the main characteristic of aids is a severe immunodeficiency caused by the progressive depletion of cd4 + t - cells and consequent immune impairment .
these facts ultimately lead to an increasing risk of developing opportunistic infections and malignancies [ 2 , 3 ] .
non - hodgkin lymphoma ( nhl ) is an aids - defining condition , and its frequency seems to be decreasing after the highly active antiretroviral therapy ( haart ) became the standard of care for the management of aids patients [ 4 , 5 ] .
haart has promoted a great increase in the lifespan of hiv - infected patients and decreased the morbidity and mortality caused by aids .
however , the available evidence suggests that around half of the patients treated are unable to reach a normal cd4 + cell count , even after years of persistent viral suppression .
one of the reasons for such findings is the persistent immune activation , but its causative mechanisms are still a matter of debate
.   these facts may be responsible for the persistence of a higher risk for the development of other malignancies , a trend recently detected in treated aids patients , as a likely consequence of incomplete immune restoration . while there is a clear trend toward reducing aids - defining events ( which include kaposi 's sarcoma and non - hodgkin lymphomas ) after haart introduction
, several published works have shown an increase in the frequency of other malignancies among aids patients under suppressive therapy , including some cancers not previously associated with hiv infection , such as hodgkin 's lymphoma ( hl ) .
although the majority of the neoplasms identified are anal and lung cancer , an increment in the frequency of diagnosis of hodgkin 's disease among hiv - infected patients has also been observed [ 4 , 811 ] . in brazil , since the beginning of the aids epidemic , the federal government has provided universal access to antiretroviral drugs , for all patients in need of treatment .
this strategy was shown to be very efficacious in promoting an increase in the survival time for aids patients , as well as in stabilizing the number of cases over time .
currently , the life expectation of hiv - infected individuals is approaching found in the general population .
however , the available information suggests that there is an increase in the frequency of malignancies among brazilian hiv - infected patients , as observed in other countries [ 12 , 13 ] .
unfortunately , there is scarce information on the frequency of each type of cancer and on survival time for hiv - related malignancies . in this paper , we present an evaluation of survival time and prognostic markers for aids patients presenting with nhl .
this was a retrospective , nested , case - control study ( 1 exposed for 2 nonexposed ) within a cohort of hiv patients receiving follow - up at the aids clinics of complexo hospitalar universitrio professor edgard santos ( hupes ) , the federal university of bahia ( ufba ) teaching hospital .
we also reviewed the medical records of oncology clinics in salvador , bahia , brazil , to include hiv - negative controls .
patients were with confirmed diagnosis of non - hodgkin 's lymphomas ( nhl ) between 2000 and 2006 , who had available information on follow - up until december 2009 , older than 18 years , with a confirmed diagnosis of hiv infection .  
patients met all case criteria , but a negative serology for hiv infection . cases and controls
were matched by gender , age ( 5 years ) , and same year of diagnosis .
all individual medical charts were reviewed for data collection on demographics , disease staging ( ann arbor classification system ) , ecog ( eastern cooperative oncology group ) , response to therapy , type b symptoms ( fever , weight loss , and night sweats ) , survival time , laboratory and imaging evaluations , bulky disease ( mass  10  cm ) , and bone marrow infiltration evidence .
for the international prognosis index ( ipi )   five variables were used ( age , disease staging , number of extra nodal sites , ecog and ldh levels ) .
demographics were compared using chi - square test ( comparison of proportions ) or student 's t - test ( means ) .
kaplan - mayer survival analysis was performed to compare total survival ( up to death ) and event free survival ( efs ) , considering the period between the date of diagnosis and the date of death or relapse , end of or losing follow - up .
event - free survival ( efs ) was calculated from date of diagnosis up to the date of disease recurrence or end of follow - up .
all statistical analysis was performed by using the software package spss for windows , version 17.0 .
the study was approved by the ethics committee of the maternidade climrio de oliveira - universidade federal da bahia ( approval no . : 0648/2008 ) .
thirty - one aids patients with a diagnosis of nhl between 2000 and 2006 were included in the study , as well as 62 hiv - negative unexposed controls , which had the same diagnosis , matched by age , gender , and year of diagnosis of nhl . 

table 1 shows the baseline characteristics of both groups . of note , aids patients had at diagnosis a significantly higher frequency ( 42.1% ) of ecog  2 than negative controls ( 10.7% , p = 0.005 ) .
in addition , we detected a higher proportion of exposed patients ( 84.2% ) with an ipi  2 , compared to unexposed controls ( 51.8% , p = 0.01 ) .
iii / iv ) was also a more frequent finding among exposed patients ( 77.8% ) than among unexposed controls ( 55.7% ) although it was only marginally significant ( p = 0.05 ) .
most of the exposed cases ( 58.1% ) had received an hiv diagnosis before the detection of nhl , and the mean time between hiv diagnosis and nhl detection was 32 months ( range 4144 months ) . in 13 patients ( 41.9% )
the diagnosis was performed simultaneously , during clinical investigation due to a delay in request hiv serology . the majority ( 28/31 patients , 90.3% ) of aids patients
had a diffuse large b - cell lymphoma ( three had the immunoblastic variant and 4 the plasmablastic one ) .
the remaining patients did not have information about variant morphological of the lymphoma available in their medical records .
three patients had burkitt 's lymphoma ( two as the classic form and the third as the atypical one ) .
the hiv staging at diagnosis of lymphoma showed that 14 ( 45.2% ) had a cd4 + cell count below 200  cells / mm .
the mean cd4 + cell count was 211  cells / mm ( range 4683 ) , while the mean plasma hiv-1 rna viral load was 96,000  copies / mm ( range < 40350,000  copies / mm ) .
mean absolute lymphocyte count was similar for cases ( mean 1499  cells / mm , range 2604000 ) and controls ( mean 1536  cells / mm , range 1103906 , p = 0.77 ) .
lactate dehydrogenase ( ldh ) levels were also similar for both groups ( 808  mg / dl , range 1443520 for cases , versus 132  mg / dl , range 1177791 for controls , p = 0.81 ) .
all patients were treated with anthracycline - based chemotherapy regimens ( chop or similar ) . among those exposed to hiv infection , 5 patients died before starting chemotherapy .
twelve patients ( 38.7% ) were undergoing haart at the moment of diagnosis , and four died before starting antiretroviral therapy . among the controls ,
the majority ( 38 patients ) were submitted to chemotherapy alone , while the remaining 23 received chemotherapy plus radiotherapy .   the mean cd4 count ( n = 26 ) was 211  cells / mm ( range 4683 ) , while hiv-1 rna plasma viral load ( n = 23 ) varied from < 40 to 350,000  copies / mm .
the mean absolute lymphocyte count was similar for hiv positive ( 1499  cells / mm , range 2604000  cells / mm ) and negative patients ( 1536  cells / mm , range 1103906 , p = 0.77 ) .  
twenty - two patients were treated with chemotherapy , and four cases received chemotherapy plus radiotherapy . a complete response to therapy
was obtained by nine patients ( 34.6% ) , while 16 individuals ( 61.5% ) presented with disease recurrence and eventually died .
median cd4 count was similar for patients successfully treated ( 152  85  cells / mm ) and for those who failed therapy ( 127.5  35  cells / mm , p > 0.05 ) .
twenty - three received chemotherapy plus radiotherapy , while the remaining 38 were treated with chemotherapy alone .
complete remission was achieved in 41 patients ( 67.2% ) while 19 ( 31% ) presented disease progression and died . among the responders ,
11 presented disease recurrence ( 7 died , 2 were lost to follow - up , and 2 presented subsequent sustained clinical remission ) .
overall survival time was significantly different for exposed and nonexposed controls , as shown in figure 1 .
exposed patients had a global mean survival of 35.8 months ( range 1120 months ) , while for controls it was equal to 72.4 months ( range 1120 , p < 0.001 ) .
a similar pattern was observed when we evaluated the event - free survival time ( efst ) , with cases showing a shorter ( 34.5 months ) mean efst than controls ( 66.8 months , p = 0.002 ) .  
the main predictors of shorter survival for aids patients were ipi  2 , presence of bulky disease , increased dhl levels , bone marrow infiltration , absolute lymphocyte count < 1.000/mm , and presence of type b symptoms .  
in addition , hiv - positive patients had a significantly higher rate of ipi  ( p = 0.02 ) , higher ldh levels ( p < 0.001 ) , lower absolute lymphocyte count ( p = 0.01 ) , and a higher frequency of type b symptoms ( p = 0.007 ) than seronegative individuals .
they also had higher and earlier mortality than the control group , even when it was adjusted for the presence of these parameters ( table 3 ) .
a similar picture was observed when we compared predictive factors for efs ; aids patients presented a significantly higher frequency of bulky disease , bone marrow infiltration , and type b symptoms , as well as a lower absolute lymphocyte count and higher ldh levels than controls .
the overall survival of aids patients without poor prognostic findings was similar to that found for hiv - negative individuals with those characteristics .
the present study demonstrates that overall survival time and efs for patients diagnosed with nhl are significantly reduced by hiv infection .
while hiv - negative patients had a global survival and event - free survival of 72.4 months and 58.9 months , respectively , these time intervals were reduced to 35.8 and 34.5 months , respectively , when patients were hiv positive .
the main predictors of a shorter survival for hiv - positive patients were ipi  2 , bulky disease , increased ldh levels , low absolute lymphocyte count ( < 1,000  cells / mm ) , and presence of b symptoms .
the incidence of nhl in hiv patients varies from 13% and was higher in the pre - haart era [ 17 , 18 ] . during the study period ,
2,274 aids cases were reported to health authorities in salvador , and 31 patients ( 1.4% ) with nhl were identified .
this incidence rate is similar to that reported in other studies , but in our case it can underestimate the real rate , since we were not able to cover all the oncology services in town , and , in some cases hiv screening was not performed .
it is noteworthy that the diagnosis of nhl was reached in patients previously diagnosed with aids in almost 2/3 ( 58% ) of them , and in 39% , it was the first manifestation of the disease .
the mean time for nhl diagnosis after detection of hiv infection was 31 months but was as long as 166 months in one case .
in addition , 45% of these patients had a cd4 + cell count lower than 200  cells / mm .
this confirms nhl as a late manifestation of aids , as well as the findings detected by other studies .  
the vast majority ( 90.3% ) of hiv - positive patients in our study had ldbcl , an aids - defining disease since 1993 .
this proportion was similar to that found by pereira ( 80% ) , in so paulo , and barreto ( 61% ) in rio de janeiro , both located in brazil . in our study , all hiv - negative patients had a diagnosis of ldbcl , which allowed us a better comparison of survival time for groups with the same disease but with different immunological conditions .
although it is well known that other viral agents can play a role in lymphomagenesis , we could not evaluate this factor for our patients , due to the lack of serological information in a great number of patients . of note ,
among the hiv - positive group we detected a 6.5% coinfection rate by hepatitis c virus ( 2 patients ) , and only one case ( 3.2% ) coinfected by htlv-1 .
for comparison purposes , simcock et al .   found a 27.5% coinfection rate by hcv , among aids patients with nhl .
in addition , the coinfection rates we have already found in our overall population of hiv patients is much higher than this , with coinfection by hcv reaching 1015% and by htlv varying from 8% to 16% .
it is important to emphasize that these patients need a better evaluation , regarding the screening for potentially coinfecting agents , since the simultaneous infection by other viruses can have an impact on the clinical evolution and outcomes of these individuals . the overall survival time and
however , when these findings were present , being hiv positive was a significant negative factor for survival .
an ipi equal or higher than two was significantly associated with a shorter os and efs , for hiv - positive patients , as well as the presence of other poor prognostic factors , like those reflecting a greater tumor load ( bulky disease and elevated ldh ) , or advanced / disseminated disease ( bone marrow involvement and presence of type b symptoms ) .
another independent factor associated with a poorer prognosis was an absolute lymphocyte count below 1,000  cells / mm .
patients with a higher absolute lymphocyte count had a similar os and efs , regardless of their hiv serostatus .
however , for patients infected by hiv , a lymphocyte count below that threshold was significantly associated with a shorter survival .
this fact suggests that immunosuppression is a risk factor not only for the development of neoplasms , but it is also an important negative prognostic factor .
on the other hand , it seems that the cd4 + cell count was not associated with the response to treatment , since patients with complete response had similar baseline cd4 + cell count to those who presented with progressive disease even after chemotherapy .
the potential mechanisms to explain the association between decreased absolute lymphocyte count and shorter survival time include ( a ) the factors released by the tumor cells , which could cause suppression of dendritic cells and t cells ; ( b ) the effect of chemotherapy , which can transiently intensify the degree of immunosuppression , increasing the risk of potentially lethal infections ; and ( c ) a combination of these factors [ 25 , 26 ] .
taken together , these findings suggest that the infection by hiv-1 is significantly associated with a shorter survival time for patients presenting with nhl .
our results confirm hiv-1 as a negative prognostic factor for such patients , regardless of other predictive factors and of the disease stage for both nhl and hiv infection .
 despite the benefits of haart , hiv - infected patients are increasingly affected by different malignancies . we compared a 5-year - period survival time and prognostic factors for hiv-1-infected individuals diagnosed with non - hodgkin lymphomas ( nhl ) in a nested case - control study , with non - hiv - infected individuals in salvador , brazil . 
 survival time and prognostic factors were compared to hiv - negative patients . 
 31 cases ( versus 63 controls ) had a significantly more advanced nhl at diagnosis and lower mean cd4 count ( 26  cells / mm3 ) than controls . mean overall survival ( os ) was 35.8 versus 75.4 months , for cases and controls , respectively ( p < 0.001 ) , while mean event - free survival time ( efs ) was 34.5 months for cases , versus 68.8 for controls ( p = 0.002 ) . 
 higher ipi , increased ldh levels , bone marrow infiltration , lower absolute lymphocyte counts ( < 1,000  cells / mm3 ) , and type b symptoms were associated with a shorter survival time for cases . although patients without poorer prognostic factors at baseline had an os comparable to controls , the mean cd4 cell count for cases was similar for patients with favorable and nonfavorable response to therapy . 
 our findings suggest that hiv-1 infection is significantly associated with a shorter survival time for patients with nhl , independently of other predictive factors and of disease stage . 
1. Introduction
2. Patients and Methods
3. Results
4. Discussion