Pre-cART Elevation of CRP and CD4+ T-Cell Immune Activation
Pre-cART Elevation of CRP and CD4+ T-Cell Immune Activation
To our knowledge, this is the first study to assess and identify baseline biomarkers associated with early clinical HIV progression after cART initiation across multiple resource and clinical settings. After measuring a comprehensive panel of immune activation biomarkers, our analysis indicates that the highest quartiles of baseline pre-cART CRP concentration and CD4 T-cell activation predict subsequent progression to WHO stage 3 or 4 disease or death within 96 weeks on cART after adjusting for baseline age, sex, BMI, and CD4 T-cell count. Notably, the associations were independent of country-to-country differences in baseline biomarker levels and cART regimen. Conversely, while a trend toward significant association was observed for sCD14 and CD8 T-cell activation, we could not confirm an association between early HIV progression on cART and biomarkers that have been previously described in relation to HIV disease progression, namely in LPS, EndoCAb IgM, IL-6, TNF-α, and IP-10. In resource-limited settings where follow-up intervals can be prolonged, our findings may help clinicians identify high-risk cART-naive patients who require additional vigilance for OIs and AIDS progression even after cART initiation.
The response to HIV treatment can vary considerably and AIDS-related events can still develop in the early months after cART initiation. Indeed, AIDS-related events are still the leading cause of early mortality among persons living with HIV on cART in low- and middle-income settings, even among those with virologic suppression. Consequently, current treatment guidelines offer no provision for patients who start cART but who will ultimately clinically progress. A baseline prognostic marker would be of particular importance in such settings, where tests for HIV RNA level and CD4 T-cell counts tests may be prohibitively expensive.
Immune activation has been previously described in HIV-infected persons, but has been defined using differing biomarker panels, and most previous studies have been conducted at a single site or in resource-rich countries. In resource-limited settings, high CRP levels among untreated HIV-infected women who were pregnant has been previously associated with progression to WHO stage 4 disease or death in the mothers and in their children. In addition, elevated CRP levels were associated with clinical progression in an HIV-infected cART-naive population of Ugandans. More recently, the SMART and INSIGHT studies have associated elevated pre-cART CRP levels with death, opportunistic infection, and AIDS progression among patients in resource-rich countries. To our knowledge, however, these are the first data to show that pre-cART CRP levels are associated with clinical progression in HIV-infected persons initiating cART in settings with mixed resource levels. In contrast, evidence regarding CD4 T-cell activation has been less consistent. Apart from the present analysis, only 1 other study has associated baseline CD4 T-cell activation with outcomes among patients initiating cART, whereas several studies have found no such association. Thus, our analysis supports and expands previous CRP findings in resource-rich settings now to diverse resource-limited settings while also adding evidence linking CD4 T-cell activation to cART outcomes.
CRP assays are relatively inexpensive and could be used in resource-limited and resource-rich settings. Our finding that elevated baseline CRP concentration greater than 10 mg/L is independently associated with poor clinical response to cART may provide clinicians in multiple settings with a more generalizable approach to risk-stratify patients before cART initiation. Furthermore, despite its lack of specificity, CRP (an acute phase reactant produced by the liver in response to general inflammatory stimuli) has remarkable predictive value in varied conditions from cardiovascular disease to osteomyelitis. For example, among healthy persons, a CRP concentration greater than 3 mg/L is an independent risk factor for cardiovascular risk. In our study, cases had a median baseline CRP of 6 mg/L compared with that of 3 mg/L in controls, supporting its potential clinical utility to distinguish HIV-infected persons who may progress after cART initiation. However, larger cohort studies will be needed to determine appropriate breakpoints before using CRP concentration as a clinical marker among cART initiators.
Interestingly, we did not confirm a significant association between the remaining immune activation biomarkers and early HIV progression on cART. While CD8 T-cell activation has been associated with HIV disease progression, it has not been consistently associated with cART treatment outcomes. Similarly, elevated baseline IL-6 levels, which have long been associated with HIV progression, has been an inconsistent predictor of outcomes among cART initiators. IP-10, a chemokine that is strongly predictive of hepatitis C virus treatment outcomes, has been associated with HIV outcomes in some studies. We did find a trend for an association between sCD14 and clinical progression that confirms previous studies. Finally, the MT markers LPS and EndoCAb IgM have been associated with mortality and disease progression among cART initiators in some, but not all, studies. Therefore, there may be a distinction between markers that predict disease progression in untreated patients, and markers that are predictive among HIV-infected patients receiving cART.
This study did not provide evidence for MT in this cohort as defined by detectable LPS levels despite using an optimized assay that accounts for serum interference. It is possible that prevalent diarrheal disease in some endemic settings may alter the associations of MT and HIV. However, sCD14 and CD8 T-cell activation had a trend toward association with incident WHO stage 3 or 4 disease or death on cART, which is consistent with and extends previous findings to multiple geographic settings. Overall, we speculate that a combination of factors, including socioeconomics, malnutrition, and prevalent acute infections (eg, malaria, diarrheal disease), may have contributed to the generalized immune activation state of patients but that these factors may not have been directly involved in the causal pathways that led to HIV disease progression.
Strengths of this study include the diversity of settings and the comprehensive panel of immune activation biomarkers assessed. However, this study has some potential limitations. Our study was limited to participants with CD4 T-cell counts <300 cells per cubic millimeter; given current guidelines, future investigations will need to determine whether our findings are applicable to HIV-infected persons initiating cART at higher CD4 T-cell counts. There were a large number of prevalent and incident cases of TB, a leading cause of morbidity and mortality among HIV-infected persons in resource-limited settings. Therefore, it is possible that baseline subclinical TB may have resulted in augmented immune activation, thus confounding the analysis. Notably, however, non-TB diagnoses comprised more than 70% of the incident diagnoses among cases; therefore, our findings are likely to be generalizable to HIV-infected populations, irrespective of TB risk. Moreover, our analysis accounted for the effect of prevalent TB at baseline, which did not substantially affect the overall strength of the predictive models. Notably, the entry criteria for the PEARLS study included a relatively healthy population. For example, fewer than 20% of cases and controls in the subcohort were underweight. Whereas on the one hand, the relative health of the study population suggests that these findings will need confirmation, on the other hand, we propose that an immune activation biomarker is particularly useful in identifying people where the risk of clinical progression is not obvious. Another challenge was the limited availability of viable PBMC samples for T-cell activation marker testing, especially from India and Thailand. Participants with available PBMC samples were similar to those without samples among baseline characteristics, except for lower median baseline HIV RNA level, which would be expected to underestimate the association between baseline CD4 T-cell activation and HIV disease progression. Nevertheless, our findings will need to be confirmed in Asian populations to broaden the generalizability of CD4 T-cell activation.
In summary, our analysis identified 2 biomarkers of immune activation that seem to independently predict early clinical HIV disease progression in multiple countries among HIV-infected adults initiating cART. While measurement of baseline CD4/DR+/CD38 T-cell activation may provide predictive information about the clinical response to cART, the utility of this biomarker may be limited due to its high cost and complexity in measuring it. CRP assays are low-cost, relatively easy to perform, and may be available in some resource-limited settings. Pre-cART risk stratification using CRP measurements may prove worthwhile to identify patients for whom added vigilance, such as more frequent clinical monitoring or disease-specific screening after treatment initiation, may be warranted, similar to the cardiovascular disease paradigm.
Discussion
To our knowledge, this is the first study to assess and identify baseline biomarkers associated with early clinical HIV progression after cART initiation across multiple resource and clinical settings. After measuring a comprehensive panel of immune activation biomarkers, our analysis indicates that the highest quartiles of baseline pre-cART CRP concentration and CD4 T-cell activation predict subsequent progression to WHO stage 3 or 4 disease or death within 96 weeks on cART after adjusting for baseline age, sex, BMI, and CD4 T-cell count. Notably, the associations were independent of country-to-country differences in baseline biomarker levels and cART regimen. Conversely, while a trend toward significant association was observed for sCD14 and CD8 T-cell activation, we could not confirm an association between early HIV progression on cART and biomarkers that have been previously described in relation to HIV disease progression, namely in LPS, EndoCAb IgM, IL-6, TNF-α, and IP-10. In resource-limited settings where follow-up intervals can be prolonged, our findings may help clinicians identify high-risk cART-naive patients who require additional vigilance for OIs and AIDS progression even after cART initiation.
The response to HIV treatment can vary considerably and AIDS-related events can still develop in the early months after cART initiation. Indeed, AIDS-related events are still the leading cause of early mortality among persons living with HIV on cART in low- and middle-income settings, even among those with virologic suppression. Consequently, current treatment guidelines offer no provision for patients who start cART but who will ultimately clinically progress. A baseline prognostic marker would be of particular importance in such settings, where tests for HIV RNA level and CD4 T-cell counts tests may be prohibitively expensive.
Immune activation has been previously described in HIV-infected persons, but has been defined using differing biomarker panels, and most previous studies have been conducted at a single site or in resource-rich countries. In resource-limited settings, high CRP levels among untreated HIV-infected women who were pregnant has been previously associated with progression to WHO stage 4 disease or death in the mothers and in their children. In addition, elevated CRP levels were associated with clinical progression in an HIV-infected cART-naive population of Ugandans. More recently, the SMART and INSIGHT studies have associated elevated pre-cART CRP levels with death, opportunistic infection, and AIDS progression among patients in resource-rich countries. To our knowledge, however, these are the first data to show that pre-cART CRP levels are associated with clinical progression in HIV-infected persons initiating cART in settings with mixed resource levels. In contrast, evidence regarding CD4 T-cell activation has been less consistent. Apart from the present analysis, only 1 other study has associated baseline CD4 T-cell activation with outcomes among patients initiating cART, whereas several studies have found no such association. Thus, our analysis supports and expands previous CRP findings in resource-rich settings now to diverse resource-limited settings while also adding evidence linking CD4 T-cell activation to cART outcomes.
CRP assays are relatively inexpensive and could be used in resource-limited and resource-rich settings. Our finding that elevated baseline CRP concentration greater than 10 mg/L is independently associated with poor clinical response to cART may provide clinicians in multiple settings with a more generalizable approach to risk-stratify patients before cART initiation. Furthermore, despite its lack of specificity, CRP (an acute phase reactant produced by the liver in response to general inflammatory stimuli) has remarkable predictive value in varied conditions from cardiovascular disease to osteomyelitis. For example, among healthy persons, a CRP concentration greater than 3 mg/L is an independent risk factor for cardiovascular risk. In our study, cases had a median baseline CRP of 6 mg/L compared with that of 3 mg/L in controls, supporting its potential clinical utility to distinguish HIV-infected persons who may progress after cART initiation. However, larger cohort studies will be needed to determine appropriate breakpoints before using CRP concentration as a clinical marker among cART initiators.
Interestingly, we did not confirm a significant association between the remaining immune activation biomarkers and early HIV progression on cART. While CD8 T-cell activation has been associated with HIV disease progression, it has not been consistently associated with cART treatment outcomes. Similarly, elevated baseline IL-6 levels, which have long been associated with HIV progression, has been an inconsistent predictor of outcomes among cART initiators. IP-10, a chemokine that is strongly predictive of hepatitis C virus treatment outcomes, has been associated with HIV outcomes in some studies. We did find a trend for an association between sCD14 and clinical progression that confirms previous studies. Finally, the MT markers LPS and EndoCAb IgM have been associated with mortality and disease progression among cART initiators in some, but not all, studies. Therefore, there may be a distinction between markers that predict disease progression in untreated patients, and markers that are predictive among HIV-infected patients receiving cART.
This study did not provide evidence for MT in this cohort as defined by detectable LPS levels despite using an optimized assay that accounts for serum interference. It is possible that prevalent diarrheal disease in some endemic settings may alter the associations of MT and HIV. However, sCD14 and CD8 T-cell activation had a trend toward association with incident WHO stage 3 or 4 disease or death on cART, which is consistent with and extends previous findings to multiple geographic settings. Overall, we speculate that a combination of factors, including socioeconomics, malnutrition, and prevalent acute infections (eg, malaria, diarrheal disease), may have contributed to the generalized immune activation state of patients but that these factors may not have been directly involved in the causal pathways that led to HIV disease progression.
Strengths of this study include the diversity of settings and the comprehensive panel of immune activation biomarkers assessed. However, this study has some potential limitations. Our study was limited to participants with CD4 T-cell counts <300 cells per cubic millimeter; given current guidelines, future investigations will need to determine whether our findings are applicable to HIV-infected persons initiating cART at higher CD4 T-cell counts. There were a large number of prevalent and incident cases of TB, a leading cause of morbidity and mortality among HIV-infected persons in resource-limited settings. Therefore, it is possible that baseline subclinical TB may have resulted in augmented immune activation, thus confounding the analysis. Notably, however, non-TB diagnoses comprised more than 70% of the incident diagnoses among cases; therefore, our findings are likely to be generalizable to HIV-infected populations, irrespective of TB risk. Moreover, our analysis accounted for the effect of prevalent TB at baseline, which did not substantially affect the overall strength of the predictive models. Notably, the entry criteria for the PEARLS study included a relatively healthy population. For example, fewer than 20% of cases and controls in the subcohort were underweight. Whereas on the one hand, the relative health of the study population suggests that these findings will need confirmation, on the other hand, we propose that an immune activation biomarker is particularly useful in identifying people where the risk of clinical progression is not obvious. Another challenge was the limited availability of viable PBMC samples for T-cell activation marker testing, especially from India and Thailand. Participants with available PBMC samples were similar to those without samples among baseline characteristics, except for lower median baseline HIV RNA level, which would be expected to underestimate the association between baseline CD4 T-cell activation and HIV disease progression. Nevertheless, our findings will need to be confirmed in Asian populations to broaden the generalizability of CD4 T-cell activation.
In summary, our analysis identified 2 biomarkers of immune activation that seem to independently predict early clinical HIV disease progression in multiple countries among HIV-infected adults initiating cART. While measurement of baseline CD4/DR+/CD38 T-cell activation may provide predictive information about the clinical response to cART, the utility of this biomarker may be limited due to its high cost and complexity in measuring it. CRP assays are low-cost, relatively easy to perform, and may be available in some resource-limited settings. Pre-cART risk stratification using CRP measurements may prove worthwhile to identify patients for whom added vigilance, such as more frequent clinical monitoring or disease-specific screening after treatment initiation, may be warranted, similar to the cardiovascular disease paradigm.
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