JAC Advance Access originally published online on July 19, 2006
Journal of Antimicrobial Chemotherapy 2006 58(3):506-510; doi:10.1093/jac/dkl263
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Leading articles |
Discordant immunological and virological responses to antiretroviral therapy
1 Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro Av. Brigadeiro Trompowski s/n, Ilha do Fundão, Rio de Janeiro 21941–590, Brazil 2 Infectious Diseases Epidemiology Research Unit, Graduate School of Public Health and School of Medicine, University of Pittsburgh PA, USA
*Corresponding author. Tel: +55-21-2562-2725; Fax: +55-21-2590-1615; E-mail: maurosch{at}hucff.ufrj.br
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Abstract |
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In response to antiretroviral therapy, some patients experience what has been termed a discordant response, characterized either by a sustained CD4+ cell count rise despite persistent viraemia or by HIV-1 RNA plasma levels below the limit of detection accompanied by a blunted CD4+ cell count response. In part because of a lack of universally accepted definitions, published estimates of the frequency of discordant responses vary considerably. Little is known about the pathogenesis of discordant responses, which seems to depend on the interaction of a multitude of viral, host and treatment-related factors. Available evidence indicates that discordant responses are associated with an intermediate risk of death or clinical progression. At present, recommendations for the clinical management of patients with discordant responses to antiretroviral therapy are largely based on observational, uncontrolled data. The development of standardized and universally accepted definitions of discordant responses is necessary to allow meaningful comparisons between studies to be made, as well as to help in the design of trials of possible therapeutic interventions.
Keywords: CD4 lymphocyte count , viral load , treatment outcome
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Introduction |
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The introduction of highly active antiretroviral therapy (HAART) into clinical practice has led to dramatic reductions in morbidity and in mortality associated with infection with the human immunodeficiency virus (HIV). The initiation of HAART generally leads to a rapid reduction in HIV-1 RNA plasma levels and to an increase in peripheral CD4+ cell counts.1–3 However, some patients experience a ‘discordant response’, whereby the HIV-1 RNA plasma level is below the limit of detection but the CD4+ cell count response is blunted. Other patients exhibit a different pattern of discordant response, characterized by a sustained CD4+ cell count response, despite persistent viraemia. In this article, we discuss the epidemiology, risk factors, prognosis and recommendations for the clinical management of patients with discordant responses.
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Epidemiology |
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It is not surprising that, given the lack of universally accepted definitions of virological and immunological success, published estimates of the frequency of discordant responses vary considerably (Table 1). Definitions of virological success that have been used include HIV-1 RNA plasma levels below 50, 400 or 1000 copies/mL, whereas definitions of immunological response include increases in CD4+ cells counts above a certain value (usually 50 cells at the end of the first year of therapy) or maintenance of CD4+ cell counts above a certain threshold (generally 200 cells/mm3).
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In industrialized countries, discordant responses have been reported to occur in 20–30% of patients 6 months to 2 years after starting therapy. For example, in a cohort of 162 HIV patients receiving indinavir and followed for a median of 10.5 months, Piketty et al. found equal rates (10.5%) of immunological only and virological only responses. The authors defined immunological success as an increase of 50 CD4+ cells/mm3 and virological success as either a decrease in HIV RNA plasma viral load by 1 log10 or achieving a plasma viral load <400 copies/mL at any point during the follow-up period (median 12 months, range 2–15 months).4 In another study, conducted in France, immunological success was defined as an increase of CD4+ of more than 50 cells/mm3 and virological success as a decrease in HIV RNA viral load of more than 1 log10 copies/mL, after 6 months on treatment. In 2236 protease inhibitor (PI) naive patients studied, 19% exhibited immunological responses only, whereas 17.3% had virological responses only.5 In a study conducted in Italy, which included 3094 antiretroviral naive and experienced patients, 20.6% were reported to have immunological only responses and 15.7% were reported to have virological responses only. The definitions used in this study were an increase of at least 100 CD4+ cells/mm3 and plasma viral load levels below 500 copies/mL at 12 months.6 In a cohort of 265 injecting drug users (IDU) in Baltimore, MD, immunological and virological only responses were observed in 21% and 16%, respectively. Virological response was defined as a viral load <1000 copies/mL and immunological response as either an increase of 50 CD4+ cells or achieving CD4+ >500 cells/mm3 at the end of the first year on HAART.7 In a study conducted in British Columbia, Canada, an increase of 50 CD4+ cells/mm3 and achieving viral load <500 copies/mL at 6 months on therapy were used to define successful immunological and virological responses, respectively. The study involved 1527 treatment-naive patients and found that 11.7% and 15.4% of the subjects showed immunological and virological only responses, respectively.8
There are limited data on discordant responses in patients being treated in developing countries. The Antiretroviral Therapy in Lower Income Countries Collaboration (ART-LINC), an epidemiological network of HIV/AIDS treatment programmes in Africa, Asia and South America, has reported on the frequency of discordant responses in 1916 previously treatment-naive patients seen in 15 developing countries who initiated HAART between March 1996 and April 2004. A total of 269 patients (14%) were virological only responders and 365 (19%) were immunological only responders9 with virological response defined as achieving a plasma HIV RNA viral load <500 copies/mL, and immunological response defined as an increase of at least 50 CD4 cells/mm3 at 6 months.
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Risk factors |
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Little is known about the pathogenesis of discordant responses, which seems to depend on the interaction of a multitude of viral, host and treatment-related factors.
A blunted CD4 response despite suppression of viral replication has often been attributed to host characteristics, particularly older age.6,8,10–12 It has been hypothesized that the magnitude of immune restoration is dependent on thymus activity, which decreases with age.13 Poor CD4 cell reconstitution despite virological response has also been correlated with a lower nadir pretreatment CD4+ cell count, suggestive of more extensive depletion of CD4+ cells in the gut-associated lymphoid tissue during primary (acute) HIV infection, which may be slow or refractory to reconstitution with antiretroviral therapy.14,15 Moreover, it has been suggested that the rate of CD4+ cell depletion after HIV infection is established is also important: slower rates of decrease in CD4+ cell counts before therapy initiation are associated with a slower early recovery, whereas sharper slopes of CD4+ cell decrease are associated with maximal subsequent cell distribution once therapy is instituted.16
Genetic variability has also been investigated as a possible modulator of immunological recovery. An example is the multidrug-resistance transporter gene MDR1, which codes for P-glycoprotein, an essential protein involved in transportation of many different substrates, including antiretroviral drugs. Overexpression of P-glycoprotein lowers intracellular concentration of PIs17 and could therefore affect reconstitution of CD4+ cell pool. Association of MDR1 polymorphism (3435 TT genotype) with improved CD4 recovery was found in two studies,18,19 but not in another.20 Polymorphisms within the CCR5 gene, which codes for a key cell surface co-receptor for macrophage-tropic strains of HIV-1, have long been associated with different patterns of susceptibility to infection21 and disease progression.22 However, it appears that such polymorphisms do not have a significant impact on initial virological and immunological responses to antiretroviral therapy.23,24 Finally, a few studies have looked at genes that are associated with T lymphocyte apoptosis. Combination of some polymorphisms of Fas and Fas ligand (FasL), two important genes that control T lymphocyte homeostasis,25 and carriage of a specific allele that encodes IL-6 production24 have been implicated in altered CD4+ recovery.
Other factors that have been reported to be associated with blunted CD4+ response are infection by HIV-226 and drug toxicity. The use of the combination tenofovir/didanosine27,28 has been implicated in failure to increase CD4+ cell count despite viral suppression, an effect that is apparently dependent on the dose of didanosine used. The underlying mechanism is thought to be a synergistic effect of both tenofovir and didanosine metabolites in producing an imbalance in the purine pool within CD4+ T lymphocytes, which, in turn, has a cytostatic effect on these cells.29
The use of zidovudine or didanosine as part of the antiretroviral regimen, both which can cause leucopenia, the concurrent use of other myelotoxic drugs such as co-trimoxazole, or the presence of certain co-infections, such as HTLV-1, have all been associated with suboptimal CD4+ cell responses despite suppression of viral replication.30
The physiology of a good immunological response in the presence of virological failure is also not well understood and possibly involves various aspects of virus–drug–host dynamics. In one closely followed cohort of 402 patients who had laboratory evaluations repeatedly in the first year after initiation of HAART, all but 2 of the 25 immunological only responders had either a prior transient period of undetectable plasma viraemia or, at least, HIV-1 RNA plasma levels <1000 copies/mL suggesting that temporary or partial viral suppression was the primary mechanism involved in the observed increases in CD4+ cell counts.31 One possible explanation is that HAART selects for viral strains with lower replicative capacity and reduced pathogenicity. The observation that virus isolated from recipients of PI-based regimens with stable CD4+ cell counts despite virological failures have decreased viral replication capacity seems to corroborate this hypothesis.32,33 In one study, lower replication capacity, or reduced fitness, was associated with the presence of non-syncytium-inducing viral phenotype, decreased cellular activation and enhanced interferon-
production in response to gag and tat antigens in the setting of extensive genotypic and phenotypic resistances to PIs.33 Patients in this study exhibited sustained or even increased CD4+ counts for periods exceeding 5 years without disease progression, despite extensive and stable antiretroviral resistance profiles.34 The sustained increase in CD4+ cell count in the context of prolonged virological failure may be explained by a state of relative immunological quiescence, in which T-cell dynamics are similar but not identical to what occurs in complete responders, in whom the turnover of CD4+ cells has been shown to be slower, denoted by their reduced expression of markers of activation (CD38+, HLA-DR+) and active cycling (Ki67+), compared with untreated patients.35
Antiretroviral resistance mutations that are associated with reduced replication capacity have been frequently reported in patients with immunological response despite virological failure. Although both immunological only responders and non-responders seem to share a similar resistance pattern, a higher percentage of viral strains carrying the M184V mutation, associated with lamivudine resistance, has been reported in immunological only responders than in non-responders.36–38 In one study of patients who remained on a stable PI-based regimen despite detectable plasma viraemia, the emergence of primary mutations V82A, I84V and/or L90M were associated with a decreased replicative capacity.39 In another study in patients who had failed HAART, the M36I mutation was only found in immunological only responders.38
There are no published controlled studies evaluating the impact of different antiretroviral regimens on the incidence of discordant responses. On the other hand, published observational studies mostly include patients receiving PI-based regimens. In the observational study by Moore et al.,8 no association was found between type of regimen and presence of discordant responses 3–9 months after HAART initiation. Nonetheless, there are data to indicate that the degree of impairment in viral replicative capacity in virus isolated from patients with discordant responses may depend on the type of antiretroviral regimen being used, replicative capacity being higher in patients on non-nucleoside reverse transcriptase inhibitor-based regimens than in patients receiving PI-based regimens, perhaps reflecting different barriers to selection of resistant virus.40 There are also data to indicate that in patients with sustained CD4+ cell counts despite prolonged virological failure, interruption of the PI while maintaining the reverse transcriptase inhibitor backbone had little impact on CD4+ cell counts or plasma viraemia, whereas the reverse led to significant increases in HIV-1 RNA plasma levels and decreases in CD4+ cell counts.41
Adherence to therapy may also influence the occurrence of discordant responses. In the study by Moore et al.,8 suboptimal adherence was found to be associated both with virological and immunological only responses.
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Prognosis |
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The use of different definitions of virological and immunological responses, as well as different follow-up periods, does not allow for direct comparisons between the various studies that attempted to determine the prognostic impact of discordant responses. Nonetheless, the majority of published studies have indicated that, in comparison with complete response, discordant responses are associated with an intermediate risk of death or clinical progression.
In the previously cited study of Grabar et al.,5 virological only responders and non-responders had a higher probability of clinical progression, whereas immunological only and complete responders had similar risks. In contrast, in other studies immunological only response was also associated with a higher risk of clinical progression. In one cohort of antiretroviral-experienced patients with advanced HIV disease starting PI-based HAART, who were followed for over 30 months, discordant responders at 12 months experienced significantly more AIDS-defining events than complete responders, with immunological only responders presenting a slightly higher probability of being event-free compared with virological only responders.11 In another study involving over 2100 antiretroviral-experienced and -naive HIV patients followed for a median of 44 months, immunological only and virological only responders had a significantly lower risk of clinical progression than non-responders, but a 2.3- and 1.9-fold greater risk of death or of experiencing a new AIDS-defining event than complete responders, respectively.6
Very few studies have assessed the prognostic impact of discordant responses in naive patients and in recipients of NNRTI-based regimens. In the study by Moore et al.,8 mortality was increased in patients showing an early discordant response, but no statistically significant difference was found between immunological and virological only responders. Likewise, in a study involving HAART naive IDU patients, discordant responders had an increased mortality compared with complete responders, but progression rates did not differ by whether early response was immunological or virological only.7 We are not aware of any published study assessing the prognostic impact of discordant responses in low-income settings.
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Clinical management |
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At present, recommendations for the clinical management of patients with discordant responses to antiretroviral therapy are largely based on observational, uncontrolled data.
For patients on a new regimen, in whom after several months of treatment the HIV-1 RNA level is below the limit of detection but the CD4+ cell count response is blunted, it is recommended to maintain the current regimen. Changing or intensifying the regimen has not been shown to have an effect on the CD4+ cell count response, except in the case of patients whose regimen contains antiretroviral drugs that are associated with leucopenia, such as zidovudine or didanosine. One controlled study showed that concomitant administration of human recombinant growth hormone may be beneficial in enhancing immunological response in chronically infected patients.42 If the patient is using concomitant medications associated with bone marrow toxicity, their interruption or substitution should be judiciously considered.
Given that no benefit has so far been demonstrated and the potential for significant toxicity, the use of immune modulators, such as interleukin-2, is not recommended, except in the setting of clinical trials.30
For patients with a sustained CD4+ cell count response, despite persistent viraemia, the goal of therapy should remain the suppression of HIV-1 RNA to levels below 50 copies/mL. A detailed assessment of adherence, drug intolerance and pharmacokinetic issues should be done to rule out modifiable causes. If none is encountered, then modifications in the antiretroviral regimen should be considered, the choice of drugs being dependent upon patient history and resistance testing. For patients who have previously failed multiple regimens, it may not be feasible to achieve plasma HIV-1 RNA levels of less than 50 copies/mL. For these patients, stability of CD4+ cell counts becomes the objective of treatment.
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Conclusions |
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TopAbstractIntroductionEpidemiologyRisk factorsPrognosisClinical managementConclusionsTransparency declarationsReferences |
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There is limited information on the pathogenesis, risk factors, prognosis and clinical management of discordant immunological and virological responses to antiretroviral therapy, despite its relative frequency. The development of standardized and universally accepted definitions of discordant responses is necessary to allow meaningful comparisons between studies to be made, as well as to help in the design trials of possible therapeutic interventions.
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Transparency declarations |
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TopAbstractIntroductionEpidemiologyRisk factorsPrognosisClinical managementConclusionsTransparency declarationsReferences |
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None to declare.
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References |
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5
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28
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32
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