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The most signiﬁcant adverse events Europe for the treatment of newly diagnosed MM patients who are (AEs) observed with this combination were neutropenia (36% grade not candidates for HDT-ASCT and who cannot receive thalidomide 4) buy xenical 60 mg with amex, thrombocytopenia (13% grade 4) discount 120 mg xenical fast delivery, and infections (15% grade 4) buy generic xenical pills. The rationale for the The median PFS did not differ signiﬁcantly between the 2 induction approval was a randomized trial in which BP (bendamustine plus regimens and the beneﬁt of this combination mainly accrued from prednisone) proved to be superior to MP with respect to CR rate maintenance therapy. The results of the primary comparison of this (32% vs 13%, P. Bendamustine plus compared the proteasome inhibitor bortezomib plus MP (VMP) prednisone in combination with bortezomib is currently being with MP. VMP was superior to MP in ORR (71% vs 35%, evaluated in several pilot clinical trials. Alkylating agents in combination with second-generation protea- From the ﬁrst analysis with 16. However, the addition of bortezomib good partial response [VGPR] or better of 42%) with an acceptable to the MP regimen also increased the rate of grade 3 or 4 AEs toxicity proﬁle and no grade 3-4 PN, providing the rationale for a associated with treatment, particularly PN (14%) and gastrointestinal randomized trial comparing CMP with VMP. Antiviral prophylaxis is required to prevent the reactivation carﬁlzomib plus cyclophosphamide and low-dose dexamethasone is of herpes virus. On the basis of these data, VMP has been recognized as being evaluated in a series of 53 newly diagnosed elderly MM a new standard of care for elderly untreated MM patients. No grade 3-4 PN was reported and tolerability was Despite the favorable clinical beneﬁts of VMP, AEs are an good. Ixazomib (MLN9708), an oral second-generation proteasome important concern. The Spanish group investigated the VMP inhibitor, plus MP in a biweekly or weekly scheme is also currently regimen but in a reduced-intensity bortezomib schedule based on undergoing a phase 1/2 clinical trial to evaluate the efﬁcacy and the weekly administration of bortezomib; patients received the ﬁrst safety of this combination (Table 1). After 6 cycles, the incidence of Non-alkylating-agent–containing induction regimens grade 3 or 4 PN dropped to 7%, with an ORR of 80% (20% CR)18 Thalidomide and dexamethasone (TD) was approved in the United and, after maintenance therapy with VT or VP (see below), the PFS States in newly diagnosed MM patients on the basis of results from and OS were 37 and 60 months, respectively. TD was compared with MP in a cohort of obtained similar results in a randomized trial comparing VMP (9 elderly MM patients22; although it induced higher response rates cycles) with VMPT, followed by maintenance therapy with VT. The evident in patients more than 75 years of age (20 vs 41 months). The addition of the 4 drugs disease-related deaths observed in the TD group during the ﬁrst to VMP (VMPT) plus maintenance with VT resulted in higher ORR year. Therefore, TD in elderly patients is not a good option, unless and CR rates than obtained with VMP (89% vs 81% ORR and 38% patients receive reduced doses of both drugs. The Spanish myeloma group evaluated the combination of thalido- mide with a daily dose of 100 mg plus prednisone and bortezomib Cyclophosphamide, another alkylating agent with proven efﬁcacy (VTP) in the same reduced-intensity bortezomib schedule men- in MM, has been evaluated in the Medical Research Council (MRC) tioned in the previous section compared with VMP as induction Myeloma IX study, a randomized trial in elderly patients that therapy. After 6 cycles, the ORR was 81%, including 28% CR with compared the efﬁcacy and safety of a regimen of cyclophospha- 9% grade 3 or 4 PN. CTDa was associated with higher rates of thromboembolic Group (SWOG) trial in newly diagnosed MM patients, including 490 American Society of Hematology those more than 65 years of age. Simultaneously considering associated with an improved ORR and 12-month PFS but no OS efﬁcacy, toxic effects, and costs, we concluded that melphalan is beneﬁt, probably due to the crossover design of this study. The dose probably preferable to thalidomide for bortezomib-based combina- of dexamethasone used in combination with lenalidomide is impor- tion therapy in the setting of elderly MM patients. Nevertheless, this tant with respect to the tolerability of the regimen, especially in conclusion cannot be extrapolated to lenalidomide, which has a elderly patients. A randomized, open-label ECOG study compared better safety proﬁle and greater efﬁcacy than thalidomide. Young patients were versus MPT up to 12 cycles, with PFS as the primary end point. This able to choose whether to proceed to ASCT after 4 treatment cycles. However, a survival beneﬁt was observed with the enough to provide it over a shorter period. The efﬁcacy and safety results all patients with MM eventually relapse due to the persistence of obtained with Len/dex have led to this combination becoming a new residual disease. Recent data indicate that consolidation or long- standard of care for newly diagnosed MM patients, at least in the term treatment can sustain remission by keeping the tumor under United States, and also a new backbone for combination with control. In elderly patients, the efﬁcacy of long-term treatment proteasome inhibitors and other novel agents. Carﬁlzomib has been combined with Len/dex (CRd) in a pilot phase 1/2 trial in newly diagnosed MM patients, including young and Thalidomide maintenance elderly patients. All reported an improvement in TTP and PFS (or event-free survival), but only the Dutch-Belgian study9 found a signiﬁcant improvement patients remained free of progression and alive at the median follow-up of 1 year (Table 1). These results support a phase 3 study in OS for MPT-T compared with MP alone (40 vs 31 months, of CRd versus Rd in all age groups. However, the incidence of PN of grade 2 or above during compared with Len/dex plus Ixazomib (MLN9708) in a randomized maintenance was very high (54%). The MRC Myeloma IX trial of trial in non-transplantation-eligible MM patients, supported by attenuated CTD versus MP also involved thalidomide maintenance randomization. Thalidomide maintenance was not well tolerated and patients remained on treatment for a median of only 7 months. Elotuzumab, an anti-CS1 monoclonal antibody, has proved to be Considered together, these studies indicate that thalidomide mainte- safe and effective in combination with Len/dex in relapsed and nance is not an attractive option in elderly patients due to its poor refractory MM patients, and a randomized trial comparing Len/dex tolerability. Bortezomib maintenance The aforementioned Spanish study comparing VMP and VTP as Is there any evidence that elderly patients need alkylating induction therapies included a maintenance phase with either VT or agents? Maintenance therapy improved the overall CR The Spanish group compared VMP with VTP in a randomized trial rate from 24% to 42%, with slightly higher values for VT than for (see above) to identify the best partner for bortezomib, an alkylating VP (46% vs 39%; P NS). PFS was 39 months in the VT group agent or an immunomodulatory drug. VTP resulted in slightly compared with 32 months in the VP arm (P NS), with a trend greater efﬁcacy (CR rate of 28% for VTP vs 20% for VMP), but also toward better OS for VT (69% vs 50% at 5 years). The previously mentioned Italian trial that bortezomib-based induction regimens, 2 non-alkylating-agent– compared VMPT as an induction therapy with VMP also included a based combinations, bortezomib with dexamethasone (VD) and maintenance phase with VT in the former arm. Complete response bortezomib with thalidomide and dexamethasone (VTD), and one rates after maintenance were increased to 38% in the VMPT-VT containing melphalan (VMP). The median PFS was signiﬁcantly longer with VMPT-VT higher for VTD (80% vs 73% for VD and 69% for VMP),26 but as in than with VMP (37 vs 27 months; HR 0. No signiﬁcant differences have so far been reported in terms hematological AEs were reported by 3% of patients and grade 3 or 4 Hematology 2013 491 Table 2. Role of novel agent-based combinations in patients with a high-risk cytogenetic abnormality (CA) Number of patients with Outcome of high-risk Study Regimen high-risk CA CA patients MPT/MP No data available No data available Morgan et al28 CTDa/MP 96/90 CTDa does not overcome the effect of high-risk CA and is not signiﬁcantly better than MP in high-risk CA San Miguel et al17 VMP/MP 46 Absence of OS beneﬁt: OS 44. There are several studies currently was not improved in patients with high-risk cytogenetics and OS under way that are investigating different bortezomib-based combi- was signiﬁcantly shorter in the high-risk subset (P. In the trial in which Len-Dex was compared with Len-dex, patients with high-risk cytogenetic abnormalities were less likely to attain VGPR (46% for standard-risk and 30% for high-risk patients). Lenalidomide maintenance Moreover, high-risk patients showed shorter 2-year OS (91% for The efﬁcacy and safety of continuous treatment with lenalidomide 32 standard-risk and 76% for high-risk patients).
Most efficacy studies use strict eligibility criteria that may exclude patients based on their age order genuine xenical, sex order xenical 120mg with visa, adherence to treatment safe 120mg xenical, or severity of illness. For many drug classes, including the antipsychotics, unstable or severely impaired patients are often excluded from trials. In addition, efficacy studies frequently exclude patients who have comorbid diseases, meaning diseases other than the one under study. Efficacy studies may also use dosing regimens and follow-up protocols that may be impractical in typical practice settings. And these studies often restrict options that are of value in actual practice, such as combination therapies or switching to other drugs. Efficacy studies also often examine the short-term effects of drugs that in practice are used for much longer periods of time. Finally, efficacy studies tend to assess effects by using objective measures that do not capture all of the benefits and harms of a drug or do not reflect the outcomes that are most important to patients and their families. Systematic reviews highlight studies that reflect actual clinical effectiveness in unselected patients and community practice settings. Effectiveness studies conducted in primary care or office-based settings use less stringent eligibility criteria, more often assess health outcomes, and have longer follow-up periods than most efficacy studies. The results of effectiveness studies are more applicable to the “average” patient than results from the highly selected populations in efficacy studies. Examples of effectiveness outcomes include quality of life, frequency or duration of hospitalizations, social function, and the ability to work. These outcomes are more important to patients, family, and care providers than surrogate or intermediate measures, such as scores based on psychometric scales. For example, a study might use very narrow inclusion criteria like an efficacy study, but, like an effectiveness study, might examine flexible dosing regimens, have a long follow-up period, and measure quality of life and functional outcomes. For this report we sought evidence about outcomes that are important to patients and would normally be considered appropriate for an effectiveness study. However, many of the studies that reported these outcomes were short-term and used strict inclusion criteria to select eligible patients. For these reasons, it was neither possible nor desirable to exclude evidence based on these characteristics. Labeling each study as either an efficacy or an effectiveness study, while convenient, is of limited value; it is more useful to consider whether the patient Antiepileptic drugs Page 9 of 117 Final Report Update 2 Drug Effectiveness Review Project population, interventions, time frame, and outcomes are relevant to one’s practice or to a particular patient. Studies across the continuum from efficacy to effectiveness can be useful in comparing the clinical value of different drugs. Effectiveness studies are more applicable to practice, but efficacy studies are a useful scientific standard for determining whether characteristics of different drugs are related to their effects on disease. Systematic reviews thoroughly cover the efficacy data in order to ensure that decision-makers can assess the scope, quality, and relevance of the available data. This thoroughness is not intended to obscure the fact that efficacy data, no matter how much of it there is, may have limited applicability to practice. Clinicians can judge the relevance of the study results to their practice and should note where there are gaps in the available scientific information. Unfortunately, for many drugs there exist few or no effectiveness studies and many efficacy studies. Yet clinicians must decide on treatment for many patients who would not have been included in controlled trials and for whom the effectiveness and tolerability of the different drugs are uncertain. Systematic reviews indicate whether or not there exists evidence that drugs differ in their effects in various subgroups of patients, but they do not attempt to set a standard for how results of controlled trials should be applied to patients who would not have been eligible for them. With or without an evidence report, these decisions must be informed by clinical judgment. In the context of development of recommendations for clinical practice, systematic reviews are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of an intervention are based on strong evidence from clinical studies. Judgment, reasoning, and applying one’s values under conditions of uncertainty must also play a role in decision making. Users of an evidence report must also keep in mind that not proven does not mean proven not; that is, if the evidence supporting an assertion is insufficient, it does not mean the assertion is untrue. The quality of the evidence on effectiveness is a key component, but not the only component, in making decisions about clinical policy. Additional criteria include acceptability to physicians and patients, potential for unrecognized harm, applicability of the evidence to practice, and consideration of equity and justice. Scope and Key Questions The main goal of this report was to compare the effectiveness and adverse event profiles of antiepileptic drugs in the treatment of bipolar disorder, migraine, chronic pain, and fibromyalgia. The Oregon Evidence-based Practice Center wrote preliminary Key Questions, identifying the populations, interventions, outcomes of interest, and, based on these, the eligibility criteria for studies. A draft of these questions and inclusion and exclusion criteria were posted on the Drug Effectiveness Review Project website for public comment. The draft was reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review Project, taking into consideration comments received from the public. The participating organizations of Drug Effectiveness Review Project are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to clinicians and patients. The participating organizations approved the following Key Questions to guide the review for this updated report: Antiepileptic drugs Page 10 of 117 Final Report Update 2 Drug Effectiveness Review Project 1. For adult outpatients with bipolar disorder, fibromyalgia, migraine, or chronic pain, do antiepileptic drugs differ in effectiveness? For adult outpatients with bipolar disorder, fibromyalgia, migraine, or chronic pain, do antiepileptic drugs differ in safety or adverse events? Among these patient populations, are there subgroups of patients based on demographics (age, racial groups, and gender), other medications, or comorbidities for which one antiepileptic drug is more effective or associated with fewer adverse events? METHODS Inclusion Criteria Populations Adult outpatients with one of the following diseases or conditions: • Bipolar disorder (any) diagnosed according to Diagnostic and Statistical Manual of 1 Mental Disorders criteria. Other types of headache (such as tension headache) were excluded. Drugs Only oral formulations of the drugs listed in Table 1 (above) were included. These are carbamazepine, divalproex sodium, ethotoin (not available in Canada), gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, pregabalin, tiagabine (not available in Canada), topiramate, valproic acid, zonisamide (not available in Canada). In this report we referred to divalproex sodium and valproic acid collectively as “valproate,” except in the evaluation of adverse events and where extended-release formulations were used. Effectiveness outcomes Bipolar Disorder • Danger to self (suicide attempts and completions, suicidal ideation) • Functional capacity (quality of life, work productivity) • Hospitalization rates or duration 1 We excluded trials that included heterogeneous patient populations unless data were presented separately for patients with bipolar disorder. Antiepileptic drugs Page 11 of 117 Final Report Update 2 Drug Effectiveness Review Project • Response (rate, degree, speed of onset, duration). Remission reported as defined by studies’ protocols. A serious harm is one that results in death or long-term health effects. An increase in rates of suicide or suicidal ideation was considered here as a serious harm.
The mapping of amino acidsubstitutions to ﬁtness may be rather complex in this case generic xenical 60 mg amex. MAbs injected in vivo reduced neurovirulence and selected escape mutants that were isolated from brain tissue discount 120mg xenical mastercard. MAb escape mutants selected in vitro produced altered and variable patterns of neurovirulence when injected into the host order xenical 120mg with amex. The antibody epitopes appeared to be on the sur- face hemagglutinin protein. Amino acid substitutions in measles hem- agglutinin appear to alter both antigenicity and neurovirulence. Measles virus also appears to change its binding aﬃnity for diﬀerent cellularreceptors during adaptation to cell culture (Nielsen et al. The amino acid changes associated with receptor aﬃnity occur in the surface hemagglutinin protein. Further experimental evolution studies 226 CHAPTER 13 of this system will provide more information on how viruses modulate receptor binding and cell tropism during adaptation to diﬀerent kinds of host cells. Thelife cycle of arthropod-borne viruses (arboviruses) typically al- ternates between vertebrate hosts and blood-feeding arthropod vectors. Arboviruses have RNAgenomes and therefore the potential for high genetic diversity. However, many stud- ies have reported a high degree of antigenic conservation and slow rates of molecular evolution (reviewed byCooper and Scott 2001). Cooper and Scott (2001) used experimental evolution to study how alternating hosts potentially constrain adaptive change. They passaged viral lineages in cell culture through either mosquito cells only, avian cells only, or alternating between mosquito and avian cells. They then measured various characteristics of infectivity and growth on insect, avian, or mammalian host cells. The diﬀerent passage histories produced signiﬁcant diﬀerences in in- fectivity and growth between the lineages. The lineages that alternated between the two host types expressedintermediatephenotypes rela- tive to those lineages passaged only in one cell type. Alternation ap- parently favored compromise between changing selective regimes. Fur- ther experimental evolutionstudiesinvivo may provide more insight into how multiple selective pressuresconstraintherateofevolutionary change. They particularly emphasize that high mutation rates and large population sizes of RNA viruses aﬀect evolu- tionary potential by maintaining a large diversity of variant genotypes. Those variants provide material for a rapid response to new or chang- ing selective pressures. The consequences of varying population size on the rate of adaptation have been analyzed under controlled experi- mental conditions. Afewbacterial studies analyzed escape mutants in response to con- trolledantibody pressure (e. Other scattered studies of experimental evolution have been done on nonviral pathogens, but none approaches thescope of the viral experiments. The ﬁrst infection of a host initially stim- ulates the naive IgM antibody repertoire, which has relatively low aﬃnity and broad speciﬁcity. The mature, high-aﬃnity antibody response de- velops by various processes, including competition between antibodies based on binding aﬃnity. Apathogengains if its most highly antigenic sites have low rates of neutralization or high rates of antigenic change. Highly antigenic de- coy sites can draw antibody pressure away from sites more sensitive to neutralization or more strongly constrained against change because of essential function. Theimmunodominant sites draw the maturing repertoire away from the binding pocket. To what extent have immunodominant sites evolved to draw antibody pressure away from more sensitive sites? This is a diﬃcult question, because immunodominant sites may happen to be away from receptor binding pockets or other functional sites for a variety of reasons. No experimental systems developed so far provide a clear way to ad- dress this problem. One needs experimental control of initial antibody pressure and a feedback mechanism that enhances antibody pressure on epitopes with stronger antibody binding. Feedback favors epitopes with relatively lower rates of neutralization to evolve relatively stronger antibody binding. Such decoy sites might additionally be favored if they could tolerate a broad array of amino acid escape mutants. This sort of experimental evolution would provide clues about the forces that have shaped immunodominance. Mathematical models of immunodominance such as those developed by Nowak and May (2000) would aid in designing experiments and clarifying evolutionary process. Experimental evolution studies of avian and human H3 showed that a single amino acid change at position 226 of HA1 determines avian α(2, 3)-tropic or human α(2, 6)-tropic binding forsialicacid(Rogers et al. An open question concerns the 228 CHAPTER 13 role of the genetic background in conditioning the eﬀects of a particular substitution. These experiments could be repeated, starting with geno- types that have diﬀerent amino acid substitutions at varying distances from site 226. Several escape mutants have been generated by application of MAbs. It would be interesting to know the pleiotropic consequences of antibody escape mutants for other components of ﬁt- ness, such as binding to host receptors, growth rate, and virulence. These ﬁtness components depend on various kinetic processes within the host. A study that matched amino acid substitutions to kinetic pro- cesses would illuminate the mechanistic basis of ﬁtness and provide insight into the microevolutionary patterns of change in proteins. Most work on inﬂuenza has emphasized human isolates of inﬂuenza A. Those isolates can be grown in vivoinmiceandother hosts, but the change in hosts compromises interpretations of kinetics and ﬁtness. It would be interesting to develop an experimental model of inﬂuenza A in aquatic birds,theancestralhostforthisvirus. This would allow study of natural variation in avian isolates coupled with in vivo experimental analysis of ﬁtness components. Inﬂuenza binding aﬃnity for host receptors appearstobebalanced at an intermediate level. Some substitutions raise aﬃnity, and other substitutions lower aﬃnity. Cell culture studies of FMDV and other pathogens show that binding aﬃnity and receptor tropism evolve readily in experimental settings.
Since synergy between HIV and JCV has been demonstrated in vitro cheap xenical 120mg fast delivery, maximal HIV suppression should be the goal xenical 60mg on-line. Although progression of disease has been described with sufficient antiretroviral therapy buy xenical paypal, ART often remains the only real hope for patients. There is also some evidence that intracerebral penetrating antiretrovi- ral agents such as AZT, FTC, abacavir, nevirapine and lopinavir are more efficient regarding survival of patients with PML (Gasnault 2008). There is one small pilot trial suggesting that an intensive 5-drug ART may improve survival of patients with PML (Gasnault 2011). Treatment/prophylaxis of PML Acute therapy Treatment of choice ART The most important goal is maximal HIV suppression and immune reconstitution! Use intracerebral penetrating agents such as AZT, FTC, abacavir, nevirapine and lopinavir Experimental Only within clinical trials (risperidone? HAART significantly improves the prognosis of patients with HIV-asso- ciated progressive multifocal leukoencephalopathy. Epidemiology and prognosis of AIDS-associated progressive multi- focal leukoencephalopathy in the HAART era. Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal. Clin Infect Dis 2009, 48:1138-51 Berenguer J, Miralles P, Arrizabalaga J, et al. Clinical course and prognostic factors of progressive multifocal leukoen- cephalopathy in patients treated with highly active antiretroviral therapy. Predictive factors for prolonged survival in AIDS-associated progressive multifocal leukoencephalopathy. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Prognostic significance of JC virus DNA levels in cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy. Identification and characterization of mefloquine efficacy against JC virus in vitro. Progressive multifocal leukoencephalopathy following rituximab therapy in HIV negative patients: a report of 57 cases from the Research on Adverse Drug Event and Reports (RADAR) project. Human Herpesvirus 6 Infection of the Central Nervous System. Mirtazapine use in human immunodeficiency virus-infected patients with progressive multifocal leukoencephalopathy. HAART improves prognosis in HIV-associated progressive multi- focal leukoen-cephalopathy. A study of mefloquine treatment for progressive multifocal leukoen- cephalopathy: results and exploration of predictors of PML outcomes. J Neurovirol 2013 [Epub ahead of print] De Luca A, Ammassari A, Pezzotti P, et al. Cidofovir in addition to antiretroviral treatment is not effective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis. Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? Quantification of JC virus DNA in the cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy – a longitudinal study. The human polyomavirus, JCV, uses serotonin receptors to infect cells. Incidence, clinical presentation, and outcome of progressive multifo- cal leukoencephalopathy in HIV-infected patients during the highly active antiretroviral therapy era: a nation- wide cohort study. Influence of HAART on the clinical course of HIV-1-infected patients with pro- gressive multifocal leukoencephalopathy: results of an observational multicenter study. Garcia De Viedma D, Diaz Infantes M, Miralles P, et al. JC virus load in progressive multifocal leukoencephalopathy: analysis of the correlation between the viral burden in cerebrospinal fluid, patient survival, and the volume of neurological lesions. Intracerebral penetrating ART are more efficient on survival of HIV+ patients with progressive multifocal leucoencephalopathy (ANRS CO4 – FHDH). Prolonged survival without neurological improvement in patients with AIDS-related PML on potent combined antiretroviral therapy. Improved survival of HIV-1-infected patients with progressive multifocal leukoencephalopathy receiving early 5-drug combination antiretroviral therapy. Failure of cytarabine in progressive multifocal leukoencephalopathy associ- ated with HIV infection. Progressive multifocal leucoencephalopathy with unusual inflam- matory response during antiretroviral treatment. Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study. JC virus-specific immune responses in human immunodeficiency virus type 1 patients with progressive multifocal leukoencephalopathy. J Virol 2009, 83:4404-11 Langford TD, Letendre SL, Marcotte TD, et al. Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy. Major EO, Amemiya K, Tornatore CS, Houff SA, Berger JR. Pathogenesis and molecular biology of progressive mul- tifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies. Marzocchetti A, Sanguinetti M, Giambenedetto SD, et al. Characterization of JC virus in cerebrospinal fluid from HIV-1 infected patients with progressive multifocal leukoencephalopathy: insights into viral pathogenesis and disease prognosis. Determinants of survival in progressive multifocal leukoen- cephalopathy. Clinical manifestations and treatment with steroids. Mirtazapine in progressive multifocal leukoencephalopathy associated with polycythemia vera. Progressive multifocal leukencephalopathy in patients on highly active antiretroviral therapy: survival and risk factors of death. Evaluation of patients treated with natalizumab for progressive mul- tifocal leu-koencephalopathy. Opportunistic Infections (OIs) 381 Bacterial pneumonia Bacterial pneumonia occurs even with a relatively good immune status (>200 CD4 T cells/µl). It is not as closely associated with immunodeficiency. Furthermore, the decrease in incidence since the HAART era has been more moderate than for other opportunistic infections.