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Gliomas and brain lymphomas in HIV-1/AIDS patients: reflections from a 20-year follow up in Mexico and Brazil

  • Johns Hopkins University MCC


Opportunistic infections and invasive primary tumors represent major causes of morbidity and mortality in HIV-1-infected individuals. HIV-1 involvement of the central nervous system (CNS) affects nearly half of seropositive patients, being the primary CNS lymphoma (PCNSL) a hallmark neoplasia of this population. Interestingly, the incidence of other brain tumors (e.g. gliomas) is exceedingly rare in AIDS patients, and their co-morbidity has been limited to case reports. Here, we share our 20-year experience following brain tumors in HIV-1/AIDS patients from major referral hospitals in Mexico and Brazil. Additionally, we provide the most updated compilation of reported glioma cases in AIDS patients, with a thorough epidemiological analysis. Furthermore, we discuss HIV-1-driven mechanisms that would theoretically increase malignant transformation of glial cells; while offering newly reported explanations as to why protease inhibitors, key components of multi-drug anti-retroviral schemes, may be responsible for such a low co-incidence of gliomas in HIV-1 infected individuals. </p
[Microbiology Research 2011; 3:e11] [page 41]
Gliomas and brain lymphomas
in HIV-1/AIDS patients:
reflections from a 20-year
follow up in Mexico and Brazil
Filiberto Cedeno-Laurent,1,2
J. Roberto Trujillo2,3
1Harvard Medical School, Boston, MA;
2Pan-American Society for
Neurovirology, Washington, DC;
3TruBios Research Institute, Johns
Hopkins University, MCC, Rockville,
Maryland, USA
Opportunistic infections and invasive pri-
mary tumors represent major causes of mor-
bidity and mortality in HIV-1-infected individu-
als. HIV-1 involvement of the central nervous
system (CNS) affects nearly half of seroposi-
tive patients, being the primary CNS lym-
phoma (PCNSL) a hallmark neoplasia of this
population. Interestingly, the incidence of
other brain tumors (e.g. gliomas) is exceed-
ingly rare in AIDS patients, and their co-mor-
bidity has been limited to case reports. Here,
we share our 20-year experience following
brain tumors in HIV-1/AIDS patients from
major referral hospitals in Mexico and Brazil.
Additionally, we provide the most updated com-
pilation of reported glioma cases in AIDS
patients, with a thorough epidemiological
analysis. Furthermore, we discuss HIV-1-driv-
en mechanisms that would theoretically
increase malignant transformation of glial
cells; while offering newly reported explana-
tions as to why protease inhibitors, key compo-
nents of multi-drug anti-retroviral schemes,
may be responsible for such a low co-incidence
of gliomas in HIV-1 infected individuals.
Neurocognitive impairment remains a
major burden for HIV-1/AIDS patients. Even
when highly active antiretroviral therapy
(HAART) has become widely available, neuro-
logical manifestations affect up to 50% of
seropositive individuals.1,2 The spectrum of
HIV-1-associated neurological disorders is
wide, and encompasses complications that can
be either primarily related to the retrovirus
itself (e.g. AIDS dementia complex), or sec-
ondary to opportunistic infections, malignant
neoplasms, or the reconstitution of the
immune system.3-5 Over the last 20 years, as
we have followed the AIDS epidemic develop all
over the world, we have noticed clear-cut dif-
ferences in the incidence, prevalence and clin-
ical presentations of neurological complica-
tions reported among industrialized nations to
those reported from developing countries.2,6,7
Such dramatic differences depend on numer-
ous factors that include: the location of the
reporting institution, availability to HAART,
diagnostic tools, treatment guidelines, and the
endemic microbiological repertoire.4,8-11
As HIV-1 infection progresses, defective
immunosurveillance mechanisms favor
uncontrolled proliferation of malignant cells.
Importantly, Epstein Barr virus, the causative
agent of infectious mononucleosis, induces
aberrant genotypical changes and malignant
transformation on infected B cells within the
CNS.12 Inherent to the immunocompromise
experienced in the context of HIV-1 infection,
these malignant cells undergo uncontrolled
clonal expansion forming extranodal foci of
lymphoproliferative cells that may give rise to
primary CNS lymphomas (PCNSL).
Importantly, this neoplasm is exclusively
observed in severely immunocompromised
populations, and its presence was found in
~5% of HIV-1 seropositive patients before the
introduction of HAART (Figure 1).13
Conversely, primary intracranial tumors
derived from other cell lineages are rarely
developed in HIV-1/AIDS patients, with a total
number of 55 reported cases, ever since the
epidemic started in the early 1980’s.2,6,14-36
Gliomas, the most common type of primary
brain neoplasm reported in otherwise healthy
individuals,33 arise from malignant transfor-
mation of neuroectodermal-derived supporting
cells. The pathogenesis of these tumors has
been associated with mutations in the p53
tumor suppressor gene,37 or the p16/RB/E2F
pathway.38 While the annual incidence of
gliomas in the general population is reported
to be around 3.85 cases per 100,000 individu-
als,39 malignant gliomas, including glioblas-
toma multiforme (the most common type of
glioma), do not appear to be in the list of dif-
ferential diagnoses of an occupying brain
lesion in HIV-1/AIDS patients.
Such a rare coincidence obliged us to per-
form a systematic retrospective review and
careful analyses of the reported brain gliomas
in HIV-1 seropositive individuals, comparing
populations from industrialized nations with
two Latin American countries with universal
access to HAART, Mexico and Brazil.
In addition, we discuss relevant evidence
that would theoretically support an enhanced
incidence of gliomas in HIV-1/AIDS patients,
while offering alternative perspectives based
on recent publications, which may offer
insights into the factors promoting a protective
activity for the development of gliomas in
seropositive patients under HAART.
NeuroAIDS in Mexico, a retrospec-
tive view of primary central nerv-
ous system lymphoma and glioma
cases reported in major referral
health institutions
A few years after the first AIDS cases were
reported in the early 1980s, HIV-1 spread south
of the US border. Infectious-disease special-
ists experienced major challenges, as the array
of clinical manifestations exhibited by HIV-
1/AIDS patients in Latin America differed from
those observed in US-based health institu-
tions. Importantly, we performed one of the
first studies depicting such discrepancies.2In
that report, a broad comparison of HIV-1-relat-
ed neurological manifestations among
American and Mexican seropositive patients
was depicted in a cross-sectional and retro-
spective study that included 500 cases from
Houston, Texas, and 120 cases from a cohort in
Mexico City. Clinical reports, laboratory and
imaging data of HIV-1 patients experiencing
neurological manifestations concluded that
the prevalence of PCNSL was dramatically
higher in the US population than it was in
Mexico (8.4% vs. 2.5%), while opportunistic
infections such as intracranial tuberculomas
were observed exclusively in the Mexican
cohort.2Of note, no gliomas were found in the
Mexican population, while 2 cases of gliomas
were reported in the American cohort2
(Figures 2-3).
Years later, another retrospective analysis of
AIDS patients evaluated at the National
Institute of Neurological Diseases in Mexico
City during a 9-year time frame (1990-1998),
found a PCNSL prevalence of 1.3% (Figure 1),
with an identical prevalence for gliomas (1.3%,
2/149).34 Notably, a case of glioblastoma multi-
forme and an oligodendroglioma were reported
in this Mexican study (Figure 4). More recent-
ly, a large retrospective study suggested a sig-
nificant reduction in the prevalence of PCNSL
Microbiology Research 2011; volume 3:e11
Correspondence: J. Roberto Trujillo, Pan-
American Society for Neurovirology, Washington,
DC, USA. Tel: +1.240.753.4007.
Key words: Lymphomas, gliomas, HIV-1, AIDS.
Received for publication: 4 July 2011.
Revision received: 29 July 2011.
Accepted for publication: 29 July 2011.
This work is licensed under a Creative Commons
Attribution NonCommercial 3.0 License (CC BY-
NC 3.0).
©Copyright F. Cedeno-Laurent and J.R. Trujillo, 2011
Licensee PAGEPress, Italy
Microbiology Research 2011; 3:e11
Non-commercial use only
[page 42] [Microbiology Research 2011; 3:e11]
(0.3%) (Figure 1), an effect attributed indi-
rectly to the widespread use of HAART.41 Since
1998, no more glioma cases have ever been
reported in AIDS patients from any health cen-
ter in Mexico (Figure 2). Similarly, we have
also followed up AIDS cases for 15 years in a
major referral institution located in Monterrey,
the third largest city in the Mexico.
Collectively, in over 20 years of AIDS epidemic
only 2 cases of gliomas have ever been report-
ed in Mexico (Figures 2-3). This picture is
similar to other developing nations in Africa
and Asia where the number of reported cases
does not parallel their close surveillance and
thorough experience in neuroAIDS (Figure 3).
Brazil, a different country with a
similar story
According to the United Nations Programme
on HIV/AIDS, Brazil has between 600,000 and
890,000 people living with AIDS.41 Importantly,
this Latin American Country has free and uni-
versal access to HAART, situation that allows
measuring the impact of AIDS treatment in the
prevalence of neurological manifestations,
including primary tumors. During the past 15
years, over 50,000 patients have been admitted
to the infectious-disease service of Instituto
Emilio Ribas in Sao Paulo. A high number of
patients undergo extensive laboratory and
imaging workups for suspected intracranial
masses, being CNS toxoplasmosis, cryptococ-
cosis and progressive multifocal leukoen-
cephalopathy the most common diagnoses.
Moreover, other comprehensive studies per-
formed in Rio de Janeiro have reported fre-
quencies of PCNSL of ~4%.42 In over 20 years
of AIDS epidemic in Brazil, just a single case of
glioma has been reported in HIV-1 seropositive
individuals35 (Figure 2), reproducing a phe-
nomenon observed throughout most of the
developing world (Figure 3).
Gliomas and HIV-1, is highly active
antiretroviral therapy responsible
for their low co-incidence?
While HIV-1-driven defective immunosur-
veillance generally favors tumor growth and
metastasis, cumulative evidence of over 20
years following the AIDS epidemic demon-
strates that HIV-1-infected individuals rarely
develop gliomas.43 Nevertheless, HIV-1 tropism
and infectivity in the brain is not limited to
microglia/macrophages, but has been shown to
also include astrocytes, which represent a
potential reservoir for further productive infec-
tion.44,45 In fact, astrocytes have been reported
to be preferentially infected by virulent HIV-1
T-tropic strains through different interactions
via the V3 loop,46 and undergo enhanced
malignant proliferation in vitro via Nef-medi-
ated mechanisms.47 Furthermore, HIV-1-driv-
en cytokines like TNF-α, and TGF-βmay pro-
mote oligodendrocytic differentiation and pro-
liferation, theoretically favoring tumor devel-
opment.43,48 However, recent evidence
unveiled a direct mechanism responsible for
controlling glioma growth in HIV-1/AIDS
patients.49,50 These independent studies depict
two ways by which protease inhibitors; med-
ications commonly used in combination thera-
py with reverse transcriptase inhibitors to
dampen HIV-1 infectivity, can abrogate glioma
growth. First, Pyrko P, et al., described how
Nelfinavir and Atazanavir induce apoptosis in
gliomas by triggering endoplasmic reticulum
stress.49 Concomi tantly, Pore N, et al.,
described how Nelfinavir and Amprenavir
decreased vascular endothelial growth factor
(VEGF) and hypoxia-inducible factor (HIF)-1
alpha expression, leading to impaired angio-
genesis in glioblastoma multiforme tumors
injected into nude mice.50 Nonetheless, while
these experimental data reproduces in vivo
effects seen in HIV-1/AIDS patients under
HAART, further detailed mechanisms by which
protease inhibitors might prevent glioma
development remain to be elucidated.
Figure 1. HAART
has reduced the
number of PCNSL
cases in AIDS
patients. Graphi cal
representation of
the prevalence of
PCSNL in patients
with HIV-1/AIDS
during 3 decades.
References are
indicated within
Figure 2. Reports
of gliomas in HIV-
1/AIDS patients
follow a Gaussian
distribution dur-
ing the first three
decades of the epi-
demic. Graphical
representation of
the total number of
gliomas reported
in Mexico/Brazil
and the rest of the
world, classified
per decade.
References are
indicated within
Figure 3. Gliomas
patients are more
commonly report-
ed in Western
World. Graphical
representation of
the cumulative
cases of gliomas
reported in AIDS
patients and their
distribution per
continent. Refere -
nces are indicated
within brackets.
Non-commercial use only
[Microbiology Research 2011; 3:e11] [page 43]
While primary CNS lymphomas have been a
major cause of morbidity in HIV-1/AIDS
patients; the incidence of gliomas, the most
prevalent brain tumor in seronegative popula-
tions, has always been negligible. With a
cumulative number of 55 reported gliomas in
AIDS patients ever since the beginning of the
epidemic, we hypothesize that there may be a
protective role of HIV-1 that restrains glioma
growth (Figures 2-4). Importantly, we have
noticed an important trend; glioma cases were
specially reported from Western European
Countries and the US during the period com-
prising the years 1991-2000, where most peo-
ple still did not have full access to HAART
(Figure 4). Interestingly, between the years
2001 and 2010, where HAART became widely
available, only 5 out of 55 total glioma cases
were reported (Figure 2). Furthermore, our
analysis of the reported gliomas according to
their histological classification (Figure 4)
reveals that glioblastoma multiforme is the
most prevalent type of glioma seen in HIV-
1/AIDS patients (19/55), similar to what has
been reported for HIV-1 seronegative popula-
tions. In fact, all other types of gliomas, which
commonly affect seronegative patients, includ-
ing low grade astrocytomas and anaplastic
astrocytomas are minimally represented.
In conclusion, although there is compelling
evidence showing a direct role of protease
inhibitors as mediators of apoptosis and
inhibitors of angiogenesis in gliomas, further
epidemiological and basic science research
needs to be performed in controlled conditions
in order to elucidate if there are other factors
responsible for the protective anti-glioma
effect seen in HIV-1/AIDS patients.
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1 seropositive individuals. Graphical representation of the distribution of gliomas report-
ed in AIDS patients by histological type. References are indicated within brackets.
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Non-commercial use only
... In a 20-year study done in Mexico and Brazil, they showed an ever-decreasing incidence of gliomas in HIV patients (only 2 patients in 20 years). [1,11] This led the researchers to hypothesize that gliomas are becoming exceedingly rare in HIV/AIDS patients. Similarly, reports have been published from the other continents. ...
... Similarly, reports have been published from the other continents. [1] Such studies have not yet been done in Africa: a high HIV prevalence setting. We have done this study in sub-Saharan Africa where the prevalence of HIV is highest in the hope that this helps in elucidating more information. ...
... For the other 11 patients excluded in the subsequent analysis, the diagnosis of glioma was based on imaging studies only. The reasons for lack of biopsy were inoperability in diffuse pontine glioma (4), declined operation (3), demised before operation (2), too ill for operation (1), and lost to follow-up before biopsy (1). ...
Full-text available
Background: Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) is associated with an increased prevalence of some malignancies. However, some observational studies have revealed an ever-decreasing prevalence of HIV in glioma patients. The relationship between HIV and brain gliomas has not been well established. Methods: A cross-sectional study was carried out in sub-Sahara Africa, a high HIV prevalence setting, to determine the prevalence of HIV among all glioma patients over a 2-year period. Results: A markedly reduced prevalence of HIV was found in glioma patients (8.3%) in comparison to the general population (14.3%). The presumably "antiglioma effect" of HIV and/or its treatment resulted in a 42% decrease in glioma occurrence in HIV positive patients compared to HIV negative individuals. Age and sex-adjusted prevalence were also lower among glioma patients with the protective effect observed more in younger patients and female sex. Conclusion: Our results corroborate the protective effect of HIV positivity vis-à -vis gliomas. This "antiglioma effect" could be attributed to either the HIV, its treatment, or both. Future studies focused on this "effect" may help unveil better preventative and possible therapeutic avenues for gliomas.
... Prevalence of PCNSL in AIDS patients was 3600-fold greater than in the general population, reaching 12% in AIDS patients [44]. ART has dramatically reduced these rates, possibly due to the effect of protease inhibitors [45]. Still, the prevalence of brain tumors in PLWH appears to be higher than in general population: in USA; recorded prevalence of PCNSL in HIV-1 infected is 8.4% compared to <3.3% in the general US population [45,46] Also GBM occurs in PLWH (in various stages of HIV-1 infection) at a younger age and at a frequency 5.4-to 45-fold higher than in the general population [47]. ...
... ART has dramatically reduced these rates, possibly due to the effect of protease inhibitors [45]. Still, the prevalence of brain tumors in PLWH appears to be higher than in general population: in USA; recorded prevalence of PCNSL in HIV-1 infected is 8.4% compared to <3.3% in the general US population [45,46] Also GBM occurs in PLWH (in various stages of HIV-1 infection) at a younger age and at a frequency 5.4-to 45-fold higher than in the general population [47]. Furthermore, the median survival rate in patients with GBM for PLWH is shorter than for HIV-1-negative patients receiving same treatment (an average of 8 compared to 14 months, respectively) [48]. ...
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People living with human immunodeficiency virus (HIV-1) are at increased risk of developing cancer, such as Kaposi sarcoma (KS), non-Hodgkin lymphoma (NHL), cervical cancer, and other cancers associated with chronic viral infections. Traditionally, this is linked to HIV-1-induced immune suppression with depletion of CD4+ T-helper cells, exhaustion of lymphopoiesis and lymphocyte dysfunction. However, the long-term successful implementation of antiretroviral therapy (ART) with an early start did not preclude the oncological complications, implying that HIV-1 and its antigens are directly involved in carcinogenesis and may exert their effects on the background of restored immune system even when present at extremely low levels. Experimental data indicate that HIV-1 virions and single viral antigens can enter a wide variety of cells, including epithelial. This review is focused on the effects of five viral proteins: envelope protein gp120, accessory protein negative factor Nef, matrix protein p17, transactivator of transcription Tat and reverse transcriptase RT. Gp120, Nef, p17, Tat, and RT cause oxidative stress, can be released from HIV-1-infected cells and are oncogenic. All five are in a position to affect “innocent” bystander cells, specifically, to cause the propagation of (pre)existing malignant and malignant transformation of normal epithelial cells, giving grounds to the direct carcinogenic effects of HIV-1.
... Additionally, PLWH had a 42% lower occurrence of GBM than HIV-negative individuals [11]. Cedeno-Laurent et al. found a total of 55 reported gliomas in PLWH and AIDS since the beginning of the epidemic in Mexico and Brazil, suggesting that HIV-1 may serve a protective role that restrains glioma growth [55]. In contrast, numerous other studies have reported an increased risk of HGG and GBM in PLWH [9,10,12]. ...
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Introduction As lifespans for persons living with HIV (PLWH) have improved over the last decade, there has been a simultaneous increase in non-AIDS-related cancer in that group. However, there is a paucity of data regarding the incidence of glioblastoma multiforme (GBM) in PLWH. Better understanding of the oncogenesis, natural history, and treatment outcomes of GBM in PLWH should lead to improved treatment strategies. Methods We performed a comprehensive literature search of six electronic databases to identify eligible cases of GBM among PLWH. Kaplan–Meier estimates, Fisher’s exact test, and logistic regression were used to interrogate the data. Epidemiologic data on global HIV prevalence was obtained from the 2016 UNAIDS incidence report, and CNS cancer incidence was obtained from the GDB 2016 Brain and Other CNS Cancer Collaborators. Results There is an inverse relationship between the incidence of HIV and CNS cancer globally. Median overall survival (OS) from GBM diagnosis was 8 months. Estimates for survival at 1 and 2 years were 28 and 5%, respectively. There were no statistically significant predictors of OS in this setting. There was a significant difference (p < 0.01) in OS in PLWH and GBM when compared to TCGA age matched cohorts. Conclusion The diagnosis of GBM in PLWH is severely underreported in the literature. Despite maximal treatment, OS in this patient population is significantly less than in HIV-negative people. There was a poor prognosis of GBM in PLWH, which is inconsistent with previous reports. Further investigation is required for PLWH and concomitant GBM. Analyses must consider if HAART is maintained in PLWH during GBM treatment.
... Current knowledge of the prevalence of HIV in glioma patients is based on several small case series. Recent studies from Zimbabwe (2018), Kenya (2020), Brazil, and Mexico (2011) suggest a lower prevalence of HIV in glioma patients [11][12][13]. Other conflicting studies suggest glioblastomas occur at a greater frequency and younger age in the HIV population [10,14]. ...
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Introduction Early diagnosis and treatment of human immunodeficiency virus (HIV) can improve outcomes. HIV prevalence in brain tumor patients and the impact of an HIV diagnosis on patient outcomes are poorly understood. Materials and methods This was a prospective study of 100 consecutive brain tumor patients admitted to a Greater London Tertiary Neurosurgical center for surgery between January 2021 and October 2021. All brain tumors were included. All patients have appropriately consented. Blood was tested to detect HIV antibodies and p24 antigen. Outcomes were noted at 30-day postoperative follow-up. Results In 100 patients, there was one case of a known HIV-positive, seronegative patient, and no new diagnosis was made, giving a prevalence of 1%. The mean age of patients included was 61.7 ± 13.3, with 57% female. The patient with HIV suffered a postoperative pseudomonas infection, requiring intensive care, additional surgery, and antibiotics. This resulted in an inpatient stay of 55 days - an increase of 274% compared to patients without HIV. Conclusion Literature regarding the prevalence of HIV in glioma patients is inconclusive, of low quality, and primarily out-of-date. Our literature search found no similar study of rates of HIV in brain tumor patients in the United Kingdom. The incidence of both HIV and brain tumors, particularly glioblastomas, is low.
... The fact that in our study 36/101 (36%) were HIV positive is a relevant variable to explain our poorer outcome. One study noted that opportunistic infections and aggressive behaviour of brain tumours was more common in HIV infected individuals compared to HIV non-infected individuals [29]. Our study finding of an increased incidence of an unfavourable outcome, combined with the fact that a significant proportion of our subjects were HIV positive, supports the result of this study. ...
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Introduction Many countries, including South Africa, do not have a national brain tumour registry. Despite this limitation several institutional studies report age, gender, and histological tumour types that are in-line with the findings of the large established national brain tumour registries from the United States and Europe. Materials and methods We conducted a prospective study consecutively enrolling all elective subjects admitted to our Unit with a neoplastic brain tumour from the 01 July 2018- 31 March 2019. The data collected included age, gender, admission Glasgow Coma Score, HIV status, admission absolute CD4 count in all patients, radiological tumour diagnosis, pre-operative steroid treatment, length of in-hospital stay prior to surgery, time between prophylactic antibiotic administration and skin incision, intra-operative blood loss, length of surgery, extent of resection, histological diagnosis, post-operative nosocomial infection incidence, and Glasgow Outcome Score. Results The mean age of our subjects was 48 (+/-14.56) years. Significance was also demonstrated between age and histological tumour diagnosis (p=0.031). With regards gender 72/101 (72%) were males and 29/101 (29%) were females. Considering admission HIV status 65/101 (64%) were HIV negative and 36/101 (36%) were HIV positive. Of the 101 subjects enrolled in the study 78/101 (77%) were taken for operative intervention. The mean intra-operative blood loss in our study was 505 (+/- 336) millilitres. The mean length of surgery was 278 (+/- 80.33) minutes. Considering nosocomial infection 30/78 (38%) subjects developed this complication. Considering outcome 29/78 (37%) subjects in our study had a favourable outcome (GOS 4/5), and 49/78 (63%) had an unfavourable outcome (GOS 1-3). Conclusion Patients with brain tumours, whether HIV positive or not, show characteristic histological tumour types that are age specific. While being HIV positive does have a detrimental influence, the primary histology of the lesion and the extent of resection are the major determinants of outcome.
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Human polyomavirus JC is the causative agent of a deadly form of sudden onset dementia, progressive multifocal leukocoencephalopathy (PML). PML is highly prevalent in immunodeficient populations, specially those undergoing chemotherapy, immunosuppressive treatments for autoimmune conditions, and HIV-1/AIDS patients. In fact, before the highly active antiretroviral therapy (HAART) regimens became available, PML was a leading cause of death in HIV-1 seropositive individuals. However, patients under HAART show increased survival times with better prognoses. In this report we described the main differences between PML before and after the HAART era; highlighting the new patterns of presentation, the neurotropism of other human polyomaviruses, and the increased prevalence of immune reconstitution inflammatory syndrome (IRIS), as a complication of PML in patients under HAART. Lastly, we propose a revised classification of human poliomavirus-associated cerebral disorders that may reflect more accurately what clinicians encounter in their everyday practice.
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Tuberculosis (TB) is a leading cause of death in HIV-infected patients worldwide. We aimed to study clinical characteristics and outcome of 1075 consecutive patients diagnosed with HIV/TB from 2004 to 2006 in Europe and Argentina. One-year mortality was assessed in patients stratified according to region of residence, and factors associated with death were evaluated in multivariable Cox models. At TB diagnosis, patients in Eastern Europe had less advanced immunodeficiency, whereas a greater proportion had a history of intravenous drug use, coinfection with hepatitis C, disseminated TB, and infection with drug-resistant TB (P < 0.0001). In Eastern Europe, fewer patients initiated TB treatment containing at least rifamycin, isoniazid, and pyrazinamide or combination antiretroviral therapy (P < 0.0001). Mortality at 1 year was 27% in Eastern Europe, compared with 7, 9 and 11% in Central/Northern Europe, Southern Europe, and Argentina, respectively (P < 0.0001). In a multivariable model, the adjusted relative hazard of death was significantly lower in each of the other regions compared with Eastern Europe: 0.34 (95% confidence interval 0.17-0.65), 0.28 (0.14-0.57), 0.34 (0.15-0.77) in Argentina, Southern Europe and Central/Northern Europe, respectively. Factors significantly associated with increased mortality were CD4 cell count less than 200 cells/microl [2.31 (1.56-3.45)], prior AIDS [1.74 (1.22-2.47)], disseminated TB [2.00 (1.38-2.85)], initiation of TB treatment not including rifamycin, isoniazid and pyrazinamide [1.68 (1.20-2.36)], and rifamycin resistance [2.10 (1.29-3.41)]. Adjusting for these known confounders did not explain the increased mortality seen in Eastern Europe. The poor outcome of patients with HIV/TB in Eastern Europe deserves further study and urgent public health attention.
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Reports have shown that the publication of practice guidelines does not guarantee their use in clinical practice. The objective of this study was to evaluate the agreement between antiretroviral treatments (ARTs) prescribed in clinical practice and the recommendations in published guidelines. A retrospective cohort study was carried out in ART-naïve adults of the Spanish Asociacion Medica Vach de Estudios Multicentricos (VACH) Cohort for the period from 2003 to 2006. A total of 945 patients initiated ART. Of these patients, 12.3% had a CD4 cell count above 350 cells/microL. A 'nonrecommended' antiretroviral regimen was prescribed to 5.3, 5.1 and 7.8% of patients with CD4 counts <200, 200-350 and >350 cells/microL, respectively. Multivariate analyses demonstrated that only a higher viral load was associated with the selection of a combination treatment that was recommended by the guidelines. Most patients were prescribed initial treatments in agreement with the recommendations. Appropriate routine data collection in databases can be used to evaluate the level of antiretroviral guideline compliance. We propose that routine evaluations of the guidelines must be part of quality assessment to improve medical care.
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Glioblastoma (GBM) is a highly lethal brain tumour presenting as one of two subtypes with distinct clinical histories and molecular profiles. The primary GBM subtype presents acutely as a high-grade disease that typically harbours mutations in EGFR, PTEN and INK4A/ARF (also known as CDKN2A), and the secondary GBM subtype evolves from the slow progression of a low-grade disease that classically possesses PDGF and TP53 events. Here we show that concomitant central nervous system (CNS)-specific deletion of p53 and Pten in the mouse CNS generates a penetrant acute-onset high-grade malignant glioma phenotype with notable clinical, pathological and molecular resemblance to primary GBM in humans. This genetic observation prompted TP53 and PTEN mutational analysis in human primary GBM, demonstrating unexpectedly frequent inactivating mutations of TP53 as well as the expected PTEN mutations. Integrated transcriptomic profiling, in silico promoter analysis and functional studies of murine neural stem cells (NSCs) established that dual, but not singular, inactivation of p53 and Pten promotes an undifferentiated state with high renewal potential and drives increased Myc protein levels and its associated signature. Functional studies validated increased Myc activity as a potent contributor to the impaired differentiation and enhanced renewal of NSCs doubly null for p53 and Pten (p53(-/-) Pten(-/-)) as well as tumour neurospheres (TNSs) derived from this model. Myc also serves to maintain robust tumorigenic potential of p53(-/-) Pten(-/-) TNSs. These murine modelling studies, together with confirmatory transcriptomic/promoter studies in human primary GBM, validate a pathogenetic role of a common tumour suppressor mutation profile in human primary GBM and establish Myc as an important target for cooperative actions of p53 and Pten in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal and tumorigenic potential.
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Few data are available about progressive multifocal leukoencephalopathy (PML) in patients with acquired immunodeficiency syndrome (AIDS) from Brazil. The objectives of this study were to describe the main features of patients with PML and estimate its frequency among AIDS patients with central nervous system (CNS) opportunistic diseases admitted to the Instituto de Infectologia Emílio Ribas, São Paulo, Brazil, from April 2003 to April 2004. A retrospective and descriptive study was performed. Twelve (6%) cases of PML were identified among 219 patients with neurological diseases. The median age of patients with PML was 36 years and nine (75%) were men. Nine (75%) patients were not on antiretroviral therapy at admission. The most common clinical manifestations were: focal weakness (75%), speech disturbances (58%), visual disturbances (42%), cognitive dysfunction (42%), and impaired coordination (42%). The median CD4+ T-cell count was 45 cells/microL. Eight (67%) of 12 patients were laboratory-confirmed with PML and four (33%) were possible cases. Eleven (92%) presented classic PML and only one case had immune reconstitution inflammatory syndrome (IRIS)-related PML. In four (33%) patients, PML was the first AIDS-defining illness. During hospitalization, three patients (25%) died as a result of nosocomial pneumonia and nine (75%) were discharged to home. Cases of PML were only exceeded by cases of cerebral toxoplasmosis, cryptococcal meningoencephalitis, and CNS tuberculosis, the three more frequent neurologic opportunistic infections in Brazil. The results of this study suggest that PML is not an uncommon HIV-related neurologic disorder in a referral center in Brazil.
Malignant glioma is the most common primary brain neoplasm, but generally it is not included in the differential diagnosis of enhancing lesions of the central nervous system (CNS) in patients suffering from acquired immunodeficiency syndrome. We report a case of glioblastoma multiforme (GBM) in a 29-year-old man with human immunodeficiency virus (HIV). Primary CNS lymphoma was suspected, making a definitive histological diagnosis crucial. An initial stereotactic biopsy sample was insufficient to establish a diagnosis and a second biopsy of the lesion was obtained. The histopathological investigation confirmed GBM and adjuvant external radiation treatment was given to the patient, who survived for 4 months after the initial biopsy. A decline in the rate of Toxoplasma infection and the changing diseases observed in HIV infection indicate the importance of obtaining a biopsy in cases of CNS mass lesions.
The presence of human immunodeficiency virus (HIV)-infected macrophages in the parenchyma of central nervous system is an hallmark of acquired immunodeficiency syndrome-related neuroinflammation. Once penetrated the blood-brain barrier (BBB), macrophages closely interact with astrocytes, beginning with those lying beneath the BBB endothelium. By investigating the consequences of the cell-cell interaction between HIV-infected macrophages and astrocytes, we observed that the HIV-1 expression in macrophagic cells correlated with increased chemotactic activity in supernatants of astroglial cells. Gene array analysis revealed an impressive increase in the transcription of the gene for the CCL2/MCP-1 chemokine in astroglial cells isolated from HIV-1-infected co-cultures compared with cells from uninfected co-cultures. This phenomenon coupled with the increase in CCL2 release and depended on the cell-cell contact. In addition, it was a consequence of the HIV-1-induced enhancement of membrane-associated tumor necrosis factor-α in macrophagic cells, and correlated with increased levels of nuclear factor kappaB activation in astroglial cells. These observations could mirror a mechanism of recruitment of leukocytes through the BBB, likely contributing to the increase in both viral load and inflammation in central nervous system of HIV-infected patients.
The World Health Organization Joint Report of 2007 (WHO/UNAIDS/UNICEF) estimated that in developing world economies, 2 million people with HIV/AIDS were being treated with antiretroviral drugs (ARVs) out of the 7 million needing treatment. The ongoing political and humanistic movement in Brazil highly relates to health care provision, especially to treatment of the HIV/AIDS epidemic. "Compulsory licensing" (patent breaking) was used by Brazil to manufacture and import HIV/AIDS drugs. The Brazilian government provided top-of-the-line antiretroviral drugs in the form of HAART (highly active antiretroviral therapy) to all needing treatment for HIV/AIDS. Subsequently, the international community found Brazil as an eager "poster child" in the universal access movement for HIV/AIDS drugs. However, can this program of justice and humanity in Brazil be feasible when applied to the HIV/AIDS epidemic in other developing world countries? It is worth exploring.
HIV infection is associated with an increased incidence of glioblastoma multiforme (GBM). Here we report four new cases of HIV-associated GBM, discuss these in the context of previously reported cases, and consider aspects of current glioma management in HIV-positive patients. Twenty-one cases of GBM in HIV-positive patients, including four treated recently at our own institution, are discussed. The median age at presentation of the whole series was 38 years (range 19-60 years). The median CD4 count at GBM presentation was 400 cells/mm(3) (range 80-610 cells/mm(3)). Patients had been HIV positive for a median of 3 years (range 0-11 years) before tumour presentation. Treatment and survival were analysed in 16 of the 21 patients (five published cases were excluded: three due to lack of further information and two spinal cord tumours). Treatment included surgical debulking, radical radiotherapy and chemotherapy, all of which were well tolerated. The median survival was 8 months for the 16 patients with assessable data. GBM occurs at an increased frequency and younger age in the HIV population than in the general population. HIV itself is not found in glioma specimens, but the effect of HIV infection on reduced immune surveillance is thought to promote the development of these tumours. The approach to management of HIV-positive patients with GBM should be the same as the general population, using surgery, radiotherapy and chemotherapy. Vincristine should be used with caution due to potential interactions with highly active antiretroviral therapy, causing an increased rate of autonomic neuropathy. Continuous low-dose temozolomide treatment should also be used cautiously because of potential additive lymphopenia. Survival of glioma patients with HIV is dictated by their tumour, not their HIV status.