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Int J STD AIDS OnlineFirst, published on May 20, 2014 as doi:10.1177/0956462414536146
Original research article
Assessment of the efficacy and safety of pre-emptive anti-cytomegalovirus (CMV) therapy in HIV-infected patients with CMV viraemia
International Journal of STD & AIDS 0(0) 1–7 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0956462414536146 std.sagepub.com
Sarah Mattioni1, Juliette Pavie1, Raphae¨l Porcher2, Catherine Scieux3, Blandine Denis1, Nathalie De Castro1, Franc¸ois Simon3 and Jean-Michel Molina1
Abstract A number of studies have demonstrated that cytomegalovirus (CMV) viraemia is a strong predictor for CMV end-organ disease (EOD) and death in HIV-infected patients. We assess the efficacy and safety of pre-emptive anti-CMV therapy (PACT) for preventing these events. We performed a retrospective study of all HIV-infected patients seen in our institution who had detectable CMV viraemia in 2007. Seventy-one patients with advanced HIV disease (median CD4 cell count ¼ 61/mm3) were studied. Sixteen patients received PACT (mainly valganciclovir). Patients who received PACT had lower CD4 cell counts and higher blood CMV DNA levels. The cumulative incidence of CMV EOD and death at one year was 44% and 21% in patients with and without PACT, respectively (p ¼ 0.013). Both PACT and high blood CMV DNA levels were significantly associated with CMV EOD and death in unadjusted analysis. In adjusted analyses, only blood CMV DNA levels remained significantly associated with the risk of CMV EOD and death, whereas PACT was associated with a non-significant trend towards reduced CMV EOD or death (hazard ratio: 0.25, p ¼ 0.13). Five patients with PACT experienced severe drug related adverse events. In conclusion, the use of PACT in HIV-infected patients with CMV viraemia could improve outcome but is associated with significant toxicity.
Keywords Cytomegalovirus, HIV, AIDS, pre-emptive treatment, valganciclovir Date received: 2 February 2014; accepted: 13 April 2014
Introduction The use of antiretroviral therapy has dramatically reduced the incidence of opportunistic infections in patients with HIV-infection, including the incidence of cytomegalovirus (CMV) disease.1 However, a significant number of patients still remain at risk of CMV disease because they either fail or discontinue antiretroviral therapy or present late to care with advanced HIV disease and remain immunosuppressed despite the introduction of antiretroviral therapy.2 This burden of CMV disease remains particularly high in low and middle income settings, where the incidence of CMV retinitis for example has not changed in the past decade, despite the increased availability of antiretroviral therapy.3 A number of studies have demonstrated that the detection of CMV in blood or plasma is a strong
predictor for CMV end-organ disease (EOD) and death in HIV-infected individuals, even in the era of antiretroviral therapy both in high and low income settings.4–10 The risk of developing CMV EOD or death also increases with higher levels of CMV 1
Department of Infectious Diseases, Saint-Louis Hospital, Paris, France Department of Biostatistics, Saint-Louis Hospital, Assistance Publique, Hoˆpitaux de Paris (AP-HP), and University of Paris 7, Sorbonne Paris Cite´, Paris, France 3 Laboratory of Virology, Saint-Louis Hospital, Assistance Publique, Hoˆpitaux de Paris (AP-HP), and University of Paris 7, Sorbonne Paris Cite´, France 2
Corresponding author: Sarah Mattioni, Service de me´decine interne, Hoˆpital Tenon, 4, rue de la Chine 75970, Paris Cedex 20, France. Email: [email protected]
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International Journal of STD & AIDS 0(0)
viraemia.5,11–13 In patients with solid organ or bonemarrow transplants, universal CMV prophylaxis and/ or pre-emptive anti-CMV therapy (PACT) are recommended to prevent the occurrence of CMV EOD. In patients with HIV-infection however there are no such recommendations, since most trials assessing CMV prophylaxis were performed at the beginning of the use of combined antiretroviral therapy and yielded conflicting results.14–18 Two recently conducted studies assessing the efficacy of PACT also yielded different conclusions.19,20 We therefore wished to review in our centre the efficacy and safety of PACT when used in HIV-infected patients with CMV viraemia.
Methods Study design In this retrospective study, we identified using the electronic database of the laboratory of virology, all HIVinfected patients in our institution with a positive CMV viraemia between 1 January 2007 and 31 December 2007. We then reviewed the clinical charts of these patients, excluding those being treated for CMV EOD. We recorded for each patient the following data: age, gender, country of origin, risk factors for HIV infection, CDC clinical stage, previous occurrence of opportunistic infections, co-infections with HCV or HBV and nadir CD4 T-cell count. Baseline laboratory evaluations included CD4 cell count, plasma HIV RNA levels and results of blood polymerase chain reaction (PCR) assays for CMV. Baseline was defined as either the time of the first positive CMV viraemia for patients without PACT or the time of the last positive PCR assay before PACT for those receiving PACT. Antiretroviral therapy and immunosuppressive regimens (steroids, chemotherapy) at baseline were also recorded. PACT was defined as an antiviral treatment including at least one anti-CMV agent (ganciclovir, valganciclovir, foscarnet or cidofovir) given orally or intravenously in a patient with CMV viraemia without evidence of CMV EOD. Due to the retrospective design of the study the duration of PACT was not pre-defined but left to the physician discretion. CMV EOD was diagnosed using the ACTG criteria for clinical events.19 Briefly, CMV retinitis was defined by typical retinal lesions including white areas with or without haemorrhages and diagnosed by an experienced ophthalmologist using indirect ophtalmoscopy. CMV gastrointestinal disease was defined by the combination of suggestive clinical symptoms (abdominal pain, diarrhoea), visualization of endoscopic lesions (mucosal erythema, erosion or ulceration) and biopsies
showing histological evidence of CMV infection by characteristic intranuclear inclusions and/or antigen detection. Patients were followed until the occurrence of CMV EOD, death or 31 st December 2008. Due to the small size of the study and the role of CMV viraemia on both EOD and death, we decided to assess the efficacy of PACT on the combined outcome of CMV EOD or death, whichever occurred first. In order to assess the safety of PACT, we also recorded grade 3 and 4 drug-related averse events using the National Institute of Health Division of AIDS tables for grading adult adverse experiences (neutropenia grade 3: < 750/mm3, grade 4 < 500/mm3; anaemia grade 3 < 7.4 g/dl, grade 4 < 6.5 g/dl, hypokalaemia grade 3 < 2.5 mmol/l, grade 4 < 2 mmol/l; hypophosphoraemia grade 3 < 1.9 mg/dl, grade 4 < 1 mg/dl), and events leading to PACT discontinuation or blood transfusion, or granulocyte colony-stimulating factor or erythropoietin administration.
CMV viraemia Real-time quantitative PCR for CMV DNA in whole blood was performed as previously described. This assay was run daily in our institution, both for patients with HIV-infection and for solid and bone-marrow transplants. The primers and probe are located in the UL 123 exon 4 gene.21,22 The sensitivity of this assay is of 100 genomes per ml.
Statistical analysis Data are presented as count (percent) or median (interquartile range [IQR]) or median (range). Imbalance between baseline characteristics of patients with and without PACT was expressed in terms of standardized difference, which is 100 (ma mb)/ˇ{(sa2 þ sb2)/2}, where for each covariate ma and mb are the sample means in the PACT and no PACT groups, respectively, and sa2 and sb2 are the corresponding sample variances. The primary study endpoint, the cumulative incidence of CMV EOD or death was estimated by Kaplan-Meier product-limit estimator, among patients with or without PACT. The cumulative of incidence of CMV EOD and death separately were additionally estimated using usual methodology in a competing risks framework. The association of PACT and baseline characteristics with the hazard of CMV EOD or death was analysed using Cox proportional hazards model. Both unadjusted analyses and analyses adjusted for CMV viral load and CD4 T-cell counts were performed. Results are reported in terms of hazard ratio (HR) and 95% confidence interval (95%CI). Using the adjusted Cox model, predicted probabilities of CMV
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EOD or death were derived with Ederer estimate for the whole cohort of patients, had none of these patients received PACT or had all of them received PACT. All tests were two-sided, and the significance threshold was set at 0.05. Analyses were performed using R.2.6.2 statistical software (The R Foundation for Statistical Computing, Vienna, Austria).
Results Study population Among 2617 HIV-infected patients followed at our institution in 2007, 71 (2.7%) had at least one positive blood CMV DNA assay during the study period, excluding those being treated for CMV EOD, and were eligible for this study. Of these 71 patients, 16 (22.5%) received PACT. These patients received valganciclovir alone (n ¼ 12), ganciclovir (n ¼ 1), ganciclovir followed by valganciclovir (n ¼ 1), foscarnet (n ¼ 1) or a combination of ganciclovir, valganciclovir, foscarnet and cidofovir (n ¼ 1).
The median duration of PACT was 21 days (IQR 8.5–30.5). Baseline patients’ main characteristics are presented in Table 1. Most patients were men (80.3%) and had advanced HIV-infection with a median CD4 cell count of 61 cells/mm3, 72% having experienced a previous AIDS-defining event. Most patients originated from sub-Saharan Africa (44%), but also Europe (35%) and North Africa (8.5%). The main risk factors for HIV transmission were heterosexual contacts in 61%, and homosexuality in 35%. Four patients had a history of CMV retinitis (in 1996, 2001 [for 2 patients] and 2004). Median CMV DNA level was 3.38 log10 copies/ml (IQR, 2.86–4.35 log10 copies/ml), and only 38 (54%) patients were receiving antiretroviral therapy. There was a clear imbalance between the two patient groups at baseline, with those receiving PACT being more advanced (lower CD4 cell count, higher proportion of previous AIDS defining events) and having higher blood CMV viral loads. Indeed, all patients who received PACT had a CMV viral load of at least 4 log10 copies/ml.
Table 1. Baseline characteristics of the 71 patients with blood CMV viraemia. PACT Standardized difference (%)a
Characteristics
Yes n ¼ 16
No n ¼ 55
Median age (IQR) yrs Male gender, n (%) Median nadir of CD4 cell count (IQR*) cells/mm3 HVC co-infection, n (%) HVB co-infection, n (%) History of CMV disease, n (%) Stage C of CDC, n (%) Antiretroviral therapy, n (%) Immunosuppressive treatment, n (%) Median CD4 count- cells/mm3 (IQR*) CD4 count
(STD)
[1–7] [PREPRINTER stage]
Int J STD AIDS OnlineFirst, published on May 20, 2014 as doi:10.1177/0956462414536146
Original research article
Assessment of the efficacy and safety of pre-emptive anti-cytomegalovirus (CMV) therapy in HIV-infected patients with CMV viraemia
International Journal of STD & AIDS 0(0) 1–7 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0956462414536146 std.sagepub.com
Sarah Mattioni1, Juliette Pavie1, Raphae¨l Porcher2, Catherine Scieux3, Blandine Denis1, Nathalie De Castro1, Franc¸ois Simon3 and Jean-Michel Molina1
Abstract A number of studies have demonstrated that cytomegalovirus (CMV) viraemia is a strong predictor for CMV end-organ disease (EOD) and death in HIV-infected patients. We assess the efficacy and safety of pre-emptive anti-CMV therapy (PACT) for preventing these events. We performed a retrospective study of all HIV-infected patients seen in our institution who had detectable CMV viraemia in 2007. Seventy-one patients with advanced HIV disease (median CD4 cell count ¼ 61/mm3) were studied. Sixteen patients received PACT (mainly valganciclovir). Patients who received PACT had lower CD4 cell counts and higher blood CMV DNA levels. The cumulative incidence of CMV EOD and death at one year was 44% and 21% in patients with and without PACT, respectively (p ¼ 0.013). Both PACT and high blood CMV DNA levels were significantly associated with CMV EOD and death in unadjusted analysis. In adjusted analyses, only blood CMV DNA levels remained significantly associated with the risk of CMV EOD and death, whereas PACT was associated with a non-significant trend towards reduced CMV EOD or death (hazard ratio: 0.25, p ¼ 0.13). Five patients with PACT experienced severe drug related adverse events. In conclusion, the use of PACT in HIV-infected patients with CMV viraemia could improve outcome but is associated with significant toxicity.
Keywords Cytomegalovirus, HIV, AIDS, pre-emptive treatment, valganciclovir Date received: 2 February 2014; accepted: 13 April 2014
Introduction The use of antiretroviral therapy has dramatically reduced the incidence of opportunistic infections in patients with HIV-infection, including the incidence of cytomegalovirus (CMV) disease.1 However, a significant number of patients still remain at risk of CMV disease because they either fail or discontinue antiretroviral therapy or present late to care with advanced HIV disease and remain immunosuppressed despite the introduction of antiretroviral therapy.2 This burden of CMV disease remains particularly high in low and middle income settings, where the incidence of CMV retinitis for example has not changed in the past decade, despite the increased availability of antiretroviral therapy.3 A number of studies have demonstrated that the detection of CMV in blood or plasma is a strong
predictor for CMV end-organ disease (EOD) and death in HIV-infected individuals, even in the era of antiretroviral therapy both in high and low income settings.4–10 The risk of developing CMV EOD or death also increases with higher levels of CMV 1
Department of Infectious Diseases, Saint-Louis Hospital, Paris, France Department of Biostatistics, Saint-Louis Hospital, Assistance Publique, Hoˆpitaux de Paris (AP-HP), and University of Paris 7, Sorbonne Paris Cite´, Paris, France 3 Laboratory of Virology, Saint-Louis Hospital, Assistance Publique, Hoˆpitaux de Paris (AP-HP), and University of Paris 7, Sorbonne Paris Cite´, France 2
Corresponding author: Sarah Mattioni, Service de me´decine interne, Hoˆpital Tenon, 4, rue de la Chine 75970, Paris Cedex 20, France. Email: [email protected]
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(STD)
[1–7] [PREPRINTER stage]
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International Journal of STD & AIDS 0(0)
viraemia.5,11–13 In patients with solid organ or bonemarrow transplants, universal CMV prophylaxis and/ or pre-emptive anti-CMV therapy (PACT) are recommended to prevent the occurrence of CMV EOD. In patients with HIV-infection however there are no such recommendations, since most trials assessing CMV prophylaxis were performed at the beginning of the use of combined antiretroviral therapy and yielded conflicting results.14–18 Two recently conducted studies assessing the efficacy of PACT also yielded different conclusions.19,20 We therefore wished to review in our centre the efficacy and safety of PACT when used in HIV-infected patients with CMV viraemia.
Methods Study design In this retrospective study, we identified using the electronic database of the laboratory of virology, all HIVinfected patients in our institution with a positive CMV viraemia between 1 January 2007 and 31 December 2007. We then reviewed the clinical charts of these patients, excluding those being treated for CMV EOD. We recorded for each patient the following data: age, gender, country of origin, risk factors for HIV infection, CDC clinical stage, previous occurrence of opportunistic infections, co-infections with HCV or HBV and nadir CD4 T-cell count. Baseline laboratory evaluations included CD4 cell count, plasma HIV RNA levels and results of blood polymerase chain reaction (PCR) assays for CMV. Baseline was defined as either the time of the first positive CMV viraemia for patients without PACT or the time of the last positive PCR assay before PACT for those receiving PACT. Antiretroviral therapy and immunosuppressive regimens (steroids, chemotherapy) at baseline were also recorded. PACT was defined as an antiviral treatment including at least one anti-CMV agent (ganciclovir, valganciclovir, foscarnet or cidofovir) given orally or intravenously in a patient with CMV viraemia without evidence of CMV EOD. Due to the retrospective design of the study the duration of PACT was not pre-defined but left to the physician discretion. CMV EOD was diagnosed using the ACTG criteria for clinical events.19 Briefly, CMV retinitis was defined by typical retinal lesions including white areas with or without haemorrhages and diagnosed by an experienced ophthalmologist using indirect ophtalmoscopy. CMV gastrointestinal disease was defined by the combination of suggestive clinical symptoms (abdominal pain, diarrhoea), visualization of endoscopic lesions (mucosal erythema, erosion or ulceration) and biopsies
showing histological evidence of CMV infection by characteristic intranuclear inclusions and/or antigen detection. Patients were followed until the occurrence of CMV EOD, death or 31 st December 2008. Due to the small size of the study and the role of CMV viraemia on both EOD and death, we decided to assess the efficacy of PACT on the combined outcome of CMV EOD or death, whichever occurred first. In order to assess the safety of PACT, we also recorded grade 3 and 4 drug-related averse events using the National Institute of Health Division of AIDS tables for grading adult adverse experiences (neutropenia grade 3: < 750/mm3, grade 4 < 500/mm3; anaemia grade 3 < 7.4 g/dl, grade 4 < 6.5 g/dl, hypokalaemia grade 3 < 2.5 mmol/l, grade 4 < 2 mmol/l; hypophosphoraemia grade 3 < 1.9 mg/dl, grade 4 < 1 mg/dl), and events leading to PACT discontinuation or blood transfusion, or granulocyte colony-stimulating factor or erythropoietin administration.
CMV viraemia Real-time quantitative PCR for CMV DNA in whole blood was performed as previously described. This assay was run daily in our institution, both for patients with HIV-infection and for solid and bone-marrow transplants. The primers and probe are located in the UL 123 exon 4 gene.21,22 The sensitivity of this assay is of 100 genomes per ml.
Statistical analysis Data are presented as count (percent) or median (interquartile range [IQR]) or median (range). Imbalance between baseline characteristics of patients with and without PACT was expressed in terms of standardized difference, which is 100 (ma mb)/ˇ{(sa2 þ sb2)/2}, where for each covariate ma and mb are the sample means in the PACT and no PACT groups, respectively, and sa2 and sb2 are the corresponding sample variances. The primary study endpoint, the cumulative incidence of CMV EOD or death was estimated by Kaplan-Meier product-limit estimator, among patients with or without PACT. The cumulative of incidence of CMV EOD and death separately were additionally estimated using usual methodology in a competing risks framework. The association of PACT and baseline characteristics with the hazard of CMV EOD or death was analysed using Cox proportional hazards model. Both unadjusted analyses and analyses adjusted for CMV viral load and CD4 T-cell counts were performed. Results are reported in terms of hazard ratio (HR) and 95% confidence interval (95%CI). Using the adjusted Cox model, predicted probabilities of CMV
Downloaded from std.sagepub.com at UT SOUTHWESTERN MEDICAL CTR on January 27, 2015
XML Template (2014) [12.5.2014–5:01pm] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/STDJ/Vol00000/140099/APPFile/SG-STDJ140099.3d
(STD)
[1–7] [PREPRINTER stage]
Mattioni et al.
3
EOD or death were derived with Ederer estimate for the whole cohort of patients, had none of these patients received PACT or had all of them received PACT. All tests were two-sided, and the significance threshold was set at 0.05. Analyses were performed using R.2.6.2 statistical software (The R Foundation for Statistical Computing, Vienna, Austria).
Results Study population Among 2617 HIV-infected patients followed at our institution in 2007, 71 (2.7%) had at least one positive blood CMV DNA assay during the study period, excluding those being treated for CMV EOD, and were eligible for this study. Of these 71 patients, 16 (22.5%) received PACT. These patients received valganciclovir alone (n ¼ 12), ganciclovir (n ¼ 1), ganciclovir followed by valganciclovir (n ¼ 1), foscarnet (n ¼ 1) or a combination of ganciclovir, valganciclovir, foscarnet and cidofovir (n ¼ 1).
The median duration of PACT was 21 days (IQR 8.5–30.5). Baseline patients’ main characteristics are presented in Table 1. Most patients were men (80.3%) and had advanced HIV-infection with a median CD4 cell count of 61 cells/mm3, 72% having experienced a previous AIDS-defining event. Most patients originated from sub-Saharan Africa (44%), but also Europe (35%) and North Africa (8.5%). The main risk factors for HIV transmission were heterosexual contacts in 61%, and homosexuality in 35%. Four patients had a history of CMV retinitis (in 1996, 2001 [for 2 patients] and 2004). Median CMV DNA level was 3.38 log10 copies/ml (IQR, 2.86–4.35 log10 copies/ml), and only 38 (54%) patients were receiving antiretroviral therapy. There was a clear imbalance between the two patient groups at baseline, with those receiving PACT being more advanced (lower CD4 cell count, higher proportion of previous AIDS defining events) and having higher blood CMV viral loads. Indeed, all patients who received PACT had a CMV viral load of at least 4 log10 copies/ml.
Table 1. Baseline characteristics of the 71 patients with blood CMV viraemia. PACT Standardized difference (%)a
Characteristics
Yes n ¼ 16
No n ¼ 55
Median age (IQR) yrs Male gender, n (%) Median nadir of CD4 cell count (IQR*) cells/mm3 HVC co-infection, n (%) HVB co-infection, n (%) History of CMV disease, n (%) Stage C of CDC, n (%) Antiretroviral therapy, n (%) Immunosuppressive treatment, n (%) Median CD4 count- cells/mm3 (IQR*) CD4 count
