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Clinical Indicators of Immune Restoration following Highly Active Antiretroviral Therapy

  1. Kenneth H. Mayer, Section Editor
  1. Elizabeth L. Cooney
  1. Yale University School of Medicine, New Haven, Connecticut
  1. Reprints or correspondence: Dr. Elizabeth L. Cooney, 5 Research Pkwy., Wallingford, CT 06492-7660 (elizabeth.cooney{at}bms.com).
 
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Abstract

The course of human immunodeficiency virus (HIV) disease is characterized by a progressive decline in immune function. The advent of highly active antiretroviral therapy (HAART) has allowed patients to experience a significant degree of immune restoration when compared with the era before the availability of HAART. Multiple studies, which have employed sophisticated in vitro measures of immune function, have demonstrated improvement in CD4+ lymphocyte (T4) responses to various opportunistic pathogens. In addition, for patients treated during acute HIV infection, HIV-specific T4 responses have been restored. By contrast, there are a limited number of in vivo measures of T4 function available to assess immune recovery following initiation of HAART. The primary measurement is an increase in CD4 lymphocyte count, the significance of which may be underappreciated. Delayed-type hypersensitivity testing to recall antigens and serological response to prophylactic vaccines may also have a role. This review discusses available markers of immune function and offers suggestions regarding their use in HAART recipients.

In the absence of effective antiretroviral therapy, the majority of HIV-infected persons experience a progressive decline in immune status. Significant defects in B and CD8+ T lymphocyte function occur, which place patients at risk for several common and opportunistic infections as well as malignancies. These defects are not directly attributable to HIV but instead stem from major alterations in CD4+ T lymphocyte (T4) number and function [1].

Impaired T4 activity is indeed the hallmark of untreated HIV infection. Although the pathogenesis remains incompletely understood, multiple factors probably act together to alter normal T4 activity (table 1). Numerous studies have been conducted to characterize the extent and course of T4 dysfunction during HIV infection. In the majority of cases, T4 function has been measured by ability of T lymphocytes to respond to soluble antigens and mitogens. The most commonly employed measures have been lymphocyte proliferation response or cytokine release profile, following co-culture of peripheral blood mononuclear cells with various in vitro stimulants. A summary of the findings of these studies follows.

Table 1
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Table 1

Proposed mechanisms of impairment of T-helper lymphocyte recognition of HIV.

Impaired T4 responsiveness to foreign antigen begins early after acute HIV infection, well before there is a significant decrease in T4 number. Recently, it has been demonstrated that, during acute infection, a global decline in T4 responses occurs, which persists for several weeks. Subsequently, non–HIV-specific T4 (non-HIV T4) responses recover. However, HIV-specific (HIV-T4) responses typically remain weak or undetectable [2]. Over time, in the absence of effective antiretroviral therapy, non-HIV T4 responses again decline. Although prospective analyses are lacking, cross-sectional studies in which patients have been stratified by absolute CD4 lymphocyte number (CD4 count), have shown a similar pattern of decline. There is initially a loss of responsiveness to non-HIV recall antigens and, subsequently, to alloantigens and ultimately mitogens [3, 4].

Loss of HIV-T4 responses during acute infection is anticipated. HIV-T4 clones interact intimately with HIV when undergoing antigenic priming and are eliminated by viral lysis, apoptosis, and other mechanisms. By contrast, T4 clones programmed to recognize other antigens presumably undergo a more random process of elimination over time. However, clones circulating at low precursor frequency because of infrequent antigen encounter (e.g., tetanus-specific clones) are probably more susceptible to loss than are those circulating in higher number (e.g., cytomegalovirus [CMV]–specific clones), secondary to repeated antigen exposure through endogenous (reactivation) and/or exogenous (reinfection) pathways.

With the advent of HAART, patients have been given the opportunity to experience a degree of immune restoration rarely attained in the era before HAART. To date, there have been intensive research efforts to define the degree of immune recovery that occurs following the initiation of HAART. Recovery of T4 responses to HIV as well as non-HIV pathogens has been assessed [5–8].

More than 1 group of researchers has shown that if HAART is initiated during acute infection, HIV-T4 responses can be preserved [9, 10]. With continued therapy and effective control of viral activity, HIV-T4 responses wane, presumably because memory clones revert to a resting state in response to diminished antigenic stimulation [11]. Yet HIV-T4 clones persist. Spontaneous reappearance of HIV-T4 responses temporally associated with discontinuation of HAART and an increase in HIV RNA level supports this assumption [12]. However, when HAART is initiated later in HIV infection, with rare exception [13] HIV-T4 responses have been difficult to detect [7, 8]. Whether or not this observation reflects HIV-T4 clone depletion or severe qualitative changes remains unclear.

By contrast, independent of when HAART is initiated, the majority of patients reconstitute T4 responses to major opportunistic pathogens, such as CMV and Mycobacterium avium complex (MAC) [5, 14, 15]. Responses to infrequently encountered antigens, such as tetanus, have been more difficult to detect. However, it is encouraging that with added interventions, such as reimmunization [16], tetanus T4 responses have been elicited in some patients, which suggests that clonal deletion has not occurred.

The majority of studies on immune reconstitution following the initiation of HAART have employed sophisticated in vitro measures of cellular-mediated immunity (CMI) that are not readily available to the clinician (table 2). By comparison, there are relatively few in vivo measures of CMI that clinicians can call upon to evaluate immune recovery (table 3). The primary measure that is employed is change in CD4 count; however, technically speaking, this is a quantitative rather than qualitative measure of CMI.

Table 2
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Table 2

In vitro measures of host cellular immune function following highly active antiretroviral therapy.

Table 3
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Table 3

In vivo laboratory markers of immune restoration following highly active antiretroviral therapy.

In the remaining space, I shall discuss the significance of an increase in CD4 count following HAART, focusing on correlation between CD4 cell gain and recovery of CMI responses to opportunistic pathogens. I shall also briefly discuss other in vivo measures of CMI available to the clinician and propose how these might be used in clinical practice.

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CD4 Cell Increase During Haart Marks Recovery of CMI Responses to Opportunistic Pathogens

Lessons learned from trials on discontinuing prophylaxis for opportunistic infections.There is a considerable body of literature on discontinuing primary prophylaxis for Pneumocystis carinii pneumonia [17–23]. Results of these studies are summarized in table 4. Although study design, sample size, and duration of follow-up differed, the majority of subjects had similar eligibility criteria (CD4 count, >200 cells/mm3; no HIV RNA level criterion). Of the 1930 subjects enrolled, only 1 developed P. carinii pneumonia during follow-up, at which time the CD4 count had decreased to <200 cells/mm3 [23].

Table 4
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Table 4

Discontinuation of primary prophylaxis for Pneumocystis carinii pneumonia following initiation of highly active antiretroviral therapy.

Similarly, there have been several recent publications on discontinuing primary prophylaxis for MAC infection following an increase in CD4 count to >100 cells/mm3 ([24–26]; table 5). Again, HIV RNA level was not an entry criterion. Notably, none of the 836 patients who discontinued prophylaxis developed disseminated MAC infection during follow-up.

Table 5
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Table 5

Discontinuation of primary prophylaxis for Mycobacterium avium complex (MAC) infection following highly active antiretroviral therapy.

Finally, there have been several reports of successful discontinuation of maintenance therapy for patients with quiescent CMV retinitis, following a HAART-induced increase in CD4 count to >100–150 cells/mm3 ([27–33]; table 6). Of note, during follow-up, CD4 counts remained at >100 cells/mm3 (data not shown); however, HIV RNA levels ranged widely.

Table 6
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Table 6

Data concerning discontinuation of cytomegalovirus (CMV) maintenance therapy following highly active antiretroviral therapy (HAART).

Each of the above examples suggests the following conclusion regarding immune restoration following initiation of HAART. Once patients have achieved a CD4 count threshold above which risk for an opportunistic infection is accepted as low, they again are at decreased risk for that infection. Presumably, at this point in the trajectory of CD4 count increase, a sufficient number of functional T cell clones specific for that pathogen have been reconstituted to protect against disease.

In fact, several studies have shown that the majority of HAART recipients who respond with an increase in CD4 count have CMI responses to CMV and MAC. CMV-T4 responses have been detected in HAART responders with or without a history of CMV retinitis [15]. Moreover, a limited number of investigators have serially evaluated patients for presence of CMV immunity before and following initiation of HAART and demonstrated reconstitution of T4 responses. A recently published study has similarly shown reconstitution of MAC-specific T4 (MAC-T4) responses following HAART. Fifty percent of patients without a history of disseminated MAC infection had detectable MAC-T4 responses before they received HAART. Response rates increased to 61% and 77% by 3 and 6 months of therapy, respectively, and the magnitude of response was similar to that evidenced in healthy control subjects [14].

However, caution should be exercised when applying these findings to clinical care. It remains to be proven that attaining a particular CD4 count following HAART invariably provides a patient with the same degree of protection against an opportunistic pathogen as never having had a CD4 nadir at less than that level. Indeed, there have been reports of MAC and CMV disease developing in patients within a few weeks of initiation of HAART, at which time the CD4 count had increased to more than the accepted threshold level of risk for disease occurrence [34, 35]. Although functional analyses were not performed, these cases may in part reflect a kinetics phenomenon, whereby insufficient time had elapsed for pathogen-specific T cell clones to expand, regain normal function, and prevent disease. Hence, in these cases, the CD4 count overestimated T4 function. Alternatively, clonal expansion may have contributed to disease occurrence, through cytokine-mediated or other effects on pathogen replication. This is the rationale behind the recommendation that prophylaxis for opportunistic infections not be stopped until the CD4 count has been at more than the threshold level of risk for a period of 3–6 months.

It is also conceivable that a subset of patients may never regain adequate levels of pathogen-specific immunity following HAART, secondary to either T cell clone deletion or irreversible functional changes. Indeed, there are case reports of relapsed CMV retinitis and disseminated MAC infection occurring in patients who have had a sustained CD4 count at more than the threshold level of risk for a number of months [36, 37]. In one report of relapsed CMV retinitis, onset of retinitis was correlated with a markedly diminished frequency of circulating CMV-T4 cells, as compared with the frequency in coinfected patients with no history of CMV retinitis [36]. Unfortunately, at present, this subset of patients is not readily identifiable in the clinic. Hence, patients whose prophylaxis for opportunistic infection is discontinued should be closely monitored, with frequent follow-up visits, and prophylaxis should be reinstituted when the CD4 count decreases to a value near the threshold level of risk.

These observations raise several important questions. Should functional assessments of CMI to opportunistic pathogens, such as lymphocyte proliferation analyses and delayed-type hypersensitivity (DTH) skin testing, be incorporated into clinical practice to help ensure proper risk stratification of patients who otherwise meet the criterion for discontinuation of prophylaxis? If so, in vitro stimulants and skin test reagents would need to be developed and standardized for use. In addition, cost-effective analyses would need to be conducted. Should therapeutic vaccines directed at opportunistic pathogens be pursued to enhance pathogen-specific responses in patients whose responses fail to spontaneously reconstitute following HAART?

Lessons learned from immune response reactions.It is beyond the scope of this review to discuss in depth the topic of immune response reactions (IRRs), elsewhere referred to as “immune response inflammatory syndromes” (IRIS). The reader is referred to a recently published review on this topic [38] and to table 7 for the spectrum of reactions reported to date. However, I would like to comment on the pathogenesis of IRRs and what IRRs tell us about immune recovery following initiation of HAART.

Table 7
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Table 7

Immune restoration reactions following initiation of highly active antiretroviral therapy (HAART).

The pathogenesis of IRRs has been incompletely defined. Two theories have been proposed. The first theory is that an IRR represents unmasking of a previously latent or incubating infection, precipitated by HAART-induced immunologic changes. In this case, a pathogen-specific immune response might be partially reconstituted, yet responses would not be sufficient to prevent disease occurrence. Meanwhile, the clinical presentation might be altered secondary to an evolving immune response.

Examples suggestive of this mechanism include the reported cases of MAC lymphadenitis [35], cryptococcal meningitis [39], progressive multifocal leukoencephalopathy [40], and CMV retinitis [34] occurring within 1–4 weeks of initiation of HAART, temporally correlated with an increase in CD4 count. In these case reports, active infection was evident. However, unusual features, suggesting presence of an immune response, were also observed, including granuloma formation, CSF inflammation, contrast-enhancing CNS lesions, and vitritis, respectively.

The second theory is that an IRR represents an augmented host response to antigens present in low amounts in tissues. An example of this type of reaction is the now well-described syndrome known as “CMV vitritis.” CMV vitritis has been observed in ⩽60% of patients with quiescent CMV retinitis, following initiation of HAART and an increase in CD4 count [41]. CMV retinitis remained quiescent in all cases. Thus, in this case, the IRR appears to represent a purely inflammatory host response, directed at residual CMV antigen localized to the retina. Average reported time to onset of CMV vitritis following HAART has been 2–4 months. Variability in time to occurrence presumably reflects differences in rates of T cell recovery, affected by the number and repertoire of CMV-specific clones present prior to initiation of HAART, the ability of clones to expand, and the pathway by which new clones are generated (thymic or peripheral).

HAART-associated IRRs can thus be viewed as a double-edged sword. On the one hand, they represent the welcome recovery of pathogen-specific responses. On the other hand, they may cause considerable patient-related morbidity, negatively affect quality of life, and add cost. In addition, they are problematic from a management perspective.

First, providers may fail to correctly identify an IRR and prematurely discontinue effective antiretroviral therapy on the basis of presumed drug toxicity; this is commonly done for HAART-associated hepatitis flares. Furthermore, after resolution of the reaction, providers may hesitate to reinstitute prior medications and unnecessarily alter the HAART regimen.

Second, when an IRR occurs, patients may begin pathogen-specific therapy, when in fact the reaction might have resolved spontaneously or with addition of an anti-inflammatory agent, such as corticosteroids. Unfortunately, for some IRRs, such as MAC lymphadenitis, short of tissue biopsy, there is no reliable way of distinguishing which events would be best managed with HAART alone, with the addition of steroids, or with the initiation of anti-MAC therapy. Published cases have been managed successfully using each of these approaches, and comparative treatment data are lacking. Instead, one is left with practicing the art of medicine and individualizing therapy.

Third, an IRR may be misinterpreted as treatment failure. An example is the meningeal flare occasionally encountered in patients undergoing induction therapy for cryptococcal meningitis following the initiation of HAART [38]. The CSF changes could be misinterpreted as worsening of the underlying illness rather than an evolving host response to cryptococci. In this case, addition of steroids might be more appropriate management than serial CSF drainage.

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Other in Vivo Markers of CMI Function

DTH skin (anergy) testing to recall antigens.Anergy testing has long been employed as an in vivo measure of host CMI function, despite limitations related to sensitivity, the requirement for technical training, and inconvenience to patients. In addition, controversy exists regarding the preferred method. Most experts recommend the Mantoux method and the use of 2 antigens, preferably tetanus and candida, given studies in healthy control subjects that demonstrated 100% response rates to this 2-antigen panel. Results from studies involving HIV-infected patients similarly favor use of this methodology and antigen panel [42].

DTH skin testing has been assessed for its potential utility in 3 areas of HIV management: (1) predictor of disease progression (prior to the availability of HIV RNA level assays), (2) aid to interpretation of purified protein derivative (PPD) skin test results, and (3) surrogate marker for response to effective antiretroviral therapy. Pertinent to this review is a brief discussion of the latter. DTH skin testing was employed as a measure of response to effective antiretroviral therapy in the original zidovudine monotherapy trial, which involved patients with late-stage HIV disease [43]. In this study, 28% of zidovudine recipients evidenced a DTH response during treatment, as compared with 9% of control subjects. Although response rates were higher among patients who had a baseline CD4 count of >100 cells/mm3 (42%), 20% of patients with a CD4 count of ⩽100 cells/mm3 at entry responded.

More recently, DTH skin testing has been nested into certain HAART trials. In one study [7, 16], DTH responses to candida, mumps, and tetanus antigens improved from 9%, 0%, and 16% at baseline to 33%, 23%, and 68%, respectively, by 48 weeks of study. Reconstitution of a mumps response was delayed, consistent with the hypothesis that mumps-specific T4 cells circulate at a lower precursor frequency in adults, secondary to infrequent antigen contact and, therefore, may repopulate the circulation more slowly following effective antiretroviral therapy.

Anergy panels are no longer recommended as an accompaniment to PPD testing. However, DTH testing may still have a place in the care of HIV-infected patients. Performance of skin tests prior to starting effective antiretroviral therapy may help establish baseline CMI status. Similarly, for anergic patients, retesting after therapy may lend insight into the extent of immunologic recovery. However, pending availability of other skin test reagents (e.g., MAC, P. carinii, CMV), assessment is clearly limited in scope.

The optimal time to perform DTH skin testing following HAART has not been defined. However, it seems prudent to defer testing until the HIV RNA level is undetectable and the CD4 count has increased. For patients with persistent anergy, retesting could be considered in 6–12 months to assess for delayed immunologic recovery. Persistent tetanus anergy could be further assessed through evaluation of tetanus antibody status. Patients with low antibody titers are candidates for a tetanus booster or, in select cases in which antibody levels fail to increase after receipt of a single booster, the full immunization series.

Patients may balk at undergoing DTH skin testing on a regular basis owing to fear of a reaction or pain from the test, as well as the added inconvenience of another trip to the clinic. However, in my experience, patients who are properly educated about the immunologic goals of HAART, the purpose of this test, and the meaning of the results will willingly participate and accept these added inconveniences.

Serological response to prophylactic vaccines.Antibody response to prophylactic vaccines may serve as another measure of recovering immune function following HAART. Several studies involving HIV-infected patients have evaluated immune response after immunization with different available vaccines. Excepting pneumococcal vaccine, all vaccines studied elicit a T cell–dependent antibody response. Consequently, most studies have shown a suboptimal antibody response amongst HIV-infected patients in comparison with healthy controls; the most markedly impaired responses are seen in subjects with CD4 counts of ⩽100 cells/mm3.

There are limited but encouraging data concerning response rates to prophylactic vaccines administered following HAART. In one study [16], antibody responses were induced in 73% of hepatitis A virus vaccine recipients, and tetanus antibodies were boosted in 48% of tetanus vaccine recipients. Optimal timing of vaccination following HAART has not been defined. However, the ability to elicit better responses in some settings following administration of HAART provides a rationale for deferring vaccination to elective antigens in patients with advanced disease until control of virus replication is attained and an increase in CD4 count has occurred.

In conclusion, there are a limited number of immunologic surrogate markers available to the HIV clinician. However, these markers can help one assess the degree of immune recovery following HAART. The only currently recommended marker for use in the clinic is the CD4 count. Prospective studies demonstrating clinical utility are needed before DTH skin testing and measure of serological response to prophylactic vaccines can be routinely recommended. Other in vitro measures of CMI might ultimately be of use, following further study and standardization of assays and reagents. However, the cumulative data that demonstrate a correlation between clinical improvement and detection of responses by these various markers suggest that they measure truly meaningful parameters and may ultimately be of use to clinicians and their patients.

  • Received May 23, 2001.
  • Revision received August 3, 2001.
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  1. Clin Infect Dis. (2002) 34 (2): 224-233. doi: 10.1086/323898
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