Immune reconstitution inflammatory syndrome (IRIS) is a heterogeneous, clinically defined aggregation of opportunistic infections and other conditions that paradoxically worsen or first appear with initiation of combination antiretroviral therapy (cART) for HIV infection [1–3]. Paradoxical progression of Kaposi sarcoma following cART initiation occurs [4–8] and was reported as a common manifestation of IRIS among patients with an AIDS-defining clinical condition (ADC) in Seattle . Kaposi sarcoma, a malignancy of lymphatic endothelial cells that is often highly aggressive in people with HIV infection and severe immunodeficiency, is caused by dysregulated infection with the Kaposi sarcoma associated herpesvirus, also known as human herpesvirus 8 (KSHV/HHV8) [10,11].
First diagnosis of Kaposi sarcoma has been included in the IRIS spectrum [3,6,12]. In the HIV Outpatient Study, nine (2.4%) participants had a first diagnosis of Kaposi sarcoma within 7–180 days of starting cART, a lower cumulative incidence than observed for four other ADCs (range 2.7–17.3%) . Similar rates for Kaposi sarcoma and other ADCs following cART initiation were reported from South Africa .
Prior ADC and very low CD4 cell count are risk factors for IRIS, Kaposi sarcoma, and probably both [2,13]. However, linking immune reconstitution to an incident condition is difficult because CD4 cell count is dynamic and there is no diagnostic assay for IRIS . Falling CD4 cell count prior to cART initiation was the major predictor of incident cancer in the CASCADE collaboration . Nonetheless, adjusted for pre-cART change in CD4 cell count, a 2.3-fold elevated risk of incident cancer within 3 months of cART initiation was also seen, suggesting a genuine effect of IRIS . As CASCADE includes only people with a known date of infection who are in care, it is not representative of what happens for most patients, whose HIV infection is diagnosed at later stages.
IRIS generally occurs within weeks to months after cART initiation, although the time at highest risk is variable and unsettled. During the first 5 months on cART in the Swiss HIV Cohort Study, Kaposi sarcoma risk fell 76%, pointing to a rapid effect . Thus, as for other IRIS conditions , Kaposi sarcoma incidence might be postulated to reflect the steep decline in HIV viraemia during the first 2–4 weeks, or the increasing CD4 cell counts during the first 8 weeks, which are generally observed on cART [19,20].
The current study sought to clarify Kaposi sarcoma incidence during the initial months on cART, whether the risk was elevated compared with pre-cART, and whether the risk reflected contemporaneous changes in CD4 cell count. Pneumocystis jiroveci pneumonia (PJP), an uncommon manifestation of IRIS [9,13], was included as a comparison condition.
Materials and methods
The FHDH-ANRS CO4 cohort is described in detail elsewhere . Briefly, FHDH-ANRS CO4 is an open hospital cohort study conducted since 1992 by a clinical epidemiological network of 69 teaching hospitals belonging to 26 HIV Treatment and Information Centers (COREVIH) located in both mainland France and French overseas territories. The cohort includes patients who have documented HIV-1 or HIV-2 infection and who have given their written informed consent to participate. The FHDH-ANRS CO4 database, and its use, were approved by the French computer watchdog (CNIL) in accordance with French law. Data at each visit are recorded prospectively by trained research assistants. Visits are typically scheduled, and data are collected, at months 1 and 3 after starting cART, then every 3–4 months. Intervals up to 6 months between visits are accepted for patients whose viral load has been well controlled for several years. For the current analysis, the follow-up was through June 2009. The standardized FHDH-ANRS CO4 data collection form includes baseline characteristics, standard biological markers such as CD4 cell count and plasma HIV RNA level, clinical manifestations, treatments, clinical trials in which the patients are enrolled, deaths and causes of death, as reported in the medical records. From 1992 to December 2009, more than 117 000 HIV-infected individuals had attended at least one follow-up visit, with a mean follow-up of 81 months. The current analysis defined cART as three antiretroviral drugs (not counting ritonavir as a booster) else one or more boosted protease inhibitors with or without a nonnucleoside reverse transcriptase inhibitor (NNRTI). There were three exclusions: patients with a history of Kaposi sarcoma or PJP prior to their first visit in FHDH-ANRS CO4, those who had received single or dual antiretroviral medications prior to cART and those with only HIV-2 infection.
Numbers of patients evaluated each month were aggregated (person-time) and analysed in strata. We considered the following explanatory variables, some of which were fixed and some of which were time-varying. Use and duration of cART for each patient in each stratum was divided into five time-interval categories: ‘no cART and year <1996’, ‘no cART and year ≥1996’ (reference category), ‘≤3 months since starting cART’, ‘4–6 months since starting cART’ and ‘>6 months since starting cART’. A patient was presumed to stay on cART once it was started. Kaposi sarcoma (PJP) risk in each of the first months after cART initiation was also examined. CD4 cell counts (cells per microlitre) were categorized as follows: ‘0–49’, ‘50–99’, ‘100–199’, ‘200–349’, ‘350–499’ and ‘≥500’. For each patient, time was accumulated between each CD4 cell count measurement. As expected with follow-up every 3–4 months, median time between two CD4 cell count values was 3.2 months [interquartile range (IQR), 2.0–5.2 months]. Plasma HIV RNA (copies per millilitre) was classified as follows: ‘<500’, ‘500–4999’, ‘5000–49 999’ and ‘≥50 000’; and time between HIV RNA values was accumulated as for CD4 cell counts. History of an ADC (European definition for AIDS stage ) for each patient in each stratum was a binary variable. Sex and exposure group were combined as follows: ‘MSM’, ‘IDU’, ‘Other men’ and ‘Other women’. Patients also were classified by geographical origin: migration from sub-Saharan Africa ‘Yes’ or ‘No’. Age in each stratum was divided into three groups: 15–34, 35–49 and at least 50 years. Calendar years were grouped into three periods: ‘<1996’ (single and dual antiretroviral therapy available), ‘1996–1999’ (early cART period) and ‘≥2000’ (current cART period).
Age, calendar period, CD4 cell count, AIDS, HIV RNA and duration of cART treatment were included as time-dependent variables. The first cART regimen received by each patient was classified as follows: ‘no cART or calendar period before cART’, ‘regimen exclusively containing nucleoside reverse transcriptase inhibitors (NRTIs)’, ‘protease inhibitor containing regimen’ and ‘NNRTI-containing regimen without protease inhibitor’. Patients who developed Kaposi sarcoma or PJP during follow-up were censored at that visit. Thus, CD4 cell count and other values were the most recent before Kaposi sarcoma or PJP diagnosis.
Kaposi sarcoma (ICD-9: 173.x, ICD-10 B210, C46x) and PJP (ICD-9: 136.3, ICD-10: B59, B206) were coded with the International Classification of Disease version 9  until the end of 1996, and with version 10  thereafter.
Kaposi sarcoma and PJP incidence rates (number of Kaposi sarcoma or PJP cases, respectively, divided by person-time) were computed for each stratum of the different variables. The effect of the variables, including duration of cART exposure with ‘no cART and year ≥1996’ at the reference category, on difference in incidence (risk) of Kaposi sarcoma (PJP) was assessed using Poisson regression modelling to calculate relative risk (RR) and 95% confidence intervals (CIs). The crude effect of cART exposure on risk of Kaposi sarcoma (PJP) was assessed in a univariable Poisson regression model (Model 0). Potential confounding variables were taken into account in multivariable Poisson regression models adjusted for age, sex and exposure group, migration from sub-Saharan Africa and AIDS stage (Model 1). Model 1 was also used to estimate Kaposi sarcoma (PJP) risk during months 1, 2, 3 and 4–6 on cART. Model 2 was adjusted for the variables in Model 1 along with CD4 cell count. Model 3 was adjusted for the variables in Model 2 along with plasma HIV RNA since 1997 when this assay became available in France. Models 2 and 3 for PJP were also adjusted for PJP prophylaxis, that is, use of trimethoprim-sulfamethoxazole, dapsone or aerosolized pentamidine. Model 3 was used to assess differences among first cART regimens on the risk of Kaposi sarcoma (PJP).
Median and IQR within-patient changes in CD4 cell count (crude and per month), from cART initiation to the next CD4 cell count value within 3 months, were calculated for incident Kaposi sarcoma and PJP cases, as well as for participants without these incident conditions. Paired and unpaired Wilcoxon rank sum tests were used to compare changes and groups, respectively.
Two sensitivity analyses were performed. First, because CD4 cell count is a major predictor of both Kaposi sarcoma and PJP, models with categorical CD4 cell count were compared with the models with linear CD4 cell count, each fitted with the same adjustment variables (age, sex and exposure group, migration for sub-Saharan Africa, AIDS stage and cART duration) using the likelihood ratio test. This was repeated using cubic splines for the CD4 cell count values. Second, the primary analyses for Kaposi sarcoma were repeated with restriction to MSM, who comprised the largest exposure category and had the highest risk for Kaposi sarcoma.
Analyses were performed using Matlab 7, version 2009b (Mathworks, Inc., Natick, Massachusetts, USA).
The population included 66 369 HIV-infected patients and more than 310 000 person-years of follow-up, during which 1811 cases of Kaposi sarcoma (319 844 person-years) and 1718 cases of PJP (314 540 person-years) were diagnosed, with crude incidence rates of 5.66 and 5.46 per 1000 person-years, respectively. The cases of Kaposi sarcoma included 467 with visceral involvement, 1127 without visceral involvement and 217 unspecified sites. Table 1 presents the demographic and HIV characteristics of enrolled patients.
Crude incidence rates for Kaposi sarcoma and PJP by demographic and HIV categories are presented in Table 2. In both African immigrants and nonimmigrants, Kaposi sarcoma rates were markedly elevated in MSM, relatively low in IDU and higher in other men than in other women. PJP rates differed little by demographic and HIV categories, except in the small group of IDU immigrants (19.07 per 1000 person-years). Incidence rates of both Kaposi sarcoma and PJP were strongly related to lower current CD4 cell count and higher current HIV-RNA level. Less than 11% of the person-years were in the pre-cART era (1992–1995), but about half of the Kaposi sarcoma and of the PJP cases occurred during this time. The incidence of Kaposi sarcoma fell 6.6-fold from the pre-cART to the early cART era (1996–1999); it then fell 1.9-fold more from the early to the current cART era (2000–2009). The corresponding declines in PJP incidence were 4.7-fold and 1.6-fold.
Considering Kaposi sarcoma and PJP risk by time on cART, the referent groups were person-years of follow-up between 1996 and 2009 while not receiving cART, during which 335 Kaposi sarcoma cases and 462 PJP cases occurred. As shown in Fig. 1 and Table 3, Kaposi sarcoma risk was very high during the first 3 months on cART (N = 160, RRModel1 3.33), and this elevated risk was largely but incompletely attenuated by adjustment for current CD4 cell count (RRModel2 1.25) or current CD4 and HIV RNA (RRModel3 1.47). Kaposi sarcoma risk was significantly elevated during each of the first 6 months on cART (RRModel1 4.13 in month 1, RRModel1 3.83 in month 2, RRModel1 2.08 in month 3 and RRModel1 1.50 in months 4–6). Figure 1 presents Kaposi sarcoma and PJP incidence rates by time on cART, adjusted for current CD4 cell count and potential confounding variables. The increased risk during months 1–3 accounted for 1.6 Kaposi sarcoma cases per 1000 patient-years after starting cART.
In contrast to Kaposi sarcoma, PJP risk was minimally elevated during months 1–3 on cART (N = 84, RRModel1 1.59), and it was markedly reduced during this interval with adjustment for current CD4 cell count (RRModel2 0.52, Fig. 1 and Table 3). Without CD4 cell count adjustment, PJP risk was elevated in month 1 on cART (RRModel1 3.56), neutral in month 2 (RRModel1 0.98) and significantly reduced in all subsequent months. PJP prophylaxis, which was included in all of the adjusted models, significantly reduced PJP incidence, even with adjustment for current CD4 cell count (RRModel2 0.26, P < 0.001) or current CD4 cell count and HIV load (RRModel3 0.33, P < 0.001).
To compare the effects of different initial cART regimens, recipients of a protease inhibitor containing regimen were considered as the reference group. Compared with protease inhibitor recipients, Kaposi sarcoma risk did not differ for initial regimens that contained only NRTIs (RRModel3 1.12) or an NNRTI (RRModel3 1.15). Likewise, PJP risk did not differ with initial regimens that contained only NRTIs (RRModel3 1.02), or an NNRTI (RRModel3 0.94) compared with protease inhibitor.
Current HIV load and especially current CD4 cell count strongly affected PJP and Kaposi sarcoma risk in these models (Supplemental Table, http://links.lww.com/QAD/A285). To investigate further, Table 4 presents median CD4 cell counts, at cART initiation, as well as the change in CD4 cell count between cART initiation and the next test within 3 months. As expected, CD4 cell count at cART initiation was substantially and significantly lower in participants who subsequently developed Kaposi sarcoma (median 82, IQR 28–278 cells/μl) or PJP (median 61, IQR 8–185 cells/μl) than in those who developed neither of these ADC (P < 0.0001 for each). During a median of about 50 days (as per protocol), CD4 cell count increased by 68 cells/μl in participants who developed Kaposi sarcoma, versus 0 cells/μl in participants who developed PJP. The median rate of increase was 52.6 cells/μl per month in participants who did not develop Kaposi sarcoma (53% from baseline), versus 43.8 cells/μl per month in participants who developed Kaposi sarcoma (20% from baseline, P = 0.052). CD4 cell count increased 39.5 cells/μl per month in those who did not develop PJP, whereas it did not increase at all in participants who developed PJP [median 0, (IQR −8.2–28.6) cells/μl per month, P = 0.0009]. Rate of CD4 cell count change during the first months on cART was significantly higher in participants who developed Kaposi sarcoma than in participants who developed PJP (P = 0.0003).
In sensitivity analyses, modelling CD4 cell count in six categories (≤50 … >500 cells/μl) predicted Kaposi sarcoma and PJP significantly better than did linear CD4 cell count (P < 0.0001 for both Kaposi sarcoma and PJP), and cubic spline terms did not improve the fit of the CD4 cell count categories (P = 0.26 for Kaposi sarcoma, P = 0.34 for PJP). Poisson modelling was repeated with restriction to MSM, the subpopulation at highest risk for Kaposi sarcoma, and the RRs for Kaposi sarcoma by use and duration of cART were nearly identical to those presented in Table 3.
We sought to quantify the magnitude of incident Kaposi sarcoma and its association with cART-mediated CD4 cell count reconstitution. For comparison, we used incident PJP, which has been a common ADC in developed countries but a minor manifestation of IRIS in most reports [9,13]. Very low CD4 cell count strongly predicted Kaposi sarcoma and PJP, but we observed stark differences between these ADCs during the first months on cART. PJP was associated with failure to increase CD4 cell count, whereas Kaposi sarcoma was associated with CD4 cell count increases at approximately the same rate as in patients who developed neither PJP nor Kaposi sarcoma. By Poisson modelling, PJP crude risk was elevated only during the first month on cART, and PJP-adjusted risk was directly related to the success or failure of CD4 cell count reconstitution during the first 6 months on cART. In contrast, Kaposi sarcoma adjusted risk during months 1–3 on cART was incompletely related to concurrent CD4 or HIV-RNA level, and Kaposi sarcoma crude risk remained elevated for 3 months on cART. The elevated risk of Kaposi sarcoma was similar with all three types of cART regimen. These findings support the hypothesis that some incident Kaposi sarcoma cases occur during immune reconstitution. The absolute effect, however, was rather small, as months 1–3 on cART accounted for 1.6 additional Kaposi sarcoma cases per 1000 person-years, after adjustment for CD4 cell count and HIV-RNA level.
We excluded cohort members who had a prior diagnosis of PJP or Kaposi sarcoma, and thus, we did not address the effect of immune reconstitution on progressing Kaposi sarcoma or recurrent (paradoxical) PJP following cART initiation. In the deferred-ART initiation study (ACTG A5164), four patients with recurrent IRIS-associated PJP had robust increases in CD4 cell count during the initial weeks on cART , which contrasts with the zero median change in CD4 cell count in our incident PJP cases. IRIS-associated progressing Kaposi sarcoma cases have had increasing CD4 cell counts [6–8], and Bower et al. noted a higher CD4 cell count reconstitution in progressing Kaposi sarcoma patients than that observed in patients with stable or improving Kaposi sarcoma. Because of nonstandardized time scales, those observations cannot be directly compared with the median increase in CD4 cell count in our incident Kaposi sarcoma cases, 43.8 cells/μl per month during a median of 50 days on cART.
A robust, dysregulated, specific CD4+ T-cell response against one or more antigens of an opportunistic pathogen is likely to play a major role in IRIS [12,26]. However, the mechanisms underlying the clinical manifestations of IRIS are unsettled . Immunopathogenesis studies have been small and have included almost no cases of Kaposi sarcoma. In one worsening (paradoxical) and one incident (unmasking) Kaposi sarcoma case, no clear differences in CD4+ or CD8+ T-cell responses against KSHV/HHV8 peptide pools were found . Longer term studies might be revealing, as reconstitution of T-cell responses against KSHV/HHV8 peptides and clearance of KSHV/HHV8 viraemia generally requires more than 6 months on cART . However, this longer interval would be incompatible with clinical recognition of IRIS-Kaposi sarcoma cases and our finding that Kaposi sarcoma risk was only elevated during the first 3 months on cART.
Notable strengths of our study include its large size and uniformity. The FHDH is a large network of centres that follow a common protocol for monitoring and treating patients with HIV. Because the FHDH staff is vigilant for ADC and complications of cART, overascertainment of Kaposi sarcoma and PJP during the initial months on cART might be a weakness. This appears to have been minimal, as the cART-associated RRs that we found for Kaposi sarcoma and PJP show the strong predictive effect of current CD4 cell count, immediate potency of prophylaxis and cART against PJP, and delayed potency of cART against Kaposi sarcoma.
Another possible weakness is enrichment of our cART-unexposed referent group with patients at lowest risk for Kaposi sarcoma or PJP. Our CD4 cell count adjusted estimates of PJP risk suggest that this bias was well controlled, as PJP risk was two-fold lower with only 3 months on cART, and as it was nearly identical in our referent group and the pre-cART era population. It seems very unlikely that clinicians could defer cART on the basis of low risk for Kaposi sarcoma but not PJP. Rather, the lower Kaposi sarcoma risk in the cART era, even without cART, likely reflects the dramatically falling risk of Kaposi sarcoma that antedated single-agent zidovudine and that possibly reflects falling KSHV/HHV8 incidence in MSM that started in the mid-1980s [29–31].
In summary, our study clarifies the dynamic effects of cART initiation and CD4 cell count reconstitution on Kaposi sarcoma and PJP incidence. We showed that, even with CD4 cell count adjustment, Kaposi sarcoma risk increased significantly during the first 3 months on cART, following which Kaposi sarcoma risk fell significantly with more than 6 months on cART. This dynamic high-then-low change in risk would have been missed if Kaposi sarcoma incidence had been averaged over the first year on cART . Rapid, strong CD4 cell count reconstitution on cART was associated with an equally rapid fall in PJP risk, but with a much slower fall in Kaposi sarcoma risk. These findings suggest that clinicians should be vigilant for PJP in patients who have poor CD4 cell count reconstitution, and likewise should be vigilant for Kaposi sarcoma in patients who have robust CD4 cell count reconstitution.
The authors are grateful to all the participants and research assistants of the French Hospital Database on HIV. J.-M.L., D.C. and J.J.G. designed and conducted the study and drafted the manuscript. J.-M.L. and D.C. conducted the statistical analyses. F.B., S.Gr., N.V., S. Ga, A.-S. L.-C., J.P., M.P., O.L., S.M., E.Ros., E.Rou., P.T., and P.deT. supervised recruitment, retention, and ascertainment and collection of end points and other data, and provided critical clinical interpretations on the findings. All authors have reviewed the latest version of the manuscript and have approved its content.
The French Hospital Database on HIV is supported by Agence Nationale de Recherches sur le SIDA et les hépatites (ANRS), INSERM and the French Ministry of Health.
This work, specifically the French Hospital Database on HIV, was supported by ANRS, INSERM and the French Ministry of Health, and the Intramural Research Program of the National Cancer Institute, National Institutes of Health.
Conflicts of interest
There are no conflicts of interest.
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Keywords:Copyright © 2013 Wolters Kluwer Health, Inc.
combination antiretroviral therapy; immune reconstitution inflammatory syndrome; Kaposi sarcoma; Pneumocystis jiroveci pneumonia; prospective cohort study