration after chemotherapy are similar to changes seen after antiretroviral therapy, including limited reconstitution of naive CD4⁺ cells and initial increase and then stabilization of CD4⁺ memory cell levels. The other feature of T-cell regeneration after chemotherapy that makes it an attractive model for HIV infection after therapy is the predominance of CD8⁺ cells seen initially in both situations. The postchemotherapy model would also suggest that much of CD8⁺ cell expansion is extrathymic in nature.

Restoration of Immune Function After Potent Antiretroviral Therapy

The dramatic decrease in the incidence of opportunistic infections after potent antiretroviral therapy indicates that host defenses (specifically cell-mediated immune responses) are improved after the first few months of therapy. Are simple increases in circulating CD4⁺ cells sufficient to account for this clinical benefit, or is there evidence that the effector function of these cells is actually enhanced after potent therapy? These questions beg the more fundamental questions regarding mechanisms that underlie cellular dysfunction in HIV infection. Whereas impairments in lymphocyte proliferation and delayed-type hypersensitivity are readily demonstrable in persons with HIV infection, the precise mechanisms underlying these functional deficits remain to be determined. Although progressive loss of antigen reactivity (as detected in vitro by failure of lymphocyte proliferative responses and in vivo by loss of delayed-type hypersensitivity responses to skin testing) is characteristic of HIV disease,^36-38 there is little direct evidence suggesting that antigen-induced activation during the course of HIV disease induces loss of T-cell clones responsive to non-HIV antigens. In fact, in vitro reactivity to antigens commonly encountered during the course of HIV disease is more often preserved in advanced HIV infection and also are more likely to be restored (at least in the short term) after potent antiretroviral therapy use.^{56, 59} The magnitude of restoration of antigen-induced reactivity in vitro varies substantially among studies examining this function carefully.^{56, 59-60,68, 72}

As mentioned, CD4⁺ cell function can be measured in vivo with application of skin test antigens. True delayed-type hypersensitivity responses, characterized by induration at the application site at 48 to 72 hours after intradermal injection, are mediated by CD4⁺ cells and macrophages. These responses to application of skin test antigens gradually and progressively improve over 48 weeks of potent antiretroviral therapy use.⁶⁸ The relative preservation and recovery after potent antiretroviral therapy of reactivity to commonly encountered antigens cast some doubt on the concept that antigen exposure drives the loss of antigen-reactive CD4⁺ cell clones. Nonetheless, antigen reactivity is clearly lost with HIV disease progression. We favor a model wherein loss of non–HIV antigen–reactive cells is random (rather than directed) and observed functional defects may be attributable to progressive depletion of antigen-reactive cells such that the number of these cells is below limits of assay detection. However, it remains uncertain as to whether on a single-cell level, the functions of CD4⁺ and CD8⁺ cells are normal or impaired.

How Can the Clinical Benefits of Potent Antiretroviral Therapy Be Explained?

If antigen responsiveness is lost in HIV disease and is only modestly improved with potent antiretroviral therapy use, 2 critical questions must be addressed: first, how can the dramatic clinical benefits of potent therapy be explained in the presence of only modest improvement in overall lymphocyte function, and second, are lymphocyte effector functions impaired on a single-cell level, and if so, what are the mechanisms of these defects?

As in many healthy biologic systems, the immune system probably has much redundancy and reserve. Thus, dramatic perturbations may be necessary to place a person at risk for infection. The occurrence of AIDS-defining opportunistic infections is unusual with CD4⁺ cell counts higher than 0.200x10⁹/L, many times lower than the average CD4⁺ cell count in healthy populations. Increases in CD4⁺ cell numbers that do not approach the "healthy average" may be sufficient to provide protection against these opportunistic infections, particularly in the setting of improved antimicrobial prophylaxis that has become standard of care.⁷³

Qualitative defects in lymphocyte function have been suggested to play a role in AIDS-related immune deficiencies (see above). It remains difficult, however, to define failure of antigen-induced responses in HIV infection as a consequence of cell loss, cell dysfunction, or both. Also, modest improvements in lymphocyte function may be difficult to detect using current systems for measuring antigen-specific responses in vitro. Although assays of lymphocyte proliferation are the "gold standard" for measurement of CD4⁺ cell responses and assays of cytotoxic T-lymphocyte activity are the standard for measurement of CD8⁺ cell responses, these assays have sufficient variability and, in the instance of cytotoxic T-lymphocyte assays, sufficient complexity, to render modest changes in function difficult to quantify with confidence. What is needed now are better and standardized methods to evaluate cell function on an individual cell level with reproducible readouts of antigen recognition that can be readily quantified.

Effects of Potent Antiretroviral Therapy on Immune Activation

Trials of potent antiretroviral therapy have clearly demonstrated that abnormally elevated indexes of immune activation can be decreased with potent therapy. High plasma levels of TNF- decreased by one third (but did not return to normal levels) after 3 months of potent antiretroviral therapy⁵⁹ and the frequency of CD38 and HLA-DR expression on both CD4⁺ and CD8⁺ cells decreased rapidly with potent regimens.^{56, 59} Results of these studies suggest that it is HIV replication and probably not exposure to opportunistic pathogens that drives immune activation in HIV disease. Preliminary studies indicate that heightened cytokine expression⁷⁴ and programmed cell death⁶² are rapidly decreased in lymphoid tissues after potent antiretroviral therapy, and this is seen at the same time lymphocyte activation antigen expression is decreasing.^{56, 59}

Can Virologic Failure Coexist With Clinical and Immunologic Responses?

Plasma RNA level rebound in persons who had experienced prior periods of viral suppression is increasingly common.⁷⁵ Despite these apparent antiretroviral "failures," most of these patients appear to be doing well clinically, and the CD4⁺ cell increases have, in most instances, been sustained, although not to the same levels as seen in persons with more complete suppression.⁷⁶ In many patients, "rebound" in plasma RNA levels remains below the levels seen prior to potent therapy use. Thus, the "failing" regimen may still provide some degree of benefit. How much antiviral effect is needed to sustain therapy-induced CD4⁺ cell increases is uncertain at present. It is quite possible that progressive HIV infection will in time induce CD4⁺ cell loss, and clinical evidence of immune dysfunction will recur in such persons. As the progressive immunologic failure of HIV disease may take years to develop fully, continuing viral replication may exert progressive immune depletion that may take several years to manifest both clinically and immunologically. Alternative explanations for this divergence of virologic vs clinical and immunologic outcomes such as benefits of potent antiretroviral therapy not related to antiviral effects and a diminished "fitness" of multidrug-resistant virus in terms of induction of immune deficiency are interesting concepts not yet tested.

At present it is not reasonable to assume that clinical and immunologic benefits of a "failing" antiretroviral regimen will be sustained indefinitely. Suppression of viral replication as much as possible remains the HIV treatment cornerstone.

CONCLUSIONS

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Available evidence suggests substantial recovery of the immune system will occur in most persons with HIV infection in whom viral replication can be suppressed. Immune recovery is not immediate and appears to continue after viral suppression is achieved. In many persons, immune regeneration appears to be a continuous process over several years.

Clinical implications of these changes are still uncertain. Prophylaxis guidelines recommend continuing prophylaxis on the basis of the nadir of the CD4⁺ count,⁷³ largely because of concern that effective host defenses against opportunistic pathogens are not restored even as CD4⁺ cell numbers rise. Risk for unusual presentation of these pathogens may persist during the first 2 to 3 months of potent antiretroviral therapy; however, growing evidence suggests that after this period treated patients may recover sufficient host defenses to protect against infection (even if these defenses are not restored to normal levels). Specifically, CMV retinitis tends to occur early in the first 3 to 4 months after potent therapy initiation²⁰ but then occurs rarely in patients with successful antiretroviral treatment. If this scenario is correct, prophylaxis will remain necessary in those failing to have a sustained antiviral response, but it may be possible to discontinue prophylaxis in those with long-term viral control and associated CD4⁺ cell increases. This hypothesis is supported by reported clinical anecdotes and is being tested in several prospective randomized controlled trials.

The possibility of providing complete immune recovery after intense antiretroviral treatment also has implications for timing of such therapy. Current antiretroviral guidelines are premised on the hypothesis that ongoing HIV replication is always harmful and that the immune system is irreversibly damaged,⁹ presenting the argument that patients should be treated aggressively as early as possible to prevent irreversible immune system damage. However, if potent antiretroviral therapy can ultimately reverse immune damage and normalize host defenses, there may be no imperative to treat patients with established asymptomatic infection. This would have profound implications for using such therapy and concerns about adherence and cost would be altered considerably. At present, however, long-term immunologic and clinical outcomes in persons receiving potent antiretroviral therapy remain unknown. Whether complete recovery is possible is not yet clear; even if it is possible, it may not be achievable in all patients. It is possible that both host- and virus-specific factors will be predictive of the degree of immune reconstitution, with additional important therapeutic implications. For example, magnitude of immune reconstitution or ability to achieve complete and sustained recovery may depend on when in the course of illness effective therapy is initiated. Type of therapy (ie, use of specific agents) may also be critical. However, it is also possible that complete recovery of the immune system is unnecessary and that partial success will provide meaningful long-term protection against opportunistic events. Although more data are needed to help us understand predictors of protective immunity against specific opportunistic infections and the effectiveness of potent antiretroviral therapy, we would confidently predict that rates of opportunistic infections will continue to be considerably less than previously, fulfilling the expectation that effective antiretroviral therapy will provide the best prophylaxis for opportunistic infections.⁷⁷ However, it is not likely that opportunistic infections will disappear completely. Control of viral replication is not achieved in all persons, and for those in whom even partial control is not possible, immune deterioration and risk for opportunistic complications of AIDS will continue.

AUTHOR INFORMATION

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Dr Powderly has received grant support from Abbott Laboratories, Abbott Park, Ill, Agouron, La Jolla, Calif, Boehringer Ingelheim, Ridgeway, Conn, Bristol-Myers Squibb, Princeton, NJ, Glaxo Wellcome, Research Triangle Park, NC, Hoffmann-La Roche, Nutley, NJ, Merck, West Point, Pa, and Pharmacia & Upjohn, Kalamazoo, Mich, and has served on advisory boards for Abbott Laboratories, Hoffmann-La Roche, Roxane Laboratories, Columbus, Ohio, and Vertex Pharmaceuticals, Cambridge, Mass. Dr Landay receives grant support from Genzyme, Cambridge, Mass, and Merck. Dr Lederman receives grant support from Abbott Laboratories, Amgen, Thousand Oaks, Calif, Boehringer Mannheim Lab Diagnostics, Indianapolis, Ind, Digene, Beltsville, Md, Glaxo Wellcome, and Hoffmann-La Roche and is a consultant to Pharmacia & Upjohn and Chiron, Emeryville, Calif.

This study was supported in part by National Institutes of Health grants AI 25903, AI 25879, AI 36219, and AI 38858.

Reprints: William G. Powderly, MD, Division of Infectious Diseases, Washington University School of Medicine, Campus Box 8051, 660 S Euclid Ave, St Louis, MO 63110.

From the Division of Infectious Diseases, Washington University School of Medicine, St Louis, Mo (Dr Powderly); the Department of Immunology/Microbiology, Rush Medical School, Chicago, Ill (Dr Landay); and the Division of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio (Dr Lederman).

REFERENCES

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