Report of the NIH Panel to Define Principles of Therapy of HIV Infection
SCIENTIFIC BACKGROUND
HIV Infection Leads to Progressive Immune System Damage in Nearly
All Infected Persons
Early efforts to synthesize a coherent model of the pathogenic consequences
of HIV infection were based on the presumption that few cells in infected
persons harbor or produce HIV and that virus replication is restricted
during the period of clinical latency. However, early virus detection methods
were insensitive, and newer, more sensitive tests have demonstrated that
virus replication is active throughout the course of the infection and
proceeds at levels far higher than previously imagined. HIV replication
has been directly linked to the process of T cell destruction and depletion.
In addition, ongoing HIV replication in the face of an active but incompletely
effective host antiviral immune response is probably responsible for the
secondary manifestations of HIV disease, including wasting and dementia.
Beginning with the first cycles of virus replication within the newly infected host, HIV infection results in the progressive destruction of the population of CD4+T cells that serve essential roles in the generation and maintenance of host immune responses (1 - 10). The target cell preference for HIV infection and depletion is determined by the identity of the cell surface molecule, CD4, that is recognized by the HIV envelope (Env) glycoprotein as the virus binds to and enters host cells to initiate the virus replication cycle (74). Additional cell surface molecules that normally function as receptors for chemokines have recently been identified as essential coreceptors required for the process of HIV entry into target cells (75). Macrophages and their counterparts within the central nervous system, the microglial cells, also express cell surface CD4 and provide targets for HIV infection. As macrophages are more resistant to the cytopathic consequences of HIV infection than are CD4+T cells and are widely distributed throughout the body, they may play critical roles in persistence of HIV infection by providing reservoirs of chronically infected cells.
Although most of the immunologic and virologic assessments of HIV-infected persons have focused on studies of peripheral blood lymphocytes, these cells represent only approximately 2% of the total lymphocyte population in the body. The importance of the lymphoid organs, which contain the majority of CD4+T cells, has been highlighted by the finding that the concentrations of virus and percentages of HIV-infected CD4+T cells are substantially higher in lymph nodes (where immune responses are generated and where activated and proliferating CD4+T cells that are highly susceptible to HIV infection are prevalent) than in peripheral blood (3,4,48). Thus, although the depletion of CD4+T cells after HIV infection is most readily revealed by sampling peripheral blood, damage to the immune system is exacted in lymphoid organs throughout the body (3,4). For as yet unidentified reasons, gradual destruction of normal lymph node architecture occurs with time, which probably compromises the ability of an HIV-infected person to generate effective immune responses and replace CD4+T cells already lost to HIV infection through the expansion of mature T cell populations in peripheral lymphoid tissues. The thymus is also an early target of HIV infection and damage, thereby limiting the continuation of effective T cell production even in younger persons in whom thymic production of CD4+T cells is active (76,77). Thus, in both adults and children, HIV infection compromises both of the potential sources of T cell production, so the rate of T cell replenishment cannot continue indefinitely to match cell loss. Consequently, total CD4+T cell numbers may decline inexorably in HIV-infected persons.
After initial infection, the pace at which immunodeficiency develops and the attendant susceptibility to OIs which arise are associated with the rate of decline of CD4+T cell counts (11,26,27). The rate at which CD4+T cell counts decline differs considerably from person to person and is not constant throughout all stages of the infection. Acceleration in the rate of decline of CD4+T cells heralds the progression of disease. The virologic and immunologic events that occur around this time are poorly understood, but increasing rates of HIV replication, the emergence of viruses demonstrating increased cytopathic effects for CD4+T cells, and declining host cell-mediated anti-HIV immune responses are often seen (12,78). For as yet unknown reasons, host compensatory responses that preserve the homeostasis of total T cell levels (CD4+ plus CD8+T cells) appear to break down in HIV-infected persons approximately 1 - 2 years before the development of AIDS, resulting in net loss of total T cells in the peripheral blood, and signaling immune system collapse (79).
Although the progression of HIV disease is most readily gauged by declining CD4+T cell numbers, evidence indicates that the sequential loss of specific types of immune responses also occurs (80 - 82). Memory CD4+T cells are known to be preferential targets for HIV infection, and early loss of CD4+ memory T cell responses is observed in HIV-infected persons, even before there are substantial decreases in total CD4+T cell numbers (80,81). With time, gradual attrition of antigen-specific CD4+T cell-dependent immune recognition may limit the repertoire of immune responses that can be mounted effectively and so predispose the host to infection with opportunistic pathogens (82).
HIV Replication Rates in Infected Persons Can Be Accurately Gauged
By Measurement of Plasma HIV Concentrations
Until recently, methods for monitoring HIV replication (commonly referred
to as viral load) in infected persons were either hampered by poor sensitivity
and reproducibility or were so technically laborious that they could not
be adapted for routine clinical practice. However, new techniques for sensitive
detection and accurate quantification of HIV RNA levels in the plasma of
infected persons provide extremely useful measures of active virus replication
(1,2,19,20,37,41 - 43). HIV RNA in plasma is contained within
circulating virus particles or virions, with each virion containing two
copies of HIV genomic RNA. Plasma HIV RNA concentrations can be quantified
by either target amplification methods (e.g., quantitative RT polymerase
chain reaction [RT-PCR], Amplicor HIV Monitor‘ assay, Roche Molecular Systems;
or nucleic acid sequence-based amplification, [NASBA ® ], NucliSens‘
HIV-1 QT assay, Organon Teknika) or signal amplification methods (e.g.,
branched DNA [bDNA], Quantiplex‘ HIV RNA bDNA assay, Chiron Diagnostics)
(42,43). The bDNA signal amplification method (41) amplifies the signal
obtained from a captured HIV RNA target by using sequential oligonucleotide
hybridization steps, whereas the RT-PCR and NASBA ® assays use enzymatic
methods to amplify the target HIV RNA into measurable amounts of nucleic
acid product (41 - 43). Target HIV RNA sequences are quantitated
by comparison with internal or external reference standards, depending
upon the assay used.
Versions of both types of assays are now commercially available, and the Amplicor assay was recently approved by the Food and Drug Administration for assessment for risk of disease progression and monitoring of antiretroviral therapy in HIV-infected persons. Target amplification assays are more sensitive (400 copies HIV RNA/mL plasma) than the first generation bDNA assay (10,000 copies HIV plasma), but the sensitivity of the bDNA assay has recently been improved (500 copies HIV RNA/mL plasma). More sensitive versions of each of these assays are currently in development (detection limits 20 - 100 copies/mL) and will likely be commercially available in the future.
All of the commercially available assays can accurately quantitate plasma HIV RNA levels across a wide range of concentrations (so-called dynamic range). Although the results of the three assays (i.e., the RT-PCR, NASBA ® , and bDNA) are strongly correlated, the absolute values of HIV RNA measured in the same plasma sample using two different assays can differ by twofold or more (44 - 46). Until a common standard is available that can be used to normalize values obtained with different assay methods, it is advisable to choose one assay method consistently when HIV RNA levels in infected persons are monitored for use as a guide in making therapeutic decisions.
The performance characteristics and recommended collection methods for the individual HIV RNA assays are provided (Table). For reliable results, it is essential that the recommended procedures be followed for collection and processing of blood to prepare plasma for HIV RNA measurements. Different plasma HIV RNA assays require different plasma volumes (an important consideration in infants and in young children).
These assays are best performed on plasma specimens prepared from blood obtained in collection tubes containing specific anticoagulants (e.g., ethylenediaminetetraacetic acid [EDTA] or acid-citrate-dextran [ACD]) (Table) (44 - 46).
Quantitative measurement of plasma HIV RNA levels can be expressed in two ways: a) the number of copies/mL of HIV RNA and b) the logarithm (to the base 10) of the number of copies/mL of HIV RNA. In clinically stable, HIV-infected adults, results obtained by using commercially available plasma HIV RNA assays can vary by approximately threefold (0.5 log10) in either direction on repeated measurements obtained within the same day or on different days (35,36). Factors influencing the variation seen in plasma HIV RNA assays include biological fluctuations and those introduced by the performance characteristics of the particular assay (35,36,44 - 46). Variability of current plasma HIV RNA assays is greater toward their lower limits of detection and consequently changes greater than 0.5 log10 HIV RNA copies can be seen near the assay detection limits without changes in clinical status (35). Differences greater than 0.5 log10 copies on repeated measures of plasma HIV RNA likely reflect biologically and clinically relevant changes. Increased variance toward the limit of assay detection presents an important consideration as the recommended target of suppression of HIV replication by antiretroviral therapy is now defined as being HIV RNA levels below the detection limit of plasma HIV RNA assays. Immune system activation (by immunizations or intercurrent infections) can lead to increased numbers of activated CD4+T cells, and thereby result in increased levels of HIV replication (reflected by significant elevations of plasma HIV RNA levels from their baseline values) that may persist for as long as the inciting stimulus remains (32 - 34). Therefore, measurements obtained surrounding these events may not reflect a patient’s actual steady-state level of plasma HIV RNA. Unlike CD4+T cell count determinations, plasma HIV RNA levels do not exhibit diurnal variation (26,36). Within the large dynamic range of plasma HIV RNA levels that can be measured (varying over several log10 copies), the observed level of assay variance is low (Table). Measurement of two samples at baseline in clinically stable patients has been recommended as a way of reducing the impact of the variability of plasma HIV RNA assays (19), and recent data support this approach (22).
The level of viremia, as measured by the amount of HIV RNA in the plasma, accurately reflects the extent of virus replication in an infected person (1,2,20,37). Although the lymphoid tissues (e.g., lymph nodes and other compartments of the reticuloendothelial system) provide the major sites of active virus production in HIV-infected persons, virus produced in these tissues is released into the peripheral circulation where it can be readily sampled (3,4,48). Thus, plasma HIV RNA concentrations reflect the level of active virus replication throughout the body, although it is not known whether specific compartments (e.g., the central nervous system [CNS]) represent sites of infection that are not in direct communication with the peripheral pool of virus.
The Magnitude of HIV Replication in Infected Persons Determines Their
Rate of Disease Progression
Plasma HIV RNA can be detected in virtually all HIV-infected persons
although its concentration can vary widely depending on the stage of the
infection (Figure 1) and on incompletely understood aspects of the host - virus
interactions. During primary infection in adults when there are numerous
target cells susceptible to HIV infection without a countervailing host
immune response, concentrations of plasma HIV RNA can exceed 10 7 copies/mL
(83). HIV disseminates widely throughout the body during this period,
and many newly infected persons display symptoms of an acute viral illness,
including fever, fatigue, pharyngitis, rash, myalgias, and headache (84 - 86).
Coincident with the emergence of antiviral immune responses, concentrations of plasma HIV RNA decline precipitously (by 2 to 3 log10 copies or more). After a period of fluctuation, often lasting 6 months or more, plasma HIV RNA levels usually stabilize around a so-called set-point (5,6,10,27,31,86). The determinants of this set-point are incompletely understood but probably include the number of susceptible CD4+T cells and macrophages available for infection, the degree of immune activation, and the tropism and replicative vigor (fitness) of the prevailing HIV strain at various times following the initial infection, as well as the effectiveness of the host anti-HIV immune response. In contrast to adults, HIV-infected infants often have very high levels of plasma HIV RNA that decline slowly with time and do not reach set-point levels until more than a year after infection (14 - 18).
Different infected persons display different steady-state levels of HIV replication. When populations of HIV-infected adults are studied in a cross-sectional manner, an inverse correlation between plasma HIV RNA levels and CD4+T cell counts is seen (87,88). However, at any given CD4+T cell count, plasma HIV RNA concentrations show wide interindividual variation (87,88). In established HIV infection, persistent concentrations of plasma HIV RNA range from <200 copies/mL in extraordinary persons who have apparently nonprogressive HIV infection to >10 6 copies/mL in persons who are in the advanced stages of immunodeficiency or are at risk for very rapid disease progression. In most HIV-infected and untreated adults, set-point plasma HIV RNA levels range between 10 3 and 10 5 copies/mL. Persons who have higher steady-state set-point levels of plasma HIV RNA generally lose CD4+T cells more quickly, progress to AIDS more rapidly, and die sooner than those with lower HIV RNA set-point levels (5 - 7,10,27)(Figures 2 - 4). Once established, set-point HIV RNA levels can remain fairly constant for months to years. However, studies of populations of HIV-infected persons suggest a gradual trend toward increasing HIV RNA concentrations with time after infection (10). Within individual HIV-infected persons, rates of increase of plasma HIV RNA levels can change gradually, abruptly, or hardly at all (10). Progressively increasing plasma HIV RNA concentrations can signal the development of advancing immunodeficiency, regardless of the initial set-point value (10,75).
Plasma HIV RNA levels provide more powerful predictors of risk of progression to AIDS and death than do CD4+T cell levels; however, the combined measurement of the two values provides an even more accurate method to assess the prognosis of HIV-infected persons (27). The relationship between baseline HIV RNA levels measured in a large cohort of HIV-infected adults and their subsequent rate of CD4+T cell decline is shown (Figure 3) (27). Progressive loss of CD4+T cells is observed in all strata of baseline plasma HIV RNA concentrations, but substantially more rapid rates of decline are seen in persons who have higher baseline levels of plasma HIV RNA (Figure 3) (27). Likewise, a clear gradient in risk for disease progression and death is seen with increasing baseline plasma HIV RNA levels (5,6,10,27) (Figure 2 & Figure 4).
HIV Replicates Actively at All Stages of the Infection
The steady-state level of HIV RNA in the plasma is a function of the
rates of production and clearance (i.e., the turnover) of the virus in
circulation (1,2,20,21,37). Effective antiretroviral therapy perturbs
this steady state and allows an assessment of the kinetic events that underlie
it. Thus, virus clearance, the magnitude of virus production, and the longevity
of virus-producing cells can all be measured. Recent studies in which measurements
of virus and infected-cell turnover were analyzed in this way in persons
who had moderate to advanced HIV disease have demonstrated that a very
dynamic process of virus production and clearance underlies the seemingly
static steady-state level of HIV virions in the plasma (1,2,20,21,37).
Within 2 weeks of initiation of potent antiretroviral therapy, plasma HIV RNA levels usually fall to approximately 1% of their initial values (20,37)(Figure 5). The slope of this initial decline reflects the clearance of virus from the circulation and the longevity of recently infected CD4+T cells and is remarkably constant among different persons (1,2,20,37). The half-life of virions in circulation is exceedingly short—less than 6 hours. Thus, on average, half of the population of plasma virions turns over every 6 hours or less. Given such a rapid rate of virus clearance, it is estimated that 10 9 to 10 10 (or more) virions must be produced each day to maintain the steady-state plasma HIV RNA levels typically found in persons who have moderate to advanced HIV disease (20). When new rounds of virus replication are blocked by potent antiretroviral drugs, virus production from the majority of infected cells (approximately 99%) continues for only a short period, averaging approximately 2 days (1,2,20,37). HIV-infected CD4+T cells are lost, presumably as the result of direct cytopathic effects of virus infection, with an average half-life of an infected cell being approximately 1.25 days (20). The estimated generation time of HIV (the time from release of a virion until it infects another cell and results in the release of a new generation of virions) is approximately 2.5 days, which implies that the virus is replicating at a rate of approximately 140 or more cycles per year in an infected person (20,21). Thus, at the median period between initial infection and the diagnosis of AIDS, each virus genome present in an HIV-infected person is removed by more than a thousand generations from the virus that initiated the infection.
After the initial rapid decline in plasma HIV RNA levels following initiation of potent antiretroviral therapy, a slower decay of the remaining 1% of initial plasma HIV RNA levels is observed (37) (Figure 5). The length of this second phase of virus decay differs among different persons, lasting approximately 8 - 28 days. Most of the residual viremia is thought to arise from infected macrophages that are lost over an average half-life of about 2 weeks, whereas the remainder is produced following activation of latently infected CD4+T cells that decay with an average half-life of about 8 days. Within 8 weeks of initiation of potent antiretroviral therapy (in previously untreated patients), plasma HIV RNA levels commonly fall below the level of detection of even the most sensitive plasma HIV RNA assays available (sensitivity of 25 copies HIV RNA/mL), indicating that new rounds of HIV infection are profoundly suppressed (Figure 5) (37). Fortunately, this level of suppression of HIV replication appears to have been maintained for more than 16 months in most patients who adhere to effective combination antiretroviral drug regimens (39). However, even this marked pharmacologic interference of HIV replication has not yet been reported to eradicate an established infection. Those rare persons who have been studied after having stopped effective combination antiretroviral therapy following months with undetectable levels of plasma HIV RNA have all shown rapid rebounds in HIV replication. Furthermore, infectious HIV can still be isolated from CD4+T cells obtained from antiretroviral treated persons whose plasma HIV RNA levels have been suppressed to undetectable levels (<50 copies/mL) for 2 years or more (49,50). Viruses recovered from these persons were demonstrated to be sensitive to the antiretroviral drugs used, indicating that a reservoir of latently infected resting CD4+T cells exists that can maintain HIV infection for prolonged periods even when new cycles of virus replication are blocked. It is not known whether additional reservoirs of residual HIV infection exist in infected persons that can permit persistence of HIV infection despite profound inhibition of virus replication by effective combination antiretroviral therapies (37,47,48). HIV infection within the CNS represents an additional potential sanctuary for virus persistence, as many of the antiretroviral drugs now available do not efficiently cross the blood-brain barrier.
Active HIV Replication Continuously Generates Viral Variants That
are Resistant to Antiretroviral Drugs
HIV replication depends on a virally encoded enzyme, RT (an RNA-dependent
DNA polymerase) that copies the single-stranded viral RNA genome into a
double-stranded DNA in an essential step in the virus life cycle (21).
Unlike cellular DNA polymerases used to copy host cell chromosomal DNA
during the course of cell replication, RT lacks a 3’ exonuclease activity
that serves a “proofreading” function to repair errors made during transcription
of the HIV genome. As a result, the HIV RT is an “errorprone” enzyme, making
frequent errors while copying the RNA into DNA and giving rise to numerous
mutations in the progeny virus genomes produced from infected cells. Estimates
of the mutation rate of HIV RT predict that an average of one mutation
is introduced in every one to three HIV genomes copied (21,89).
Additional variation is introduced into the replicating population of HIV variants as a result of genetic recombination that occurs during the process of reverse transcription via template-switching between the two HIV RNA molecules that are included in each virus particle (21,90). Many mutations introduced into the HIV genome during the process of reverse transcription will compromise or abolish the infectivity of the virus; however, other mutations are compatible with virus infectivity. In HIV-infected persons, the actual frequency with which different genetic variants of HIV are seen is a function of their replicative vigor (fitness) and the nature of the selective pressures that may be acting on the existing swarm of genetic variants present (21). Important selective pressures that may exist in HIV-infected persons include their anti-HIV immune responses, the availability of host cells that are susceptible to virus infection in different tissues, and the use of antiretroviral drug treatments.
The rate of appearance of genetic variants of HIV within infected persons is a function of the number of cycles of virus replication that occurs during a person’s infection (20,21). That numerous rounds of HIV replication are occurring daily in infected persons provides the opportunity to generate large numbers of variant viruses, including those that display diminished sensitivity to antiretroviral drugs. A mutation is probably introduced into every position of the HIV genome many times each day within an infected person, and the resulting HIV variants may accumulate within the resident virus population with successive cycles of virus replication (21). As a result of the great genetic diversity of the resident population of HIV, viruses harboring mutations that confer resistance to a given antiretroviral drug, and perhaps multiple antiretroviral drugs, are likely to be present in HIV-infected persons before antiretroviral therapy is initiated (21).
Indeed, mutations that confer resistance to nucleoside analog RT inhibitors, NNRTIs, and PIs have been identified in HIV-infected persons who have never been treated with antiretroviral drugs (61,91,92). Once drug therapy is initiated, the pre-existing population of drug-resistant viruses can rapidly predominate. For drugs such as 3TC and nevirapine (and other NNRTIs), a single nucleotide change in the HIV RT gene can confer 100- to 1,000-fold reductions in drug susceptibility (1,61,93 - 95). Although these agents may be potent inhibitors of HIV replication, the antiretroviral activity of these drugs when used alone is largely reversed within 4 weeks of initiation of therapy due to the rapid outgrowth of drug-resistant variants (1,61,93 - 95). The rapidity with which drug-resistant variants emerge in this setting is consistent with the existence of drug-resistant subpopulations of HIV within infected patients before to the initiation of treatment (21,61). Because treatment with many of the available antiretroviral drugs selects for HIV variants that harbor the same or related mutations, specific treatments can select for the outgrowth of HIV variants that are resistant to drugs with which the patient has not been treated (referred to as cross resistance) (96,97).
Drug-resistant viruses that emerge during drug therapy are predicted to replicate less well (are less fit) than their wild-type counterparts and are expected to attain lower steady-state levels of viral load than are present before the initiation of therapy (21). Evidence for such decreased fitness of drug resistant viruses has been gleaned from studies of protease-inhibitor - treated or 3TC-treated patients, but this effect has not been apparent in NNRTI-treated patients (e.g., nevirapine or delavirdine) (1,61). Depending on its relative fitness, the drug resistant variant can persist at appreciable levels even after the antiretroviral therapy that selected for its outgrowth is withdrawn. HIV variants resistant to nevirapine can persist for more than a year after withdrawal of nevirapine treatment (61). Zidovudine-resistant HIV variants and variants resistant to both zidovudine and nevirapine have also been shown to persist in infected persons and to replicate well enough to be transmitted from one person to another (98). Because HIV variants that are resistant to PIs often appear to be less fit than drug-sensitive viruses, their prevalence in patients who develop PI resistance may decline after withdrawal of the drug. However, although such variants may decline after drug withdrawal, they also may persist in patients at higher levels than their original levels and can be rapidly selected for should the same antiretroviral agent (or a PI demonstrating cross resistance) be used again (97).
The definition of mutations associated with resistance to specific antiretroviral drugs and the advent of genetic methods to detect drug-resistant variants in treated patients have raised the possibility of screening HIV-infected patients for the presence of HIV variants as a tool to guide therapeutic decisions (92,99). However, this approach must be considered experimental and may prove very difficult to implement because of the complex patterns of mutations that increase resistance to some antiretroviral agents. Furthermore, the prevalence of clinically important populations of drug resistant variants in many HIV-infected persons is likely to be below the level of detection of the available assays, thus potentially creating falsely optimistic predictions of drug efficacy (21,61).
Combination Antiretroviral Therapy That Suppresses HIV Replication
to Undetectable Levels Can Delay or Prevent the Emergence of Drug-Resistant
Viral Variants
Current strategies for antiretroviral therapy are much more effective
than those previously available, and the efficacy of these approaches confirms
predictions emerging from fundamental studies of the biology of HIV infection.
Several important principles have emerged from these studies that can be
used to guide the application of antiretroviral therapies in clinical practice:
Antiretroviral Therapy-Induced Inhibition of HIV Replication Predicts
Clinical Benefit
As active HIV replication is directly linked to the progressive depletion
of CD4+T cell populations, reduction in levels of virus replication by
antiretroviral drug therapy is predicted to correlate with the clinical
benefits observed in treated patients. Data from an increasing number of
clinical trials of antiretroviral agents provide strong support for this
prediction and indicate that greater clinical benefit is obtained from
more profound suppression of HIV replication (9,13,23,38 - 40,56
). For example, virologic analyses from ACTG 175 (a study of zidovudine
or didanosine monotherapy compared with combination therapy with zidovudine
plus either didanosine or zalcitabine) indicate that a reduction in plasma
HIV RNA levels to 1.0 log below baseline at 56 weeks after initiation of
therapy was associated with a 90% reduction in risk of progression of clinical
disease (13). In a pooled analysis of seven different ACTG studies, durable
suppression of plasma HIV RNA levels to <5,000 copies of HIV RNA/mL
between 1 and 2 years after initiation of treatment was associated with
an average increase in CD4+T cell levels of approximately 90 cells/mm 3
(24). Patients whose plasma HIV RNA levels failed to be stably suppressed
to <5,000 copies/mL showed progressive decline in CD4+T cell counts
during the same period (24).
Decreases in plasma HIV RNA levels induced by antiretroviral therapy provide better indicators of clinical benefit than CD4+T cell responses (9,13,24). Furthermore, in patients who have advanced HIV disease, clinical benefit correlates with treatment-induced decreases in plasma HIV RNA levels, even when CD4+T cell increases are not seen. The failure to observe CD4+T cell increases in some treated patients despite suppression of HIV replication may reflect irreversible damage to the regenerative capacity of the immune system in the later stages of HIV disease.
The most extensive data on the relationship between the magnitude of suppression of HIV replication induced by antiretroviral therapy and the degree of improved clinical outcome were generated during studies of nucleoside analog RT inhibitors used alone or in combination (9,13,24). These treatments yield less profound and less durable suppression of HIV replication than currently available combination therapy regimens that include potent PIs (and that are able to suppress HIV replication to levels below the detection limits of plasma HIV RNA assays) (23,37,39). Thus, it is likely that the relationship between suppression of HIV replication and clinical benefit will become even more apparent as experience with potent combination therapies accumulates. Repair of immune system function may be incomplete following effective inhibition of continuing HIV replication and damage by antiretroviral drug therapy.
As discussed in the preceding principles, disease progression in HIV-infected patients results from active virus replication that inflicts chronic damage upon the function of the immune system and its structural elements, the lymphoid tissues. Because of the clonal nature of the antigen-specific immune response, in the absence of generation of immunocompetent CD4+T cells from immature progenitor cells, it is likely that T cell responses may not be regained once lost, even if new rounds of HIV infection can be stopped by effective antiretroviral therapy (80,82,101). Similarly, it is not known if the damaged architecture of the lymphoid organs seen in persons with moderate to advanced HIV disease can be repaired following antiretroviral drug therapy. Should the residual proliferative potential of CD4+ and CD8+T cells decline with increased duration of HIV infection and the magnitude of the cumulative loss and regeneration of lymphocyte populations, late introduction of antiretroviral therapy may have limited ability to reconstitute levels of functional lymphocytes. Thus, it is believed that the initiation of antiretroviral therapy before extensive immune system damage has occurred will be more effective in preserving and improving the ability of the HIV-infected person to mount protective immune responses.
Few reliable methods are now available to assess the integrity of immune responses in humans. However, the application of specific methods to the study of immune responses in HIV-infected patients before and after initiation of antiretroviral therapy indicates that immunologic recovery is incomplete even when HIV replication falls to undetectable levels. CD4+T cell levels do not return to the normal range in most antiretroviral drug-treated patients, and the extent of CD4+T cell increase is typically more limited when therapy is started in the later stages of HIV disease (82).
Recent evidence indicates that the repertoire of antigen-specific CD4+T cells becomes progressively constricted with declining T cell numbers (82). In persons who have evidence of a restricted T cell repertoire, antiretroviral therapy can increase total CD4+T cell numbers but fails to increase the diversity of antigen recognition ability (82). It is not yet known if expansion of a constricted CD4+T cell repertoire of antigen recognition might be seen with longer-term follow up of such persons.
Reports of OIs occurring in antiretroviral-treated patients at substantially higher CD4+T cell counts than those typically associated with susceptibility to the specific opportunistic infections raise the concern that restoration of protective immune responses may be incomplete, even when effective suppression of continuing HIV replication is achieved (102). However, other reports describe instances in which the clinical symptoms or signs of preexisting OIs were ameliorated (103 - 105), or in which new inflammatory responses to preexisting, but subclinical, OIs became manifest following initiation of effective combination antiretroviral therapy (106,107). These observations indicate that some improvement in immune function may be possible, even in patients who have advanced HIV disease, if sufficient numbers of pathogen-specific CD4+T cells are still present when effective antiretroviral therapy is begun.
The extent to which antiretroviral therapy can restore immune function when initiated in persons at varying stages of HIV disease is currently unknown but represents an essential question for future research.
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