Immune reconstitution inflammatory syndrome versus non-immune reconstitution inflammatory syndrome lymphoma in HIV patients on antiretroviral therapy.

Little is known about differences between immune reconstitution inflammatory syndrome (IRIS) and non-IRIS lymphoma in HIV patients on antiretroviral therapy (ART). The aim of this study was to describe the characteristics of IRIS and non-IRIS lymphoma in Korean HIV-positive patients on ART compared with lymphoma in those off ART. Of 1490 patients, 41 (3%) had lymphoma. Of these, 27 cases (66%) were classified as lymphoma off ART, eight as IRIS lymphoma, and six as non-IRIS lymphoma on ART. Hodgkin lymphoma was significantly more common among patients with non-IRIS lymphoma on ART than among those with lymphoma off ART (P = 0.005), whereas there was no Hodgkin lymphoma among IRIS lymphoma. Stage IV lymphoma was significantly rarer in non-IRIS lymphoma on ART than in lymphoma off ART (P = 0.007). Non-IRIS lymphoma on ART tends to have a better survival rate than lymphoma off ART (Kaplan-Meier survival analysis, P = 0.167), while IRIS lymphoma exhibited a survival rate similar to lymphoma off ART (P = 0.618). In Korean HIV-positive patients, there were significantly more cases of Hodgkin lymphoma of a less advanced stage in non-IRIS lymphoma on ART than in lymphoma off ART, in contrast to IRIS lymphoma.

Robust Reconstitution of Tuberculosis-Specific Polyfunctional CD4+ T-Cell Responses and Rising Systemic Interleukin 6 in Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome.

BACKGROUND: The immunopathogenesis of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) remains unclear. We determined the association between pathogen-specific T-cell responses and development of paradoxical TB-IRIS on antiretroviral therapy (ART). METHODS: This study was nested within a prospective cohort study of HIV-infected patients with active pulmonary tuberculosis and baseline CD4 counts ≤125 cells/µL initiating ART. T-cell immune activation (CD38, HLA-DR, and PD-1 expression), phenotype, and polyfunctional pathogen-specific cellular immune responses prior to and 4 weeks after ART initiation were determined by flow cytometry. Patients with TB-IRIS were compared to non-IRIS controls using χ(2) and rank-sum tests and logistic regression. RESULTS: TB-IRIS patients and controls had similar CD4 counts, levels of T-cell-associated immune activation, frequencies of T-cell memory subsets, and frequencies of interferon gamma (IFN-γ(+))/interleukin 2 (IL-2(+))/tumor necrosis factor alpha (TNF-α(+)) CD4(+) T-cells prior to ART initiation. After ART initiation, cellular immune activation and T-cell subsets also were similar in TB-IRIS patients and controls. In contrast, TB-IRIS patients had significantly greater early increases in the frequency of tuberculosis-specific polyfunctional IFN-γ(+)/IL-2(+)/TNF-α(+) CD4(+) T-cells on ART (P = .02); each quartile increase in the percentage of these cells was independently associated with a 2.8-fold increased risk of TB-IRIS (95% confidence interval, 1.1 to 7.5-fold). In a secondary analysis, patients with TB-IRIS had rapid, concomitant increases in tuberculosis-specific adaptive immune responses and interleukin 6 (IL-6) levels, whereas controls with similarly rapid increases in cellular immune function had IL-6 levels that tended to decrease on ART. CONCLUSIONS: Rapid expansion of tuberculosis-specific polyfunctional CD4(+) T-cell responses, likely linked to increases in IL-6, is associated with development of paradoxical TB-IRIS.

Steroids are a risk factor for Kaposi's sarcoma-immune reconstitution inflammatory syndrome and mortality in HIV infection.

OBJECTIVES: To investigate the association between Kaposi's sarcoma-associated immune reconstitution inflammatory syndrome (KS-IRIS) and mortality, with the use of glucocorticoids in HIV-infected individuals. DESIGN: Case-control study. METHODS: We reviewed the medical records of 145 individuals with HIV-associated Kaposi's sarcoma receiving antiretroviral therapy. The association of different variables with KS-IRIS and Kaposi's sarcoma-related mortality was explored by univariate and multivariate analyses. The main exposure of interest was the use of glucocorticoids. We also compared the time to KS-IRIS and the time to death of individuals treated with glucocorticoids vs. those nontreated with glucocorticoids, and the time to death of individuals with KS-IRIS vs. those without KS-IRIS by hazards regression. RESULTS: Sixty of 145 individuals received glucocorticoids (41.4%) for the management or suspicion of Pneumocystis jirovecii pneumonia. Fifty individuals had KS-IRIS (37%). The use of glucocorticoids was more frequent in individuals with KS-IRIS than in those without KS-IRIS (54.9 vs. 36.47%, P = 0.047). Kaposi's sarcoma-related mortality occurred in 17 cases (11.7%), and glucocorticoid use was more frequent in this group (76.47 vs. 36.7%, P = 0.003). Glucocorticoid use was a risk factor for mortality (adjusted odds ratio = 4.719, 95% confidence interval = 1.383-16.103, P = 0.0132), and was associated with shorter periods to KS-IRIS (P = 0.03) and death (P = 0.0073). KS-IRIS was a risk factor for mortality (P = 0.049). CONCLUSION: In HIV-infected individuals, the use of glucocorticoids is a risk factor for KS-IRIS and Kaposi's sarcoma-associated mortality. In addition, KS-IRIS is a risk factor for mortality. Therefore, glucocorticoid administration in this population requires careful consideration based on individualized risk-benefit analysis.

Síndrome de reconstitución inmunitaria en un caso de sarcoma de Kaposi asociado a sida con desenlace mortal / Fatal outcome of immune reconstitution inflammatory síndrome in a patient with AIDS-associated Kaposi sarcoma

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Paradoxical immune reconstitution inflammatory syndrome associated with cryptococcal meningitis in China: a 5-year retrospective cohort study.

We performed a retrospective cohort study of hospitalised cryptococcal meningitis (CM) patients at a single centre to evaluate the clinical epidemiological features of paradoxical cryptococcal-related immune reconstitution inflammatory syndrome (CM-IRIS) in a setting in China. A total of 154 AIDS patients with CM were involved, and 17.5% experienced IRIS at a median of 27 days after initiation of antiretroviral therapy (ART). Overall, 3 deaths were directly attributed to IRIS. The occurrences of CM-IRIS were independently associated with the pre-ART CD4+count, pre-C-reactive protein level, and the timing of ART initiation.

Immune reconstitution inflammatory syndrome in neutropenic patients with invasive pulmonary aspergillosis.

OBJECTIVES: Clinical and radiologic deterioration is sometimes observed during neutrophil recovery in patients with invasive pulmonary aspergillosis (IPA). This deterioration can be caused by immune reconstitution inflammatory syndrome (IRIS) as well as by progression of the IPA. However, there is limited data on IRIS in neutropenic patients. METHODS: Over a 6-year period, adult patients with neutropenia who met the criteria for probable or proven IPA by the revised EORTC/MSG definition were retrospectively enrolled. IRIS was defined as de novo appearance or worsening of radiologic pulmonary findings temporally related to neutrophil recovery, with evidence of a decrease of 50% in serum galactomannan level. RESULTS: Of 153 patients, 36 (24%, 95% CI 18%-31%) developed IRIS during neutrophil recovery. More of these patients received voriconazole than did those with non-IRIS (42% vs. 25%, P = 0.05). Thirty- and ninety-day mortalities were lower in the patients with IRIS than in those with non-IRIS (11% vs. 33%, P = 0.01, and 33% vs. 58%, P = 0.01, respectively). CONCLUSION: IRIS is relatively common among neutropenic patients with IPA, occurring in about one quarter of such patients. It is associated with voriconazole use and has a good prognosis.

Prevalencia y morbimortalidad del síndrome inflamatorio de reconstitución inmunológica en pacientes que viven con VIH en TARGA en el Hospital Nacional PNP Luis N. Sáenz - enero del 2008 a mayo del 2013 / Prevalence and morbidity and mortality of the immune reconstitution inflammatory syndrome in patients living with HIV on HAART in the National Hospital PNP Luis N. Saenz - January 2008 to May 2013

Objetivos: Determinar la prevalencia y morbimortalidad del síndrome inflamatorio de reconstitución inmunológica en pacientes que viven con VIH-SIDA en TARGA en el Hospital Nacional PNP Luis N. Sáenz de enero del 2008 a mayo del 2013. Material y métodos: Se realizó un estudio descriptivo, retrospectivo, de Pacientes con diagnóstico VIH que reciben TARGA que presentan el síndrome inflamatorio de reconstitución inmunológica. Resultados: el 70 por ciento fueron varones y el 30 por ciento mujeres. Los tipo de TARGA usados con mayor frecuencia fueron: Naive (38,5 por ciento), y el cambio de esquema (34,6 por ciento).En cuanto al tipo de esquema, estuvieron basados con mayor frecuencia en inhibidores de proteasas (69,2 por ciento). Dentro de las complicaciones encontramos que el 75 por ciento fueron infecciosas y de estas las de mayor frecuencia fueron la infección por Mycobacterium tuberculosos (30,8 por ciento) y criptococos neoformans (13,5 por ciento). Dentro de las complicaciones no infecciosas encontramos al linfoma no Hodgkin (15,4 por ciento). La manifestación clínica más frecuente fue la reacción inflamatoria como fiebre de origen desconocido (51,9 por ciento). En cuanto a los niveles de LTCD4 encontramos que el 55,8 por ciento presentaron valores menores de 50 cel/mL al inicio de la TARGA. El 48,1 por ciento presentaron valores de LTCD4 entre 201 a 300 cel/ml durante el SIRI. La tasa de mortalidad del síndrome de reconstitución inmunológica en pacientes con VIH que reciben TARGA, fue del 25 por ciento. Asimismo observamos una mejor sobrevida en los pacientes que recibieron inhibidores de proteasas. Conclusiones: La prevalencia del síndrome inflamatorio de reconstitución inmunológica en PVVS que reciben TARGA en el Hospital Nacional PNP Luis N. Sáenz fue de 18,4 por ciento. La morbilidad infecciosa de mayor frecuencia fue la tuberculosis y la no infecciosa fue el Linfoma no Hodgkin. El nivel de L TCD4 antes del inicio o cambio del TARGA fue menor de...

Objectives: To determine the prevalence and morbidity of immune reconstitution inflammatory syndrome in patients with HIV-AIDS in HAART at the National Hospital PNP Luis N. Saenz, January 2008 to May 2013. Material and Methods: A retrospective study descriptive HIV patients receiving HAART diagnosis presenting the immune reconstitution inflammatory syndrome was made. Results: 70 per cent were male and 30 per cent female. The type of HAART used most frequently were: Naive (38.5 per cent) and the schema change (34.6 per cent) Regarding the type of scheme, were based more often on protease inhibitors (69.2 per cent). Among the complications found that, 75 per cent were infectious and these were the most frequent infection with Mycobacterium tuberculosis (30.8 per cent) and Cryptococcus neoformans (13.5 per cent). Among the non-infectious complications of lymphoma are not Hodgkin (15.4 per cent). The most common clinical manifestation was inflammatory reaction as fever of unknown origin (51.9 per cent). As LTCD4 levels found that, 55.8 per cent had values below 50 cells/mL at the start of HAART. 48.1 per cent had values LTCD4 between 201-300 cells/ml during the SIRI. The mortality rate of immune reconstitution syndrome in HIV patients receivíng HAART, was 25 per cent. Also observed better survival in patients receiving protease inhibitors. Conclusions: The prevalence of immune reconstitution inflammatory syndrome in PLWHA receiving HAART at the National Hospital PNP Luis N Saenz was 18.4 per cent. The most frequent infectious morbidity was tuberculosis and noninfectious was non-Hodgkin lymphoma. The level of LTCD4 before initiation or change of HAART was less than 50 cells/ml, and for the manifestation of SIRI, was 201 to 300 cells/mL. The SIRI predominates in naive patients and HAART schemes based on protease inhibitors. The mortality of immune reconstitution syndrome in HIV patients receiving HAART was 25 per cent.

Treating tuberculosis in solid organ transplant recipients.

PURPOSE OF REVIEW: To summarize recent findings in the management of active tuberculosis (TB) in solid organ transplant (SOT) recipients. RECENT FINDINGS: Mycobacterium tuberculosis causes substantial morbidity and mortality in SOT recipients. According to the literature, transplantation might not be an absolute contraindication for patients with active TB. Although the use of rifampin, resulting in the decreased levels of calcineurin inhibitors, might lead to rejection, studies showed that rifampin-based regimens did not appear to be associated with post-TB rejection or mortality. Nevertheless, judicious adjustment and close monitoring of immunosuppressant levels during concurrent rifampin use for patients with active TB are needed. TB-associated immune reconstitution syndrome occurred in 14% of SOT recipients; liver transplantation, cytomegalovirus infection, and rifampin use are identified risk factors for the development of immune reconstitution syndrome. SUMMARY: Patients with active TB might be able to undergo transplantation if indicated. Rifampin-based regimen can be considered in the treatment of TB in SOT recipients. In addition to HIV-positive patients, immune reconstitution syndrome also occurs in SOT recipients, and deserves the recognition by primary care physicians to avoid unnecessary management.

Lymphoma immune reconstitution inflammatory syndrome in the center for AIDS research network of integrated clinical systems cohort.

BACKGROUND: Lymphoma incidence is increased among human immunodeficiency virus (HIV)-infected individuals soon after antiretroviral therapy (ART), perhaps due to unmasking immune reconstitution inflammatory syndrome (IRIS). Clinical characteristics and survival for unmasking lymphoma IRIS have not been described. METHODS: We studied lymphoma patients in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) from 1996 until 2011. Unmasking lymphoma IRIS was defined as lymphoma within 6 months after ART accompanied by a ≥ 0.5 log10 copies/mL HIV RNA reduction. Differences in presentation and survival were examined between IRIS and non-IRIS cases. RESULTS: Of 482 lymphoma patients, 56 (12%) met criteria for unmasking lymphoma IRIS. Of these, 12 (21%) had Hodgkin lymphoma, 22 (39%) diffuse large B-cell lymphoma, 5 (9%) Burkitt lymphoma, 10 (18%) primary central nervous system lymphoma, and 7 (13%) other non-Hodgkin lymphoma. Median CD4 cell count at lymphoma diagnosis among IRIS cases was 173 cells/µL (interquartile range, 73-302), and 48% had suppressed HIV RNA <400 copies/mL. IRIS cases were similar overall to non-IRIS cases in histologic distribution and clinical characteristics, excepting more frequent hepatitis B and C (30% vs 19%, P = .05), and lower HIV RNA at lymphoma diagnosis resulting from the IRIS case definition. Overall survival at 5 years was similar between IRIS (49%; 95% confidence interval [CI], 37%-64%) and non-IRIS (44%; 95% CI, 39%-50%), although increased early mortality was suggested among IRIS cases. CONCLUSIONS: In a large HIV-associated lymphoma cohort, 12% of patients met a uniformly applied unmasking lymphoma IRIS case definition. Detailed studies of lymphoma IRIS might identify immunologic mechanisms of lymphoma control.

Immune reconstitution syndrome-like entity in lung transplant recipients with invasive aspergillosis.

BACKGROUND: Incidence, characteristics, and risk-factors for invasive aspergillosis (IA)-associated immune reconstitution syndrome (IRS) in lung transplant recipients are not known. METHODS: Patients comprised 68 lung transplant recipients with proven/probable IA followed for 12 months. IRS was defined based on previously proposed criteria. RESULTS: In all, 7.3% (5/68) of the patients developed IRS based on aforementioned criteria, a median of 56 days after initiation of antifungal therapy. This entity was associated with heart-lung transplantation (p=0.006), anti T-cell agent use (p=0.003), discontinuation of calcineurin inhibitor agent (p=0.002), and disseminated IA (p=0.069). In a risk assessment model, IRS developed in 0% (0/55) of the patients with none of the aforementioned factors, 28.6% (2/7) with one, 33.3% (1/3) with two, and in 1/1 patient with 3 factors (X(2) for trend p=0.0001). Three out of 5 patients with IRS died and 2 of 3 deaths in this group were due to chronic rejection. CONCLUSIONS: Overall 7% of the lung transplant recipients with IA appear to develop an IRS-like entity. Clinically assessable factors can identify patients at risk for post-transplant IA-associated IRS. Deaths due to chronic rejection were significantly higher in patients with IRS than those without IRS.

Disease course and outcome of 15 monocentrically treated natalizumab-associated progressive multifocal leukoencephalopathy patients.

OBJECTIVE: Although the prognosis of natalizumab-associated progressive multifocal leukoencephalopathy (PML) seems to be better than HIV-associated PML, little is known about the long-term functional outcome in multiple sclerosis (MS) patients and the subsequent return of MS disease activity. We evaluated retrospectively 15 patients with natalizumab-associated PML treated at our centre. PATIENTS AND METHODS: Fifteen MS-PML patients (nine women, six men) were referred to us from adjacent local centres. The patients had a median natalizumab exposure of 34 months at PML diagnosis. They received standardised treatment as described in previous work. Expanded Disability Status Scale (EDSS) and Karnofsky score in the year pre-PML, at PML-diagnosis (pre-immune reconstitution inflammatory syndrome (IRIS)) and post-PML were determined in 3-6 monthly intervals. RESULTS: The median follow-up of these 15 patients was 21.5 months. None of the 15 patients died. Three patients had a Karnofsky score of 80 or higher, nine patients between 50-70 and three patients of 40 or lower at latest examination. Eight of the 15 patients developed seizures during acute PML phase. Fifty percent of those patients were not seizure-free one year post PML, despite continuation of antiepileptic treatment. The median EDSS in the year pre-PML was 2.5, 4.5 at PML diagnosis, 6.5 post-IRIS and 5.5 at latest examination. CSF became virus-free in eight of the 15 patients after a median time of 4.5 months. In nine patients, disease reappeared after a median time of seven months from PML diagnosis. CONCLUSIONS: Although the clinical outcome of natalizumab-treated PML patients is much better than in patients with HIV-associated PML, this may be further improved by treatment at reference centres using standardised therapy regimens and transient intensive care if needed. Systematic studies of appropriate MS immunotherapies after PML are critically needed.

Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma: higher incidence and mortality in Africa than in the UK.

OBJECTIVES: To assess the incidence, predictors, and outcomes of Kaposi sarcoma-associated paradoxical immune reconstitution inflammatory syndrome (KS-IRIS) in antiretroviral therapy (ART)-naive HIV-infected patients with Kaposi sarcoma initiating ART in both well resourced and limited-resourced settings. DESIGN: Pooled analysis of three prospective cohorts of ART-naive HIV-infected patients with Kaposi sarcoma from sub-Saharan Africa (SSA) and one from the UK. METHODS: KS-IRIS case definition was standardized across sites. Cox regression and Kaplan-Meier survival analysis were used to identify the incidence and predictors of KS-IRIS and Kaposi sarcoma-associated mortality. RESULTS: Fifty-eight of 417 (13.9%) eligible individuals experienced KS-IRIS with an incidence 2.5 times higher in the African vs. European cohorts (P=0.001). ART alone as initial Kaposi sarcoma treatment (hazard ratio 2.97, 95% confidence interval (CI) 1.02-8.69); T1 Kaposi sarcoma stage (hazard ratio 2.96, 95% CI 1.26-6.94); and plasma HIV-1 RNA more than 5 log10 copies/ml (hazard ratio 2.14, 95% CI 1.25-3.67) independently predicted KS-IRIS at baseline. Detectable plasma Kaposi sarcoma-associated herpes virus (KSHV) DNA additionally predicted KS-IRIS among the 259 patients with KSHV DNA assessed (hazard ratio 2.98, 95% CI 1.23-7.19). Nineteen KS-IRIS patients died, all in SSA. Kaposi sarcoma mortality was 3.3-fold higher in Africa, and was predicted by KS-IRIS (hazard ratio 19.24, CI 7.62-48.58), lack of chemotherapy (hazard ratio 2.35, 95% CI 1.09-5.05), pre-ART CD4 cell count less than 200 cells/µl (hazard ratio 2.04, 95% CI 0.99-4.2), and detectable baseline KSHV DNA (hazard ratio 2.12, 95% CI 0.94-4.77). CONCLUSION: KS-IRIS incidence and mortality are higher in SSA than in the UK. This is largely explained by the more advanced Kaposi sarcoma disease and lower chemotherapy availability. KS-IRIS is a major contributor to Kaposi sarcoma-associated mortality in Africa. Our results support the need to increase awareness on KS-IRIS, encourage earlier presentation, referral and diagnosis of Kaposi sarcoma, and advocate on access to systemic chemotherapy in Africa.

Clinical characteristics and outcomes of HIV-infected children diagnosed with Kaposi sarcoma in Malawi and Botswana.

BACKGROUND: Kaposi sarcoma (KS) is the most common HIV-associated malignancy in sub-Saharan Africa. The presentation and outcomes of pediatric KS are not well understood. PROCEDURE: We performed a retrospective cohort analysis of 81 HIV-infected children with KS at the Baylor Children's Clinical Centres of Excellence in Malawi and Botswana from March 2003 to October 2009. RESULTS: Eighty-one children with KS were identified whose median age was 8.0 (inter-quartile range 5.1-11.3) years. KS lesions were presented primarily on the skin (83%), lymph nodes (52%), and oral mucosa (41%). Occasionally disease was limited to the lymph nodes only (10%). Severe immunosuppression (70%), anemia (29%), and thrombocytopenia (17%) were common laboratory findings. Highly active antiretroviral therapy (HAART) was administered to 94% of children, including 77% who received HAART plus chemotherapy. KS immune reconstitution inflammatory syndrome (IRIS) occurred in 22%. Disease status 12 months after KS diagnosis was determined for 69 children: 43% were alive and 57% had died. Severe immunosuppression was independently associated with mortality in multivariate analysis (OR = 4.3; 95% CI 1.3-14.6; P = 0.02). CONCLUSION: KS occurs in a significant number of HIV infected children in sub-Saharan Africa. Pediatric KS is distinct from KS in adults. Lymph node involvement was a common manifestation of KS in children, and severe immunosuppression was associated with the highest mortality risk. Though overall mortality was high in children with KS, patients did achieve clinical remission in settings with limited diagnostic and therapeutic resources.

Mycobacterium tuberculosis-associated immune reconstitution syndrome in solid-organ transplant recipients.

BACKGROUND: Incidence, characteristics, and risk factors for tuberculosis (TB)-associated immune reconstitution inflammatory syndrome (IRS) in solid-organ transplant (SOT) recipients are not known. METHODS: Patients are composed of 64 consecutive SOT recipients with TB followed for 12 months. IRS was defined based on previously proposed criteria. RESULTS: IRS developed in 14% (9/64) of the patients, a median of 47 days after the use of anti-TB therapy. Liver versus other types of organ transplant recipients (adjusted odds ratio [OR], 6.11; 95% confidence interval [CI], 1.08-34.86), prior cytomegalovirus infection (adjusted OR, 5.65; 95% CI, 0.93-34.47), and rifampin use (adjusted OR, 4.56; 95% CI, 0.74-27) were associated with a higher risk of IRS. The presence of more than one factor (liver transplantation, cytomegalovirus infection, and rifampin use) when compared with none of these factors conferred a 19-fold increase in the risk of IRS (P=0.01). Mortality at 1 year after diagnosis was 33.3% in patients with IRS and 17.2% in those without IRS (P=0.31). CONCLUSIONS: IRS was documented in 14% of the SOT recipients with TB. We determined clinically identifiable factors that may be useful in assessing the risk of tuberculosis-associated posttransplantation IRS.

Management of tuberculosis in HIV-infected patients.

HIV-tuberculosis coinfection is currently one of the greatest health threats, affecting millions of people worldwide, with high morbidity and mortality. Treating both infections can be a challenge and requires some expertise due to multidirectional drug interactions, risk of overlapping side effects, high pill burden and risk of immune reconstitution inflammatory syndrome. This article reviews the general management of tuberculosis/HIV coinfection, focusing on the optimal time to start antiretroviral therapy and which treatments can be safely used. The randomized clinical trials designed to answer the question of when to start antiretroviral therapy (SAPIT, CAMELIA, STRIDE and TIME), published in the last two years, are described and discussed in detail. Summarizing these trials' conclusions, antiretroviral therapy should be started within two weeks of starting tuberculosis treatment if the patient has less than 50 CD4/mm3 and wait to the end of the induction phase (8-12 weeks after starting tuberculosis treatment) if higher CD4 cell counts exist. Treatment options for both tuberculosis and HIV, including the newer available drugs and those in clinical trials, are revised and recommendations for dose adjustments are made based on the latest available literature, with special attention to drug-drug interactions and the necessity of dose adjustments with some drug combinations.

Incidence, clinical spectrum, risk factors and impact of HIV-associated immune reconstitution inflammatory syndrome in South Africa.

BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) is a widely recognised complication of antiretroviral therapy (ART), but there are still limited data from resource-limited settings. Our objective was to characterize the incidence, clinical spectrum, risk factors and contribution to mortality of IRIS in two urban ART clinics in South Africa. METHODS AND FINDINGS: 498 adults initiating ART in Durban, South Africa were followed prospectively for 24 weeks. IRIS diagnosis was based on consensus expert opinion, and classified by mode of presentation (paradoxical worsening of known opportunistic infection [OI] or unmasking of subclinical disease). 114 patients (22.9%) developed IRIS (36% paradoxical, 64% unmasking). Mucocutaneous conditions accounted for 68% of IRIS events, mainly folliculitis, warts, genital ulcers and herpes zoster. Tuberculosis (TB) accounted for 25% of IRIS events. 18/135 (13.3%) patients with major pre-ART OIs (e.g. TB, cryptococcosis) developed paradoxical IRIS related to the same OI. Risk factors for this type of IRIS were baseline viral load >5.5 vs. <4.5 log(10) (adjusted hazard ratio 7.23; 95% confidence interval 1.35-38.76) and ≤30 vs. >30 days of OI treatment prior to ART (2.66; 1.16-6.09). Unmasking IRIS related to major OIs occurred in 25/498 patients (5.0%), and risk factors for this type of IRIS were baseline C-reactive protein ≥25 vs. <25 mg/L (2.77; 1.31-5.85), haemoglobin <10 vs. >12 g/dL (3.36; 1.32-8.52), ≥10% vs. <10% weight loss prior to ART (2.31; 1.05-5.11) and mediastinal lymphadenopathy on pre-ART chest x-ray (9.15; 4.10-20.42). IRIS accounted for 6/25 (24%) deaths, 13/65 (20%) hospitalizations and 10/35 (29%) ART interruptions or discontinuations. CONCLUSION: IRIS occurred in almost one quarter of patients initiating ART, and accounted for one quarter of deaths in the first 6 months. Priority strategies to reduce IRIS-associated morbidity and mortality in ART programmes include earlier ART initiation before onset of advanced immunodeficiency, improved pre-ART screening for TB and cryptococcal infection, optimization of OI therapy prior to ART initiation, more intensive clinical monitoring in initial weeks of ART, and education of health care workers and patients about IRIS.

Causes of death on antiretroviral therapy: a post-mortem study from South Africa.

BACKGROUND: Mortality in the first months of antiretroviral therapy (ART) is a significant clinical problem in sub-Saharan Africa. To date, no post-mortem study has investigated the causes of mortality in these patients. METHODS: HIV-positive adults who died as in-patients at a Johannesburg academic hospital underwent chart-review and ultrasound-guided needle autopsy for histological and microbiological examination of lung, liver, spleen, kidney, bone marrow, lymph node, skin and cerebrospinal fluid. A clinico-pathologic committee considered all available data and adjudicated immediate and contributing causes of death. RESULTS: Thirty-nine adults were enrolled: 14 pre-ART, 15 early-ART (7-90 days), and 10 late-ART (>90 days). Needle sampling yielded adequate specimen in 100% of kidney, skin, heart and cerebrospinal fluid samples, 97% of livers and lungs, 92% of bone marrows, 87% of spleens and 68% of lymph nodes. Mycobacterial infections were implicated in 69% of deaths (26 of 27 of these due to M. tuberculosis), bacterial infections in 33%, fungal infections in 21%, neoplasm in 26%, and non-infectious organ failure in 26%. Immune reconstitution inflammatory syndrome (IRIS) was implicated in 73% of early-ART deaths. Post-mortem investigations revealed previously undiagnosed causes of death in 49% of cases. Multiple pathologies were common with 62% of subjects with mycobacterial infection also having at least one other infectious or neoplastic cause of death. CONCLUSIONS: Needle biopsy was efficient and yielded excellent pathology. The large majority of deaths in all three groups were caused by M. tuberculosis suggesting an urgent need for improved diagnosis and expedited treatment prior to and throughout the course of antiretroviral therapy. Complex, unrecognized co-morbidities pose an additional challenge.

Clinical spectrum, risk factors and outcome of immune reconstitution inflammatory syndrome in patients with tuberculosis-HIV coinfection.

BACKGROUND: Here, we aimed to determine the clinical spectrum, predictors and outcomes of paradoxical tuberculosis-immune reconstitution inflammatory syndrome (TB-IRIS) in a resource-limited setting. METHODS: In a prospective cohort, we studied 254 patients with tuberculosis and HIV coinfection commencing antiretroviral therapy (ART). We identified patients with TB-IRIS using the International Network for Studies Against HIV-Associated IRIS (INSHI) case definition. Risk factors and clinical outcomes of TB-IRIS were determined and reported. RESULTS: A total of 53 (21%) patients developed TB-IRIS a median of 2 weeks (IQR 12-22 days) after starting ART. The majority of the patients (70%) with TB-IRIS had extrapulmonary manifestations of TB-IRIS. In a multiple logistic regression model, baseline haemoglobin <100 g/l (OR 2.23 [95% CI 1.08-4.60]; P=0.031) and baseline CD4(+) T-cell count <50 cells/µl (OR 4.13 [95% CI 1.80-9.51]; P=0.001) were significant predictors of IRIS. Seven additional patients fulfilled all INSHI criteria of TB-IRIS but had the episode of TB-IRIS later than 3 months after ART start. CONCLUSIONS: TB-IRIS was a frequent reason for clinical deterioration among patients with TB commencing ART but was not a primary contributor to mortality. Patients with advanced CD4 depletion and anaemia were at increased risk of TB-IRIS. Some patients developed late-onset TB-IRIS and/or a recurrent TB-IRIS episode.

Immune reconstitution inflammatory syndrome: incidence and implications for mortality.

OBJECTIVE: To describe incidence of immune reconstitution inflammatory syndrome (IRIS) and its association with mortality in a large multisite US HIV-infected cohort applying an objective, comprehensive definition. DESIGN: We studied 2,610 patients seen during 1996-2007 who initiated or resumed highly active combination antiretroviral therapy (cART) and, during the next 6 months, demonstrated a decline in plasma HIV-RNA viral load of at least 0.5 log(10) copies/ml or an increase of at least 50% in CD4 cell count per microliter. We defined IRIS as the diagnosis of a type B or C condition [as per the Centers for Disease Control and Prevention (CDC) 1993 AIDS case definition] or any new mucocutaneous disorder during this same 6-month period. METHODS: We assessed the incidence of IRIS and evaluated risk factors for IRIS using conditional logistic regression and for all-cause mortality using proportional hazards models. RESULTS: We identified 370 cases of IRIS (in 276 patients). Median and nadir CD4 cell counts at cART initiation were 90 and 43 cells/µl, respectively; median viral load was 2.7 log(10) copies/ml. The most common IRIS-defining diagnoses were candidiasis (all forms), cytomegalovirus infection, disseminated Mycobacterium avium intracellulare, Pneumocystis pneumonia, varicella zoster, Kaposi's sarcoma and non-Hodgkin lymphoma. Only one case of Mycobacterium tuberculosis was observed. IRIS was independently associated with CD4 cell count less than 50 cells/µl vs. at least 200 cells/µl [odds ratio (OR) 5.0] and a viral load of at least 5.0 log(10) copies vs. less than 4.0 log(10) copies (OR 2.3). IRIS with a type B-defining or type C-defining diagnosis approximately doubled the risk for all-cause mortality. CONCLUSION: In this large US-based HIV-infected cohort, IRIS occurred in 10.6% of patients who responded to effective ART and contributed to increased mortality.

Risk factors for mortality in a south Indian population on generic antiretroviral therapy.

BACKGROUND: Antiretroviral treatment (ART) programs from low-income countries utilizing standardized ART regimens, simplified approaches to clinical decision making and basic lab monitoring have reported high mortality rates. We determined the risk factors for mortality among HIV-infected adults following the initiation of ART from a single center in south India. METHODS: ART-naive HIV-infected south Indian adults attending the Infectious Diseases clinic in a 2000-bed academic medical center in south India who were initiated on ART (generic, fixed-dose combinations) as per the national guidelines were followed up. Cases (32 patients who died) were compared with age and sex matched controls. RESULTS: Eight-hundred and twenty-two patients were started on ART from January 1, 2000 to December 31, 2008. The cumulative mortality was 6.8% (56/822). Among the cases mean age was 44 years, 18% were women and mean CD4 counts was 107 cells/microl. Among the controls mean age was 41 years, 18% were women and mean CD4 counts were 113 cells/microl. Stavudine based ART was predominant 62.5% in the cases vs 37.5% in the controls, followed by zidovudine based therapy in 31.2% of cases and 43.7% in the controls. Tenofovir based therapy was used in 6.2% of cases vs 18.7% in the controls. The commonest causes of death were drug toxicity 19%, advanced Acquired Immunodeficiency Syndrome (AIDS) in 37%, Immune Reconstitution Inflammatory Syndrome (IRIS) in 16%, non AIDS related deaths in 22% and malignancies 6%. In a univariate analysis, absolute lymphocyte count <1200 cells/cmm (p=0.03), development of immune reconstitution inflammatory syndrome (IRIS) (p=0.000) and mean CD4 cell count increase <75 cells/microl after 1 year of ART (p=0.001) were significantly associated with mortality. CONCLUSIONS: The mortality among our patients was comparable to that reported from other low-income countries. Earlier initiation of ART may reduce the high mortality rates observed.