The effects of radiation on blood cells have been known for a long time,1 and the decrease in T cells and T-cell subsets after radiotherapy (RT) has been well documented.1–3 In HIV-negative breast cancer patients, RT reduced CD4 cell counts for a prolonged period of time, with declines of approximately 200 × 106 cells per liter for up to 5–6 years after RT.4 Only sporadic literature is available for HIV-1 patients. One study in 29 HIV-1-positive patients described a decline of CD4+ T cells during RT, from a mean of 388 × 106 to 158 × 106 cells per liter.5 In another study, chemoradiotherapy for anal or colorectal cancer in 11 HIV patients was associated with a decline of the median CD4+ T-cell count from 357 × 106 to 199 × 106 cells per liter, but it is very well possible that in these patients chemotherapy potentiated the effects of RT.6 These studies did not report the long-term effects on the CD4 cell counts.
As HIV patients grow older, diseases associated with older age, such as non-AIDS defining malignancies, will become increasingly important, especially because it is clear that the incidence of malignancies in HIV-infected individuals is increased compared with HIV-negative persons.7 Therefore, it is relevant to know to what extent RT adversely affects HIV disease and CD4 cell counts. We therefore identified those patients in our Dutch HIV registry that had RT for a solid tumor and evaluated its short- and long-term effects on CD4 cell counts.
HIV-1-positive patients living in the Netherlands with a subsequent diagnosis of a solid tumor were selected from the ATHENA national observational HIV cohort.8 This database includes anonymized data from all HIV-1 infected patients who receive medical care in one of the 25 Dutch HIV treatment centers. Epidemiological, clinical, virological, and immunological data are collected retrospectively at entry in the cohort and prospectively thereafter. As information on specifics of radiotherapy or chemotherapy is not part of standard data collection, medical records of patients in care in the 8 largest treatment centers were searched for additional data about the tumor and the treatment. Patients with a HIV-related Kaposi sarcoma were excluded, because they usually receive only a short course of low-dose RT.
The patients were grouped according to whether they had received RT or not. Primary endpoint of the study was time from baseline CD4 count to reaching CD4 cell counts higher than those at baseline. As baseline CD4 cell count we took the mean CD4 cell count between 0 and 6 months before diagnosis of the tumor. If RT was started more than 6 months after the diagnosis of the tumor, we used the mean CD4 cell count between 0 and 6 months before the start of RT as baseline. The patients receiving RT could only reach the endpoint after the stop date of the RT. Patients not receiving RT could reach the endpoint any time after diagnosis of the malignancy. To enable comparison of different dose-fractionation schedules for late normal tissue response, we calculated the biological effective dose (BED) for each patient, assuming a linear-quadratic model with an α/β-ratio of 3 Gy for late effects (BED_3).9,10
The patients were further stratified according to whether chemotherapy was used and whether patients received combination antiretroviral therapy (cART) at the time of tumor diagnosis. CD4 cell counts in patients with a change in their cART status (either a stop or a start) were censored at the date of the cART change. Follow-up time was censored at the date of the last available CD4 cell count in case the endpoint was not reached. Deceased patients who had not reached the endpoint were censored at the maximum follow-up time among all patients.11 Kaplan–Meier estimates of the percentage of patients reaching the endpoint were calculated. Cox regression analyses were performed to estimate the association of RT and time to the endpoint, adjusted for the following potential confounders: gender, age at baseline, CD4 cell count at baseline, cART, and use of chemotherapy, and to estimate the association between BED_3 and time to return to baseline CD4 cell counts.
Analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC).
A total of 389 patients with a solid tumor were identified in the ATHENA database, and we retrieved from the 8 largest HIV centers the medical records of 223 patients with a histologically proven malignant solid tumor. In total, 133 patients were excluded for the following reasons: unclear whether RT had been given (n = 46), missing data on start and stop date of RT (n = 31), missing baseline CD4 cell count (n = 41), change of cART status after baseline (n = 5), and no CD4 cell counts available after baseline and not known to be deceased (n = 10).
Details of the remaining 36 patients who had received RT and the 54 patients who had not are given in Table 1. Median calendar year of malignancy diagnosis was 2005 (min–max 1993–2008). The median time between diagnosis and start RT was 65 [interquartile range (IQR) 43–127] days and between diagnosis and stop RT 130 (IQR 80–186) days. The median duration of RT was 46 (IQR 30–63) days. The median BED (BED_3) for the 22 patients for whom data were available was 418 (IQR: 322–490) Gy.
In the 36 patients receiving RT, the median baseline CD4 cell count was 400 (IQR 300–529) × 106 cells per liter, and the median first CD4 cell count after stop of RT was 234 (IQR 153–355) × 106 cells per liter. The median decline of the CD4 cell count was 150 (IQR 30–270) × 106 cells per liter and 15 out of the 36 patients (42%) had at least 1 measurement <200 × 106 cells per liter during RT. Median decline of the CD4 cell count was 215 (IQR 75–282) × 106 cells per liter among patients (N = 20) also receiving chemotherapy.
Of the patients receiving RT, 9 patients died before reaching the endpoint. In 13 of the 36 patients receiving RT, CD4 cell counts returned to baseline levels, with a median time of 469 (IQR 345–595) days. In the other 23 patients, the CD4 cell count did not recover to baseline values, after a median follow-up time of 1457 (IQR 482–2000) days.
In the 54 patients not receiving RT, 7 patients died before reaching the endpoint, and 35 returned to baseline CD4 cell counts. The median time from baseline to CD4 cell counts equally or higher than at baseline was 112 (IQR 42–182) days.
In patients treated with chemotherapy, only the time to return to baseline CD4 cell count was not longer than in patients without chemotherapy: hazard ratio (HR) 0.87 (0.42–1.83; P = 0.72).
The Kaplan–Meier estimate of the percentage of patients with CD4 cell counts higher than those at baseline at 3 years after baseline was 39% in patients who had received RT and 71% in patients without RT (Fig. 1; P < 0.0001). In the subgroup of 64 patients on cART, the recovery of CD4 cell counts in patients receiving RT was 40% at 3 years after baseline compared with 79% in those without RT (P < 0.0001).
In an adjusted Cox regression analysis of time to return to baseline CD4 cell counts the HR of the RT group compared with those without RT was 0.29 [95% confidence interval (CI) 0.13 to 0.63]. The cART status was associated with a shorter time to return to baseline CD4 cell counts, HR 2.46 (95% CI 1.11 to 5.48), comparing cART treated patients with untreated patients. There was a borderline association between younger age and a shorter time to baseline CD4 cell counts, HR per 10 year increase in age 0.70, 95% CI 0.47 to 1.03, P = 0.07.
For 22 of the 36 patients who had received RT the BED_3 could be calculated. In a Cox regression analysis restricted to these 22 patients, we did not find evidence for an association between BED_3 and time to return to baseline CD4 cell counts [HR 0.72 (95% CI 0.26 to 1.97; P = 0.53) for each increase of 100 units in BED_3 score].
RT resulted in a significant and prolonged decline of CD4+ T cells in HIV-1 infected patients, whereas chemotherapy did not significantly influence CD4 cell count recovery.
It has been demonstrated that a solid malignant tumor itself has minimal effects on the CD4+ T-cell count in HIV-1 negative patients,12 but in HIV-1 patients, a significant decrease of CD4 cell counts in the 6 months before diagnosis of a malignancy could be seen (patients overall 29 × 106 cells per liter; patients with viral suppression 36 × 106 cells per liter).13 It is well known that in HIV-negative patients RT-induced lymphopenia can last for many years after RT.4,14,15 CD4+ T-cell cycle arrest and reproductive cell death might be responsible for this effect.16 In the Cox analysis, patients on cART had a faster recovery of CD4 counts than those without cART, probably because in the latter patients a gradual decline of CD4 counts over time is to be expected.
This study is the first that looked at the long-term effects of RT in HIV-1 positive patients. Our study was too small to study a dose effect of RT or the effect of localization of tumor and RT. However, the primary tumor site and fractionation schedules of patients in the RT group suggest that most patients had localized curative RT, which usually do not encompass large bone marrow reserves that could have explained the delayed recovery of CD4 counts. Another limitation, inherent to the observational nature of the study, is that sampling moments of the CD4 cell counts were not standardized, which affects the precision of the estimate of the CD4 recovery time.
As HIV-1 patients become older, malignant tumors can be expected to occur more frequently in the future. Especially in patients with low CD4 counts, the additional and prolonged CD4 lowering effect of RT has to be considered, and appropriate prophylaxis should be given when necessary.
Academic Medical Center, Amsterdam: J.M. Prins, T.W. Kuijpers, H.J. Scherpbier, K. Boer, J.T.M. van der Meer, F.W.M.N. Wit, M.H. Godfried, P. Reiss, T. van der Poll, F.J.B. Nellen, J.M.A. Lange, S.E. Geerlings, M. van Vugt, D. Pajkrt, J.C. Bos, M. van der Valk, M.L. Grijsen, W.J. Wiersinga, Erasmus Medical Center, Rotterdam: M.E. van der Ende, T.E.M.S. de Vries-Sluijs, C.A.M. Schurink, M. van der Feltz, J.L. Nouwen, M.H. van Nispen tot Pannerden, A. Verbon, B.J.A. Rijnders, T.W. Schurink, E.C.M. van Gorp, dr. P. Hassing, B. Smeulders, N.G. Hartwig, G.J.A. Driessen, Haga Ziekenhuis, Den Haag: E.F. Schippers, C. van Nieuwkoop, Leids Universitair Medisch Centrum, Leiden: F.P. Kroon, J.T. van Dissel, S.M. Arend, M.G.J. de Boer, H. Jolink, A.M. Vollaard, Medisch Centrum Haaglanden, Den Haag: E.M.S. Leyten, L.B.S. Gelinck, Onze Lieve Vrouwe Gasthuis, Amsterdam: K. Brinkman, W.L. Blok, P.H.J. Frissen, W.E.M. Schouten, G.E.L. van den Berk, Slotervaart Ziekenhuis, Amsterdam: J.W. Mulder, P.M. Smit, S.M.E. Vrouenraets, Universitair Medisch Centrum, Utrecht: A.I.M. Hoepelman, T. Mudrikova, M.M.E. Schneider, C.A.J.J. Jaspers, P.M. Ellerbroek, J.J. Oosterheert, J.E. Arends, M.W.M. Wassenberg, R.E. Barth, S.P.M. Geelen, T.F.W. Wolfs.
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