By G. Ford. Bethany College, Lindsborg, KS.

Excess of rare evaluated by Bayesian network based Bayesian multilevel variants in genes identified by genome-wide association study analysis of relevance proven 0.4 mg tamsulosin. Novel susceptibility resistance and prognosis in newly diagnosed childhood acute variants at 10p12 buy tamsulosin 0.4 mg with mastercard. Pharmacokinetic best tamsulosin 0.4 mg, pharma- with risk of acute lymphoblastic leukaemia in adults: a Group codynamic, and pharmacogenetic determinants of osteonecro- for Research on Adult Acute Lymphoblastic Leukaemia sis in children with acute lymphoblastic leukemia. Yang L, Boyd K, Kaste SC, Kamdem Kamdem L, Rahija RJ, phisms contribute to racial disparities in the incidence and Relling MV. A mouse model for glucocorticoid-induced osteo- treatment outcome of childhood acute lymphoblastic leukemia. Genomewide association studies and assessment of germline genetic variation associated with treatment re- of the risk of disease. The management of elderly patients with CLL is more complex than that of younger patients due to the greater frequency of comorbidities and functional impairment as well as reduced organ function. Many of the recent advances in the care of CLL patients (prognostication, more intense combination therapy regimens) are of unclear relevance for elderly patients. This review addresses 5 key questions in the management of elderly patients with CLL: (1) why is classifying the “fitness” of CLL patients necessary; (2) what criteria should be used to classify patient fitness; (3) when should elderly patients be treated; (4) how should therapy be selected for elderly patients; and (5) which therapy is best (for this patient)? Introduction advanced age, efficacious treatment is needed for these individuals The last 2 decades have been a time of tremendous progress in because a majority of patients beginning treatment for CLL will die as a direct result of the disease or its complications. Most patients are diagnosed with early-stage disease before developing symptoms after they are incidentally found to have This review addresses 5 key questions in the management of elderly lymphocytosis. Insights into the molecular biology and genetics patients with CLL: (1) why is classifying the “fitness” of CLL of the leukemic CLL B cell have not only led to a better patients necessary; (2) what criteria should be used to classify understanding of disease biology,1-3 but have also enhanced the patient fitness; (3) when should elderly patients be treated; (4) how accuracy of prognostication4,5 and identified potential new should therapy be selected for elderly patients; and (5) which therapeutic targets. There are several purposes for classifying fitness level in patients With such CIT approaches, a high proportion of patients achieve with CLL. The first is to accurately categorize the patient’s life a minimal residual disease–negative disease state, a depth of 9,10 expectancy unrelated to CLL (eg, due to other health problems). This information can then be used for patient counseling and to help define the importance of durable disease control when Unfortunately, these advances do not benefit all patients uni- selecting treatment. CLL is a disease of the elderly, with a median age of CLL patient is acceptable for an individual with a life expectancy onset of 70 years. According to the Surveillance Epidemiol- of 24 months due to other health problems, whereas it would be ogy and End Results (SEER) registry, 75% of patients are considered inadequate for an individual with a 10-year life more than 65 years of age at the time of diagnosis. These data illustrate the limitations of using chronologic age alone to estimate survival in patients with CLL. Because most patients have early-stage disease at diagnosis and are observed for several years before starting treatment, the median age The second reason to classify fitness is to help determine the at the time therapy is initiated is closer to 75 years. Elderly patients patient’s ability to tolerate aggressive therapy. A 70-year-old have been underrepresented in previous clinical trials, which has woman with CLL in need of treatment may have an average life resulted in uncertainty regarding the optimal treatment approaches expectancy unrelated to CLL of greater than 15 years. Rather than chrono- conditions and begin treatment after the age of 70. Life expectancy in the United States17 The number and severity of comorbid health conditions also provides Life expectancy, y important information regarding patient fitness. A Mayo Clinic study of 373 unselected CLL patients found that 89% of newly diagnosed Current age, y Men Women patients had at least one comorbid condition and 46% had at least one 65 18. Although the presence of a major comorbidity affected OS on univariate analysis, it was not a significant predictor on the multivariate analysis adjusting for CLL-specific characteristics (eg, and the pharmacokinetics (absorption, metabolism, excretion) of the 20 stage). This finding underscores that CLL-related characteristics are drugs to be used become key considerations in evaluating the suitability of a given treatment approach. This principle is well often the major factor influencing survival even when substantial illustrated by the Cancer and Leukemia Group B (CALGB) 9011 comorbidities are present. Although it enrolled only fit older patients trial, which found that creatinine clearance rather than age was the (performance status 0-2, no severe organ disfunction), the presence of 2 primary predictor of higher toxicity with fludarabine-based therapy or more comorbid health conditions was still associated with shorter 18 PFS and shorter OS in the German CLL5 trial. Historically, trials have primarily used an exclusionary (rather than a stratification) approach declaring patients above an age cutoff Organ function is a third factor in assessing patients’ suitability for or with any decrease in organ function or performance status aggressive treatment. It is well recognized that renal function decreases 19 with age. These criteria have excluded those with the characteristics typical of real-world CLL patients from participating. A consistent approach Renal Disease (MDRD) equation. For the patient they are evaluating and facilitate more rapid translation of example, a study of 100 000 individuals from Japan found that trial results into routine clinical practice. Although patients were traditionally classified based on age alone, it is now well recognized that chronologic age is not a reliable surrogate for physiologic age or fitness. Measuring only one of these dimensions can lead to an inaccurate assessment of overall patient fitness. CGA includes most widely used assessment of patient fitness in oncology practice, evaluation of function, coexisting health problems, level of social has a moderate correlation with more formal CGA instruments,32 it support, cognitive ability, nutritional status, and common syndromes is an inadequate measure of function for most older adults. Given the assessments have been shown to reliably predict the ability of elderly importance of assessing fitness/frailty in the management of CLL patients to tolerate chemotherapy in other malignancies. Selected standardized tools to evaluate various dimensions of patient fitness CGA and functional assessment Comorbidities Quality of life 101 27 Activity of Daily Living (ADL) CIRS-G European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30102 Instrument of Activities of Daily Living (AIDL)103,104 Charlson Comorbidity Index28 Functional assessment of cancer therapy-general (FACT-G)105 ECOG performance status106 Adult Comorbidity Evaluation (ACE-27)107 Patient Reported Outcome Measurement Information System (PROMIS)108 Others26 Others109 Hematology 2013 159 launched an international initiative to bring greater consistency to this Table 3. Supportive care considerations for CLL patients assessment. It is hoped that this effort will identify standard criteria by Suggestions which both fit and less fit CLL patients may be selected for trials and that can be used to stratify patients within a trial to evaluate how fitness Cancer screening ● Whole-body skin examination annually. This effort will also explore how such ● Age-appropriate screening for breast, criteria may be used to inform therapy selection in routine clinical practice. Vaccination strategies54 ● Prevnar 13 pneumococcal vaccination The indications to initiate therapy for elderly patients with CLL are should be given at diagnosis followed 8 generally the same as those for younger patients. Up to 50% of older patients have been found to have ● Annual influenza vaccination should be depression,34,36 and patients should be specifically screened for depres- given. Although a lymphocyte doubling time of less than 6 months is live attenuated typhoid vaccines. CLL experts appear to have a greater tolerance for delaying older adults. Because Consider evaluation of vitamin D levels treatment increases rather than decreases the risk of infection, because this recommendation frequent or recurrent infections are also not a reason to initiate increases risk of vitamin D deficiency. Studies from both the United mended, live attenuated vaccines, including Zostavax, are contra- States and Italy suggest that low vitamin D levels may be associated indicated in patients with CLL (Table 3). Nonetheless, vitamin D assess- is limited information on the utility of these molecular biomarkers ment in patients at risk can be considered good general care for elderly for predicting outcome in older CLL patients.

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Whenever possible order tamsulosin 0.4mg with amex, the ART least likely to worsen lipid levels should be selected for patients with dyslipidemia discount tamsulosin 0.4 mg overnight delivery. Metformin has been evaluated for the treatment of lipodystrophy syndrome purchase tamsulosin 0.2 mg mastercard. Some studies have revealed a positive effect on the parameters of insulin resistance and the potential reduction of intra-abdominal (and subcutaneous) fat, although not clinically significant. Together with exercise training, metformin has been described to reverse the muscular adiposity in HIV+ patients (Driscoll 2004). Metformin, like all biguanides, can theoretically precipitate lactic acidosis and should thus be used with caution. Use of metformin should be avoided in patients with creatinine levels above 1. Surgical intervention (liposuction) for the treatment of local fat hypertrophy has been successfully performed, but appears to be associated with an increased risk of secondary infection (Guaraldi 2011), and recurrence of fat accumulation is possible. For the treatment of facial lipoatrophy, repeated subcutaneous injection of agents such as poly-L-lactic acid (Sculptra, New-Fill), a resorbable molecule that promotes collagen formation, has been effectively used in HIV+ patients (Casavantes 2004, Mest 2004, Behrens 2008). In 2004, Sculptra was approved by the FDA as an injectable filler to correct facial fat loss in people with HIV. We recommend consul- tation with experienced specialists for surgical treatments and injection therapy. Further evaluation in long-term follow-up studies is necessary to fully assess the value of these methods. We do not recommend the following drugs for HIV-related lipodystrophy: • The therapeutic intervention of recombinant human growth hormone (rHGH) (Serostim); the role of rHGH for HIV-associated fat accumulation has not been clearly defined. This therapy is very expensive and its only at best moderate effects disappear after stopping the treatment; there was rapid rebound of visceral fat to levels above baseline after treatment discontinuation (Grunfeld 2007, Lo 2008, Lo 2010). Management of Side Effects 295 Lifestyle changes Dietary interventions are commonly accepted as the first therapeutic option for hyperlipidemia, especially hypertriglyceridemia. Use of NCEP guidelines may reduce total cholesterol and triglycerides by 11 and 21%, respectively. Whenever possible, dietary restriction of total fat to 25–35% of the total caloric intake should be a part of any treatment in conjunction with lipid-lowering drugs. Consultation with pro- fessional and experienced dieticians should be considered for HIV+ patients and their partners. Patients with excessive hypertriglyceridemia (>1,000 mg/dl) may benefit from a very low fat diet and alcohol abstinence to reduce the risk of pancreatitis, especially if there is a positive family history or concurrent medications that may harbor a risk of developing pancreatitis. Regular exercise may have beneficial effects, not only on triglycerides and insulin resistance, but probably also on fat redistribu- tion (reduction in truncal fat and intramyocellular fat) and should be considered in all HIV+ patients (Driscoll 2004). All patients should be advised and supported to give up smoking in order to reduce cardiovascular risk. Cessation of smoking is more likely to reduce cardiovascular risk than any choice or change of ART or use of any lipid-lowering drug (Petoumenos 2010). Metabolic effects of darunavir/ritonavir versus atazanavir/ritonavir in treat- ment-naive, HIV type 1-infected subjects over 48 weeks AIDS Res Hum Retroviruses 2012, 28:1184-95. A randomized, pilot trial to evaluate glomerular filtration rate by creatinine or cystatin C in naïve HIV-infected patients after tenofovir/emtricitabine in combination with atazanavir/riton- avir or efavirenz. Barrios A, Garcia-Benayas T, Gonzalez-Lahoz J, et al. Treatment option for lipodystrophy in HIV-positive patients. Suspected drug-induced liver fatalities reported to the WHO database. Clinical Review : low body weight mediates the relationship between HIV infection and low bone mineral density: a meta-analysis. Risk factors for lactic acidosis in HIV-infected patients treated with nucleo- side reverse-transcriptase inhibitors: a case-control study. Adverse cutaneous reactions associated with the newest anti- retroviral drugs in patients with human immunodeficiency virus infection. Stevens-johnson syndrome associated with abacavir therapy. Relationship betwee renal dysfunction, nephrotoxicity and death among HIV adults on tenofovir. Management of hyperlactatemia: no need for routine lactate measurements. Recommendations for evaluation and management of bone disease in HIV. Fatal lactic acidosis and pancreatitis associated with ribavirin and didanosine therapy. Efficacy and tolerability of initial antiretroviral therapy: a systematic review. Carr A, Emery S, Law M, Puls R, Lundgren JD, Powderly WG. An objective case definition of lipodystrophy in HIV-infected adults: a case-control study. Fatal portal hypertension, liver failure, and mitochondrial dysfunction after HIV- 1 nucleoside analogue-induced hepatitis and lactic acidaemia. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resist- ance in patients receiving HIV protease inhibitors. Bio-Alcamid, a high-volume injectable posthesis for facial reconstruction in HIV- related lipoatrophy: a report on 100 patients. Reduced bone mineral density in HIV-infected patients: preva- lence and associated factors. Intracranial hemorrhage and liver-associated deaths associated with tipranavir/ritonavir: review of cases from the FDA’s Adverse Event Reporting System. Clinical management of treatment-experienced, HIV infected patients with the fusion inhibitor enfuvirtide: consensus recommendations. Cohen CJ, Andrade-Villanueva J, Clotet B on behalf of the THRIVE study group. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial The Lancet 2011: 378, 229 – 237. Adherence to antiretroviral therapy in managed care members in the United States: a retrospective claims analysis. Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Dolutegravir: clinical and laboratory safety in integrase inhibitor-naive patients. Insights into the reasons for discontinuation of the first highly active antiretroviral therapy regimen in a cohort of antiretroviral naïve patients. Metabolic profiles and body composition changes in treatment-naive HIV- infected patients treated with raltegravir 400 mg twice-daily vs Efavirenz 600 mg each bedtime combination therapy: 96-week follow-up. Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults.

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Although biopsy is always preferred and should be per- formed in all cases if feasible tamsulosin 0.4mg generic, if it is not possible tamsulosin 0.2 mg low cost, lymphoma therapy may be initiated in certain cases without further delay 0.4 mg tamsulosin visa. If Conclusion both tests are negative, lymphoma is ruled out with near 100% For the most part, hematologic cancer therapeutic prospects are predictive value. If the results of the FDG-PET and EBV PCR are equivalent in the HIV-related and HIV-unrelated settings. Appropri- discordant, the predictive values are too low to act on and biopsy ate assessment of HIV as a comorbid condition is essential to 386 American Society of Hematology optimizing therapeutic strategies. El-Sadr WM, Lundgren J, Neaton JD, et al; Strategies for enced the epidemiology of hematologic cancers in HIV, and those Management of Antiretroviral Therapy (SMART) Study Group. Pooled of malignancy and the specific therapy being administered. Off-label drug use: azidothymidine and ganciclo- 14. Rituximab plus vir for treatment of Kaposi sarcoma-associated herpes virus– concurrent infusional EPOCH chemotherapy is highly effective associated MCD. Relationship of Richard Little, National Cancer Institute, National Institutes of p53, bcl-2, and tumor proliferation to clinical drug resistance in Health, 31 Center Drive, MSC 2062, Bldg 31, Rm B1-W30, non-Hodgkin’s lymphomas. Bethesda, MD 20892; Phone: 240-276-6560; Fax: 240-276-7892; 16. Rituximab does not References improve clinical outcome in a randomized phase III trial of 1. Changes in AIDS-related CHOP with or without rituximab in patients with HIV- lymphoma since the era of highly active antiretroviral therapy. Dose-reduced with dose-adjusted EPOCH: impact of antiretroviral therapy busulfan, cyclophosphamide, and autologous stem cell transplan- suspension and tumor biology. MYC aggressive dense rituximab (SC-EPOCH-RR) in HIV-associated diffuse B-cell lymphomas: novel therapy of untreated Burkitt lym- large B-cell lymphoma. Swiss HIV Cohort Study: associations with immunodeficiency, Abstract 71. HIV-1-related Hodgkin outcome of lymphoma patients transferred to the intensive care lymphoma in the era of combination antiretroviral therapy: unit. Excellent immunological AIDS-defining cancers among HIV-infected patients compared recovery following CODOX-M/IVAC, an effective intensive with the general population in a large health district of northern chemotherapy for HIV-associated Burkitt’s lymphoma. Xicoy B, Ribera JM, Miralles P, et al; PETHEMA Group; non-Hodgkin lymphoma in the United States: disentangling the GESIDA Group; GMALL Group. Estimated HIV prevalence in the United combined antiretroviral therapy. Lymphocyte HIV-infected patients with plasmablastic lymphoma: results depletion during treatment with intensive chemotherapy for from the German AIDS-related lymphoma cohort study. Human immunodefi- and significance of severe toxicity in patients with human ciency virus-associated plasmablastic lymphoma. High-dose are the main cytogenetic alteration in plasmablastic lympho- zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus- mas. Intensive ase chain reaction in CSF for the diagnosis of AIDS-related chemotherapy with cyclophosphamide, doxorubicin, high-dose primary CNS lymphoma. AIDS-associated (CODOX-M/IVAC) for human immunodeficiency virus- primary central nervous system lymphoma (AIDS-PCNSL) associated Burkitt lymphoma. Oriol A, Ribera JM, Brunet S, del Potro E, Abella E, Esteve J. HIV and AIDS Malignancy Branch experience, 2004-2011 Highly active antiretroviral therapy and outcome of AIDS-related CROI 19. Hyperfractionated cyclophos- phoma treated with chemotherapy using doxorubicin, bleomy- phamide, vincristine, doxorubicin, and dexamethasone and cin, vinblastine, and dacarbazine in the highly active antiretro- highly active antiretroviral therapy for patients with acquired viral therapy era. Frenette2-4 Departments of 1Pediatrics, 2Medicine, and 3Cell Biology, and 4Ruth L. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY Recurrent and unpredictable episodes of vaso-occlusion are the hallmark of sickle cell disease. Symptomatic management and prevention of these events using the fetal hemoglobin–reactivating agent hydroxyurea are currently the mainstay of treatment. Discoveries over the past 2 decades have highlighted the important contributions of various cellular and soluble participants in the vaso-occlusive cascade. The role of these elements and the opportunities for therapeutic intervention are summarized in this review. Introduction reported to interact with the subendothelial matrix proteins (eg, Sickle cell disease (SCD) results from a single amino acid substitu- laminin, VWF). SS-RBC interactions with the vascular endothelium tion in the gene encoding the -globin subunit. Polymerization of may lead to the production of oxygen radicals by the endothelial cell deoxygenated sickle hemoglobin leads to decreased deformability and oxidant-dependent activation of the transcription factor NF- B. Through a complex interplay of adhesive NF- B up-regulates the transcription of various genes, including events among blood cells, these altered erythrocytes can obstruct the adhesion molecules such as E-selectin, VCAM-1, and ICAM-1 on vasculature, producing episodes of pain, hemolytic anemia, organ the surface of the endothelium. Circulating endothelial cells charac- injury, and early mortality. Although the molecular basis of SCD is terized by an activated phenotype (expression of VCAM-1 and well characterized, the complex mechanisms underlying vaso- E-selectin) and increased levels of plasma sVCAM-1 have also been reported and are reflective of continuous endothelial activation. Early studies using in vitro adhesion assays or a rat mesocecum ex vivo perfusion Both endothelial selectins, P-selectin and E-selectin, have been suggested to participate in VOC. Random precapillary obstruction by a small (also called ICAM-4) is an RBC adhesion receptor that can be number of dense SS-RBCs also contributes to VOC. A new model has been proposed in which the process is viewed as Propranolol (a -adrenergic receptor antagonist) and recombinant multistep and multicellular cascade driven by inflammatory stimuli LW infusions were shown to inhibit VOC, supporting the events and the adherence of leukocytes. Table 1 provides a summary of the noted in patients who report a painful crisis precipitated by emotional stress or physical exertion. SCD mice indeed exhibit a more can undergo autooxidation and precipitate on the inner surface of dramatic VOC phenotype when the experiment is carried out at the RBC membrane, causing membrane damage via iron-mediated nighttime. Other adhesive interactions proinflammatory environment that is exacerbated during episodes of require a soluble bridge molecule (eg, thrombospondin, VWF). Circulating leukocytes and platelets also have an activated SS-RBC adhesion molecules (eg, BCAM/LU, 4 1) have also been phenotype. Ischemia-reperfusion injury, release of free hemoglobin This article was selected by the Blood and Hematology 2013 American Society of Hematology Education Program editors for concurrent submission to Blood and Hematology 2013. This article is reprinted with permission from Blood. Evolving paradigm of sickle cell VOC Year Scientific observation Contribution 1910 James Herrick: Description of the first patient with sickle-shaped Original description RBCs on peripheral smear 1930 Shriver and Waugh: Venous circulation in a patient is enriched in A disease of the RBC sickle-shaped cells that regain normal shape upon reoxygenation 1949 Linus Pauling demonstrates that the disease originates from a A molecular disease of hemoglobin mutated hemoglobin molecule 1974 Hofrichter and Eaton: “delay time” for the initiation of rapid phase VOC is dependent on deoxy HbS concentration and transit time of deoxy-HbS polymerization of the RBCs 1979, 1980 Hebbel and Hoover: Increased propensity of SS-RBCs to Widened the scope of scientific studies outside the RBC.

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Changing the TE therapy is not useful in such cases and just expends valuable time tamsulosin 0.4 mg with mastercard. Antiretroviral therapy should be initiated as soon as possible generic 0.2mg tamsulosin with amex. Drugs with the potential of allergic reactions (abacavir discount 0.2mg tamsulosin with amex, when HLA testing is not possible, NNRTIs, fosamprenavir, darunavir) should be avoided. A control MRI is recommended for stable patients after two weeks at the earliest. Significant resolution of lesions is often only visible after four weeks. In cases of increased intracranial pressure or extensive edema, steroids are given (8 mg dexam- ethasone q 6–8 h). Steroids should be given for a limited time, as there is a signifi- cantly increased risk of aspergillosis. All treatment combinations require initial monitoring of blood count, glucose, transaminases and renal parameters at least three times weekly. Maintenance therapy with the reduced dose should only be initiated if lesions have shrunk by at least 75%. Prophylaxis Exposure prophylaxis: IgG-negative patients can protect themselves from primary infection by not eating raw or undercooked meat (lamb, beef, pork, game, etc). It has not been proven, despite widespread opinion, that infection occurs by mere contact with cats, the definitive hosts of Toxoplasma gondii. To date, the only study that has seriously investigated this conjecture could not prove endangerment as a result of proximity to cats (Wallace 1993). Nevertheless, stricter measures of hygiene should be followed (e. Primary prophylaxis: All IgG-positive patients with less than 100 CD4 T cells/µl require primary prophylaxis. In cases of co-trimoxazole allergy, desensitization may be considered (see PCP). An alternative is dapsone plus pyrimethamine or high-dose dapsone. Primary prophylaxes can be discontinued safely if CD4 T cells are above 200/µl for at least three months. Maintenance therapy/secondary prophylaxis: In the absence of immune recon- stitution, patients with cerebral toxoplasmosis require lifelong maintenance therapy or secondary prophylaxis, as there are otherwise recurrences in nearly all cases. It usually consists of half the dose of the acute therapy (Podzamczer 2000). Clindamycin is presumably less suitable as it cannot cross the blood-brain barrier (Luft 2000). Co- trimoxazole seems to be not as effective for secondary prophylaxis, but should be considered because it is simple. However, it definitely requires higher doses than those used to treat PCP (Ribera 1999, Duval 2004). With immune reconstitution (at least six months above 200 CD4 T cells), secondary prophylaxis can probably be stopped (Benson 2004, Miro 2006). When possible, an updated MRI scan should be available beforehand. If there is enhancement, then it may mean that lesions have become active even after years – and there is a risk of a recurrence. A recurrence even after five years has been observed, despite CD4 T cells being around 200/µl. As a result, there have been increasing efforts in recent years to improve the characterization of this specific immune response via ELISPOT. Studies have shown that the Toxoplasma-specific immune response remains poor in approx- imately 10–30% of patients on ART, despite good CD4 T cell counts (Fournier 2001, Miro 2003, Furco 2008). In the future, ELISPOT testing may allow identification of patients who are at risk of recurrence despite good CD4 counts who should continue with secondary prophylaxis. Incidence and risk factors for toxoplasmic encephalitis in HIV-infected patients before and during the HAART era. Treating opportunistic infections among HIV-exposed and infected chil- dren: recommendations from CDC, the NIH, and the IDSA. Cotrimoxazole for treatment of cerebral toxoplasmosis: an observa- tional cohort study during 1994-2006. Bosch-Driessen LH, Verbraak FD, Suttorp-Schulten MS. A prospective, randomized trial of pyrimethamine and azithromycin vs pyrimethamine and sulfadiazine for the treatment of ocular toxoplasmosis. Epidemiologic characteristics of cerebral toxoplasmosis in 399 HIV-infected patients followed between 1983 and 1994. Molecular diagnostics in clinical parasitology and mycology: limits of the current polymerase chain reaction (PCR) assays and interest of the real-time PCR assays. Meta-analysis of prophylactic treatments against PCP and toxo- plasma encephalitis in HIV-infected patients. J Acquir Immune Defic Syndr Hum Retrovirol 1997,15:104-14. Canessa A, Del Bono V, De Leo P, Piersantelli N, Terragna A. Cotrimoxazole therapy of toxoplasma gondii encephali- tis in AIDS patients. Opportunistic Infections (OIs) 345 Chirgwin K, Hafner R, Leport C, et al. Randomized phase II trial of atovaquone with pyrimethamine or sulfadi- azine for treatment of toxoplasmic encephalitis in patients with AIDS: ACTG 237/ANRS 039 Study. Treatment of toxoplasmic encephalitis in patients with AIDS. A randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. Management of toxoplasmic encephalitis in HIV-infected adults (with an emphasis on resource-poor settings). Predictive value of Toxoplasma gondii antibody titres on the occurrence of toxoplasmic encephalitis in HIV-infected patients. Maintenance therapy with cotrimoxazole for toxoplasmic encephalitis in the era of highly active antiretroviral therapy. Immune recovery under highly active antiretroviral therapy is associated with restoration of lymphocyte proliferation and interferon- production in the presence of toxoplasma gondii antigens. Restoration of Toxoplasma gondii-specific immune responses in patients with AIDS starting HAART.