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1.  Liver Disease in the HIV-Infected Individual 
Since the advent of effective antiretroviral therapy (ART) for human immunodeficiency virus-1 (HIV), there has been a substantial decrease in deaths related to acquired immunodeficiency syndrome (AIDS). However, in the ART-era liver disease is now the most common non-AIDS related cause of death among HIV-infected patients, accounting for 14-18% of all deaths in this population and almost half of deaths among hospitalized HIV-infected patients. Just as the burden of non-AIDS morbidity and mortality has changed in the ART-era, the types of liver disease the clinician is likely to encounter among these patients have changed as well. This review will discuss the causes of liver disease in the HIV-infected population in the ART-era, including chronic hepatitis C virus, chronic hepatitis B virus, medication-related hepatotoxicity, alcohol abuse, nonalcoholic fatty liver disease, and AIDS-related liver diseases.
doi:10.1016/j.cgh.2010.08.024
PMCID: PMC2997131  PMID: 20851211
human immunodeficiency virus; liver disease; hepatitis C virus; hepatitis B virus
2.  Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy 
AIDS (London, England)  2009;23(13):1743-1753.
Objective
To assess whether immunodeficiency is associated with the most frequent non-AIDS-defining causes of death, in the era of combination antiretroviral therapy (cART).
Design
Observational multicenter cohorts.
Methods
23 cohorts of adults with estimated dates of Human Immunodeficiency Virus (HIV) seroconversion. Patients were seroconverters followed within the cART era. Measurement were latest CD4; nadir CD4 and time spent with CD4 <350 cells/mm3. Outcomes were specific causes of death using a standardized classification.
Results
Among 9,858 patients (71,230 person-years follow-up), 597 died, 333 (55.7%) from non-AIDS-defining causes. Non-AIDS-defining infection, liver disease, non-AIDS-defining malignancy and cardiovascular disease (CVD) accounted for 53% of non-AIDS deaths. For each 100 cells/mm3 increment in the latest CD4 count, we found a 64% (95%CI 58–69%) reduction in risk of death from AIDS-defining causes and significant reductions in death from non-AIDS infections (32, 18–44%), end-stage liver-disease (33, 18–46%), and non-AIDS malignancies (34, 21–45%). These risks were also associated with nadir CD4 while cART-naïve and duration of exposure to immunosuppression. No relationship between risk of death from CVD and CD4 count was found although there was a raised risk associated with elevated HIV RNA.
Conclusions
In the cART era, the most frequent non-AIDS-defining causes of death are associated with immunodeficiency, only CVD was associated with high viral replication. Avoiding profound and mild immunodeficiency, through earlier initiation of cART, may impact on morbidity and mortality of HIV infected patients.
doi:10.1097/QAD.0b013e32832e9b78
PMCID: PMC3305466  PMID: 19571723
AIDS-Related Opportunistic Infections; immunology; mortality; Acquired Immunodeficiency Syndrome; complications; drug therapy; immunology; mortality; Adolescent; Adult; Aged; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cardiovascular Diseases; complications; immunology; mortality; Epidemiologic Methods; Female; Humans; Immune Tolerance; Liver Diseases; complications; immunology; mortality; Male; Middle Aged; Neoplasms; complications; immunology; mortality; Young Adult; Causes of death; Human Immunodeficiency Virus/AIDS; CD4 cell count; Antiretroviral therapy, highly active; Neoplasm; Hepatitis; Bacterial infection
3.  Mortality rates and causes of death in a cohort of HIV-infected and uninfected women, 1993–1999 
HIV/AIDS-associated and non-HIV/AIDS-associated death rates and causes of death between 1993 and 1999 were examined in 885 HIV-infected women and 425 uninfected women of the HIV Epidemiology Research Study cohort. Causes of death were determined by review of death certificates and the National Death Index. Adjusted bazard ratios were calculated for mortality risk factors. In the 885 HIV-infected women and 425 uninfected women, 234 deaths and 8 deaths, respectively, occurred by December 31, 1999. All-cause death rates in the HIV-infected women were unchanged between the pre-HAART (1993–1996) and HAART eras (1997–1999) —5.1 versus 5.4 deaths per 100 person-years (py). AIDS as a cause of death decreased from 58% of all deaths in 1996 to 19% in 1999, while HAART use increased to 42% by the end of 1999. In spite of the modest proportion ever using HAART, HIV-related mortality rates did decline, particularly in women with CD4+cell counts less than 200/mm3. Drug-related factors were prominent: for the 129 non-AIDS-defining deaths, hepatitis C positivity (relative bazard [RH] 2.6, P<0.001) and injection drug use (RH 1.7, P=0.02) were strong predictors of mortality, but were not significant in the Cox model for 105 AIDS-defining deaths (RH 0.9, P>30 and RH 0.7, P>.30, respectively. The regression analysis findings, along with the high percentage of non-AIDS deaths attributable to illicit drug use, suggest that high levels of drug use in this population offset improvements in mortality from declining numbers of deaths due to AIDS.
doi:10.1093/jurban/jtg074
PMCID: PMC3456216  PMID: 14709715
Women; Mortality; Cause of death; HIV; AIDS; Injection drug use
4.  Cause-Specific Life Expectancies After 35 Years of Age for Human Immunodeficiency Syndrome-Infected and Human Immunodeficiency Syndrome-Negative Individuals Followed Simultaneously in Long-term Cohort Studies, 1984–2008 
American Journal of Epidemiology  2013;177(2):116-125.
Parametric and semiparametric competing risks methods were used to estimate proportions, timing, and predictors of acquired immune deficiency syndrome (AIDS)-related and non-AIDS-related mortality among individuals both positive and negative for the human immunodeficiency syndrome (HIV) in the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS) from 1984 to 2008 and 1996 to 2008, respectively. Among HIV-positive MACS participants, the proportion of deaths unrelated to AIDS increased from 6% before the introduction of highly active antiretroviral therapy (HAART) (before 1996) to 53% in the HAART era (P < 0.01); the median age of persons who died from non-AIDS-related causes after age 35 years increased from 49.0 to 66.0 years (P < 0.01). In both cohorts during the HAART era, median ages at time of non-AIDS-related death were younger for HIV-positive individuals than for comparable HIV-negative individuals (8.7 years younger in MACS (P < 0.01) and 7.6 years younger in WIHS (P < 0.01)). In a multivariate proportional cause-specific hazards model, unemployment (for non-AIDS death, hazard ratio (HR) = 1.8; for AIDS death, HR = 2.3), depression (for non-AIDS death, HR = 1.4; for AIDS death, HR = 1.4), and hepatitis B or C infection (for non-AIDS death, HR = 1.8, for AIDS death; HR = 1.4) were significantly (P < 0.05) associated with higher hazards of both non-AIDS and AIDS mortality among HIV-positive individuals in the HAART era, independent of study cohort. The results illuminate the changing face of mortality among the growing population infected with HIV.
doi:10.1093/aje/kws321
PMCID: PMC3590031  PMID: 23287403
acquired immunodeficiency syndrome; antiretroviral therapy, highly active; cohort studies; competing risks; HIV; mixture model; mortality; proportional hazards models
5.  Cancer as a cause of death among people with AIDS in the United States 
Background
People with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS), are at increased risk for cancer. Highly active antiretroviral therapy [(HAART), widely available since 1996] has resulted in dramatic declines in AIDS-related deaths.
Methods
We evaluated cancer as a cause of death in a U.S. registry-based cohort of 83,282 people with AIDS (1980–2006). Causes of death due to AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs) were assessed. We evaluated mortality rates and the fraction of deaths due to cancer. Poisson regression assessed rates according to calendar year of AIDS onset.
Results
Overall mortality declined from 302 (1980–1989), to 140 (1990–1995), to 29 per 1,000 person-years (1996–2006). ADC mortality declined from 2.95 (1980–1989) to 0.65 per 1,000 person-years (1996–2006) (P<0.01), but the fraction of ADC-deaths increased from 1.05% to 2.47%, due to declines in other AIDS-related deaths. Non-Hodgkin lymphoma was the commonest cancer-related cause of death (36% during 1996–2006). Likewise, NADC mortality declined from 2.21 to 0.84 per 1,000 person-years (1980–1989 vs. 1996–2006, P<0.05), but the fraction of NADC-deaths increased to 3.16% during 1996–2006. Lung cancer was the most common NADC cause of death (21% of cancer-related deaths in 1996–2006).
Conclusions
Cancer mortality declined in the HAART era, but due to declining mortality from AIDS, cancers account for a growing fraction of deaths. Improved cancer prevention and treatment, particularly for non-Hodgkin lymphoma and lung cancer, would reduce mortality among people with AIDS.
doi:10.1086/656416
PMCID: PMC2943990  PMID: 20825305
Cancer; cause of death; HIV/AIDS; non-Hodgkin lymphoma; lung cancer
6.  Causes of Death in HIV-1–Infected Patients Treated with Antiretroviral Therapy, 1996–2006: Collaborative Analysis of 13 HIV Cohort Studies 
Background
We examined specific causes of mortality in human immunodeficiency virus type 1 (HIV-1)–infected patients who initiated antiretroviral therapy (ART) in Europe and North America from 1996 through 2006, and we quantified associations of prognostic factors with cause-specific mortality.
Methods
We retrospectively classified all deaths among 39,272 patients enrolled in 13 HIV-1 cohorts (154,667 person years of follow-up) into the categories specified in the Cause of Death (CoDe) project protocol.
Results
In 1597 (85%) of 1876 deaths, a definitive cause of death could be assigned. Among these, 792 deaths (49.5%) were AIDS related, followed by non-AIDS malignancies (189; 11.8%), non-AIDS infections (131; 8.2%), violence- and/or drug-related causes (124; 7.7%), liver disease (113; 7.0%), and cardiovascular disease (103; 6.5%). Rates of AIDS-related death (hazard ratio [HR] per 100 cell decrease, 1.43; 95% confidence interval [CI], 1.34–1.53) and death from renal failure (HR, 1.73; 95% CI, 1.18–2.55) were strongly inversely related to CD4 count at initiation of ART, whereas rates of death attributable to AIDS (HR for viral load >5 vs ≤5 log copies/mL, 1.31; 95% CI, 1.12–1.53), infection (HR, 1.85; 95% CI, 1.25–2.73), cardiovascular (HR, 1.54; 95% CI, 1.05–2.27), and respiratory causes (HR, 3.62; 95% CI, 1.30–10.09) were higher in patients with baseline viral load >5 log copies/mL than in other patients. Rates of each cause of death were higher in patients with presumed transmission via injection drug use than in other patients, with marked increases in rates of liver-related (HR for injection drug use vs non–injection drug use, 6.06; 95% CI, 4.03–9.09) and respiratory tract–related (HR, 4.94; 95% CI, 1.96–12.45) mortality. The proportion of deaths classified as AIDS related decreased with increasing duration of ART.
Conclusions
Important contributors to non-AIDS mortality in treated HIV-1–infected individuals must be addressed if decreases in mortality rates are to continue.
doi:10.1086/652283
PMCID: PMC3157754  PMID: 20380565
7.  Estimating the Extent of Underreporting of Mortality Among HIV-Infected Individuals in Rio de Janeiro, Brazil 
Abstract
Non-HIV-related causes of death have been increasing after the introduction of highly active antiretroviral therapy. Underlying and contributing causes of death were assessed in respect to the presence/absence of HIV/AIDS among HIV-infected/AIDS patients in Rio de Janeiro, Brazil. Demographic variables (age, gender, ethnicity, and schooling) and CD4 cell counts closest to death were assessed through logistic regression models comparing those who did not have with those who had HIV/AIDS mentioned on the death certificate. The linkage with the two cohorts identified 1249 records, of which 370 (29.6%) did not have HIV/AIDS listed on any field of the death certificate [77 (20.8%) attributed to undefined and 72 (19.5%) to external causes]. After excluding external causes, 25.3% still did not have HIV/AIDS listed on the death certificate. Multiple logistic regression analysis showed that age >40 years (OR = 2.09; 95%CI = 1.49–2.93; p < 0.001) and CD4 cell count closest to the date of death (OR = 1.15; 95% CI = 1.07–1.23; p < 0.001 for 100 cell increase) were associated with an increased probability of not having HIV/AIDS mentioned on the death certificate, when external causes were excluded. Mortality among HIV-infected individuals is underreported in the Rio de Janeiro Mortality Registry, particularly among older individuals and those with higher CD4 counts. Physicians should be aware of the changing patterns of mortality among HIV individuals, and public health officials should regularly perform linkages between all-cause mortality and available HIV-infected patients databases, such as AIDS registries and large cohort studies.
doi:10.1089/aid.2010.0089
PMCID: PMC3026651  PMID: 20929394
8.  Mortality by causes in HIV-infected adults: comparison with the general population 
BMC Public Health  2011;11:300.
Background
We compared mortality by cause of death in HIV-infected adults in the era of combined antiretroviral therapy with mortality in the general population in the same age and sex groups.
Methods
Mortality by cause of death was analyzed for the period 1999-2006 in the cohort of persons aged 20-59 years diagnosed with HIV infection and residing in Navarre (Spain). This was compared with mortality from the same causes in the general population of the same age and sex using standardized mortality ratios (SMR).
Results
There were 210 deaths among 1145 persons diagnosed with HIV (29.5 per 1000 person-years). About 50% of these deaths were from AIDS. Persons diagnosed with HIV infection had exceeded all-cause mortality (SMR 14.0, 95% CI 12.2 to 16.1) and non-AIDS mortality (SMR 6.9, 5.7 to 8.5). The analysis showed excess mortality from hepatic disease (SMR 69.0, 48.1 to 78.6), drug overdose or addiction (SMR 46.0, 29.2 to 69.0), suicide (SMR 9.6, 3.8 to 19.7), cancer (SMR 3.2, 1.8 to 5.1) and cardiovascular disease (SMR 3.1, 1.3 to 6.1). Mortality in HIV-infected intravenous drug users did not change significantly between the periods 1999-2002 and 2003-2006, but it declined by 56% in non-injecting drug users (P = 0.007).
Conclusions
Persons with HIV infection continue to have considerable excess mortality despite the availability of effective antiretroviral treatments. However, excess mortality in the HIV patients has declined since these treatments were introduced, especially in persons without a history of intravenous drug use.
doi:10.1186/1471-2458-11-300
PMCID: PMC3112125  PMID: 21569323
9.  Impact of haart on causes of death of persons with late-stage AIDS 
Context
The increasing use of highly active antiretroviral therapies (HAARTs) has changed the course of AIDS-related illnesses and enhanced the quality of life of patients infected with human immunodeficiency virus (HIV) and may have changes the causes of deaths in patients with acquired immunodeficiency syndrome (AIDS).
Objective
The aim of the present study was to investigate causes of deaths in long-term care hospital patients with late-stage AIDS who expired at the Coler-Goldwater Memorial Hospital in New York City in 1995, and in 1998 and 1999, that is, immediately before and the two most recent years after the advent of HAART.
Methods
Analysis of causes of deaths as recorded on the death certificates of 232 AIDS patients.
Results
The overall mortality rate declined from 75.6 deaths per 100 person-years in 1995 to 33.2 deaths per 100 person-years in 1998–1999 (P<.001) The number of AIDS patients who expired because of sepsis and opportunistic infections, which includedPneumocystis carinii Pneumonia (PCP), decreased significantly from 30 (26.1%) and 24 (20.9%) in 1995 to 15 (12.8%) and 10 (8.5%) in 1998–1999, respectively (P<.05). In contrast, deaths from hepatic failure increased from 0(0%) in 1995 to 7 (6%) in 1998–1999 (P<.05). Increases, although not significant statistically, were associated with pneumonias excluding PCP, end-stage AIDS, renal failure, and malignancies. Analysis of cause-specific mortality by gender between 1995 and 1998–1999 revealed very little difference between men and women. This analysis showed, however, that the infectious processes taken together (pneumonias excluding PCP, sepsis, and opportunistic infections including PCP) were significantly less frequent causes of death in 1998–1999 than in 1995 (P<.01).
Conclusion
These findings indicate that HAART affected the causes of deaths in patients with AIDS, with “traditional” opportunistic infections diminishing in importance relative to chronic medical conditions and malignancies.
doi:10.1007/BF02390528
PMCID: PMC3456132  PMID: 10855998
Death; HAART; Hepatic Failure; Late-Stage AIDS; Opportunistic Infections; Sepsis
10.  Mortality in Hepatitis C Virus–Infected Patients With a Diagnosis of AIDS in the Era of Combination Antiretroviral Therapy 
Chronic hepatitis C increased mortality by approximately 50% in patients with Centers for Disease Control and Prevention–defined AIDS, despite the competing mortality risks in these patients. About 20% of the deaths were liver-related, suggesting that greater hepatitis C virus awareness and treatment could increase survival.
Background. Before the introduction of combination antiretroviral therapy (cART), patients infected with the human immunodeficiency virus (HIV) rarely died of liver disease. In resource-rich countries, cART dramatically increased longevity. As patients survived longer, hepatitis C virus (HCV) infection became a leading cause of death; however, because patients with AIDS continue to have 5-fold greater mortality than non-AIDS patients, it is unclear whether HCV infection increases mortality in them.
Methods. In this investigation, which is part of the Longitudinal Studies of the Ocular Complications of AIDS, plasma banked at enrollment from 2025 patients with AIDS as defined by the Centers for Disease Control and Prevention were tested for HCV RNA and antibodies.
Results. Three hundred thirty-seven patients had HCV RNA (chronic infection), 91 had HCV antibodies and no HCV RNA (cleared infection), and 1597 had no HCV markers. Median CD4+ T-cell counts/µL were 200 (chronic), 193 (cleared), and 175 (no markers). There were 558 deaths. At a median follow-up of 6.1 years, patients with chronic HCV had a 50% increased risk of mortality compared with patients with no HCV markers (relative risk [RR], 1.5; 95% confidence interval [CI], 1.2–1.9; P = .001) in an adjusted model that included known risk factors. Mortality was not increased in patients with cleared infection (RR, 0.9; 95% CI, .6–1.5; P = .82). In patients with chronic HCV, 20.4% of deaths were liver related compared with 3.8% in patients without HCV.
Conclusions. Chronic HCV infection is independently associated with a 50% increase in mortality among patients with a diagnosis of AIDS, despite competing risks. Effective HCV treatment may benefit HIV/HCV-coinfected patients with AIDS.
doi:10.1093/cid/cis404
PMCID: PMC3369565  PMID: 22534149
11.  Postpartum Discontinuation of Antiretroviral Therapy and Risk of Maternal AIDS-Defining Events, Non-AIDS–Defining Events, and Mortality Among a Cohort of HIV-1–Infected Women in the United States 
AIDS Patient Care and STDs  2010;24(5):279-286.
Abstract
This retrospective cohort study of HIV-infected women receiving highly active antiretroviral therapy (HAART) while pregnant assessed the effect of postpartum HAART discontinuation on maternal AIDS-defining events (ADEs), non-AIDS–defining events (non-ADEs), and death 1997–2008 in Nashville, Tennessee. Cox proportional hazards models compared rates of ADE or all-cause death and non-ADE or all-cause death, and competing risks analyses compared rates of ADE or ADE-related death and non-ADE or non-ADE–related death across the groups. There were two groups: women who stopped HAART postpartum (discontinuation, n = 54) and women who continued HAART postpartum (continuation, n = 69). Fifty percent were African American, 40% had prior non-HAART antiretroviral therapy (ART) use, and 38% had a history of illicit drug use. Median age was 27.5 years, baseline CD4(%) was 532 (34%) and CD4 nadir was 332 cells/mm3, baseline and peak HIV-1 RNA were 2.6 and 4.32 log10 copies per milliliter, respectively. Women in the continuation group were older, had lower baseline CD4, CD4%, and CD4 nadir, and had higher peak HIV-1 RNA. In multivariable proportional hazards models, the hazard ratios [95% confidence interval (CI)] of ADE or all-cause death and non-ADE or all-cause death were lower in the continuation group, but not statistically significantly: 0.50 (0.12, 2.12; p = 0.35) and 0.69 (0.24, 1.95; p = 0.48), respectively. The results were similar in competing risks analyses. Despite having characteristics associated with worse prognosis, women who continued HAART postpartum had lower hazard ratio point estimates for ADEs or death and non-ADEs or death than women who discontinued HAART. Larger studies with longer follow-up are indicated to assess this association.
doi:10.1089/apc.2009.0283
PMCID: PMC2875979  PMID: 20438375
12.  T Cell Subsets in HIV Infected Patients after Successful Combination Antiretroviral Therapy: Impact on Survival after 12 Years 
PLoS ONE  2012;7(7):e39356.
Objectives
Immune activation is decreased by combination antiretroviral therapy (cART) in patients infected with human immunodeficiency virus (HIV), but residual activation remains and has been proposed as a cause of premature aging and death, but data are lacking. We analyzed the relationship between T-cell subsets after 18 months of cART and overall survival during 12 years of follow up.
Methods
A cohort of 101 HIV infected patients who had undetectable plasma HIV after starting cART was included in 1997–1998. T cell subsets were analyzed by flowcytometry after 18 months of cART. Relation to survival was calculated using Kaplan-Meier curves and multiple Cox regression.
Results
Seventeen patients died during the observation period. The leading causes of death were non-AIDS cancer and cardiovascular disease. Higher levels of CD8 memory T cells (CD8+,CD45RO+,CD45RA-) showed a significant beneficiary effect on survival, HR of 0.95 (95% confidence interval 0.91–0.99, P = 0.016) when adjusted for age, nadir CD4 count, CD4 count, and AIDS and hepatitis C status. T cell activation was not associated with increased risk of death.
Conclusions
Larger and longitudinal studies are needed to accurately establish prognostic factors, but overall results seem to suggest that prognostic information exists within the CD8 compartment.
doi:10.1371/journal.pone.0039356
PMCID: PMC3398907  PMID: 22815704
13.  The Rising Challenge of Non–AIDS-Defining Cancers in HIV-Infected Patients 
In the post–highly active combination antiretroviral therapy era, human immunodeficiency virus (HIV)-infected patients are facing high rates of so–called non–AIDS–defining cancers. The challenge facing clinicians caring for HIV patients is how best to screen, treat, and prevent these cancers.
Since the advent of HAART, patients with HIV infection have seen a significant improvement in their morbidity, mortality, and life expectancy. The incidence of AIDS-defining illnesses, including AIDS-defining malignancies, has been on the decline. However, deaths due to non–AIDS-defining illnesses have been on the rise. These so-called non–AIDS-defining cancers (NADCs) include cancers of the lung, liver, kidney, anus, head and neck, and skin, as well as Hodgkin's lymphoma. It is poorly understood why this higher rate of NADCs is occurring. The key challenge facing oncologists is how to administer chemotherapy effectively and safely to patients on antiretroviral therapy. The challenge to clinicians caring for HIV-infected patients is to develop and implement effective means to screen, treat, and prevent NADCs in the future. This review presents data on the epidemiology and etiology of NADCs, as well as ongoing research into this evolving aspect of the HIV epidemic.
doi:10.1093/cid/cis613
PMCID: PMC3529613  PMID: 22776851
14.  Short-Term Clinical Disease Progression in HIV-Infected Patients Receiving Combination Antiretroviral Therapy: Results from the TREAT Asia HIV Observational Database 
Objective
The aim of our study was to develop, on the basis of simple clinical data, predictive short-term risk equations for AIDS or death in Asian patients infected with human immunodeficiency virus (HIV) who were included in the TREAT Asia HIV Observational Database.
Methods
Inclusion criteria were highly active antiretroviral therapy initiation and completion of required laboratory tests. Predictors of short-term AIDS or death were assessed using Poisson regression. Three different models were developed: a clinical model, a CD4 cell count model, and a CD4 cell count and HIV RNA level model. We separated patients into low-risk, high-risk, and very high-risk groups according to the key risk factors Identified.
Results
In the clinical model, patients with severe anemia or a body mass index (BMI; calculated as the weight in kilograms divided by the square of the height in meters) ≤18 were at very high risk, and patients who were aged <40 years or were male and had mild anemia were at high risk. In the CD4 cell count model, patients with a CD4 cell count <50 cells/µL, severe anemia, or a BMI ≤18 were at very high risk, and patients who had a CD4 cell count of 51–200 cells/µL, were aged <40 years, or were male and had mild anemia were at high risk. In the CD4 cell count and HIV RNA level model, patients with a CD4 cell count <50 cells/µL, a detectable viral load, severe anemia, or a BMI ≤18 were at very high risk, and patients with a CD4 cell count of 51–200 cells/µL and mild anemia were at high risk. The incidence of new AIDS or death in the clinical model was 1.3, 4.9, and 15.6 events per 100 person-years in the low-risk, high-risk, and very high-risk groups, respectively. In the CD4 cell count model the respective incidences were 0.9, 2.7, and 16.02 events per 100 person-years; in the CD4 cell count and HIV RNA level model, the respective incidences were 0.8, 1.8, and 6.2 events per 100 person-years.
Conclusions
These models are simple enough for widespread use in busy clinics and should allow clinicians to identify patients who are at high risk of AIDS or death in Asia and the Pacific region and in resource-poor settings.
doi:10.1086/597354
PMCID: PMC2758295  PMID: 19226231
15.  Towards a combined prognostic index for survival in HIV infection: the role of ‘non-HIV’ biomarkers 
HIV medicine  2009;11(2):143-151.
Background
As those with HIV infection live longer, ‘non-AIDS’ condition associated with immunodeficiency and chronic inflammation are more common. We ask whether ‘non-HIV’ biomarkers improve differentiation of mortality risk among individuals initiating combination antiretroviral therapy (cART).
Methods
Using Poisson models, we analysed data from the Veterans Aging Cohort Study (VACS) on HIV-infected veterans initiating cART between 1 January 1997 and 1 August 2002. Measurements included: HIV biomarkers (CD4 cell count, HIV RNA and AIDS-defining conditions); ‘non-HIV’ biomarkers (haemoglobin, transaminases, platelets, creatinine, and hepatitis B and C serology); substance abuse or dependence (alcohol or drug); and age. Outcome was all cause mortality. We tested the discrimination (C statistics) of each biomarker group alone and in combination in development and validation data sets, over a range of survival intervals, and adjusting for missing data.
Results
Of veterans initiating cART, 9784 (72%) had complete data. Of these, 2566 died. Subjects were middle-aged (median age 45 years), mainly male (98%) and predominantly black (51%). HIV and ‘non-HIV’ markers were associated with each other (P<0.0001) and discriminated mortality (C statistics 0.68–0.73); when combined, discrimination improved (P<0.0001). Discrimination for the VACS Index was greater for shorter survival intervals [30-day C statistic 0.86, 95% confidence interval (CI) 0.80–0.91], but good for intervals of up to 8 years (C statistic 0.73, 95% CI 0.72–0.74). Results were robust to adjustment for missing data.
Conclusions
When added to HIV biomarkers, ‘non-HIV’ biomarkers improve differentiation of mortality. When evaluated over similar intervals, the VACS Index discriminates as well as other established indices. After further validation, the VACS Index may provide a useful, integrated risk assessment for management and research.
doi:10.1111/j.1468-1293.2009.00757.x
PMCID: PMC3077949  PMID: 19751364
anaemia; CD4 cell count; hepatitis C coinfection; hepatology; injecting drug use; outcomes; renal/kidney; risk groups; viral load
16.  Trends in mortality statistics in England and Wales with particular reference to AIDS from 1984 to April 1987 
Death certification should be able to provide accurate data on the number of deaths due to AIDS as a basis for predicting future deaths from the syndrome. Trends in deaths from other causes may identify conditions that have not been recognised to be associated with HIV infection. Mortality statistics with reference to AIDS in England and Wales were completed from death certificates. Increases in deaths from selected causes likely to be associated with AIDS or HIV infection suggested that in some patients with HIV infection, AIDS was not stated on the death certificate or subsequently notified by the doctor who signed the certificate. From calculations of excess deaths between the beginning of 1985 and the end of April 1987, compared with 1984 at least 495 deaths possibly associated with HIV infection were estimated to have occurred among men aged 15-54 during that period. In 261 AIDS or HIV infection was stated on the original or amended death entry as the cause of death, and of these 198 were included in the estimated number of excess deaths.
Accurate notification of the underlying cause of death and associated diseases is required for the precise monitoring of trends in mortality from AIDS and possible identification of unrecognised conditions associated with HIV infection.
PMCID: PMC2545765  PMID: 3133053
17.  Human immunodeficiency virus type 2 in two Saudi families 
Annals of Saudi Medicine  2011;31(4):417-420.
Human immunodeficiency virus type 2 (HIV-2), the second retrovirus that causes the acquired immune deficiency syndrome (AIDS) in humans, is limited in its distribution to West Africa. We report cases in two Saudi families with HIV-2 infection and AIDS, resulting in death of the index cases—the husbands, while the wives and a daughter were maintained on antiretroviral therapy. When HIV viral loads were undetectable in initial assays, further testing confirmed the presence of HIV-2. In the first family, the 30-year-old wife was found to be HIV-positive after the diagnosis in her 30-year-old husband, who later died with AIDS. In the second family, HIV-2 infection was diagnosed in the 50-year-old wife and 18-year-old daughter of a man who had died of AIDS at the age of 48 years. Recognizing HIV-2 infection is essential for appropriate workup, assessment, therapy and care of the pregnant woman.
doi:10.4103/0256-4947.76408
PMCID: PMC3156521  PMID: 21293067
18.  HIV/AIDS and Colorectal Cancer 
Gastroenterology & Hepatology  2008;4(4):274-278.
Since the discovery of HIV/AIDS and the introduction of antiretroviral therapy, there have been many observations regarding the causes of HIV/AIDS deaths, opportunistic infections, and coexisting diseases such as non-AIDS-defining malignancies. The bulk of the literature worldwide has been epidemiologic and has involved cross-linkage of both HIV/AIDS and cancer registries. Prior retrospective studies have also utilized death certificates. Initial large-scale studies have not identified an increased risk of colon cancer in the HIV/AIDS population, and scrutiny of the literature has elucidated major limitations, most notably the lack of screening data. Only recently have there been studies addressing the rate of colon cancer screening in the HIV/AIDS population. There have also been reports suggesting an elevated risk and earlier age of onset of colonic neoplasia in the HIV/AIDS population. This review summarizes literature from the last two decades regarding HIV/AIDS and colorectal cancer and endeavors to stimulate interest in further investigation of a possible association.
PMCID: PMC3093732  PMID: 21960912
HIV/AIDS; colorectal cancer
19.  Improved survival among HIV-infected patients after initiation of triple-drug antiretroviral regimens 
BACKGROUND: The efficacy of triple-drug antiretroviral regimens in the treatment of patients infected with HIV has been established in several randomized clinical trials. However, the effectiveness of these new regimens in patient populations outside clinical trials remain unproven. This study compared mortality and AIDS-free survival among HIV-infected patients in British Columbia who were treated with double- and triple-drug regimens. METHODS: The authors used a prospective, population-based cohort design to study a population of HIV-positive men and women 18 years or older for whom antiretroviral therapy was first prescribed between Oct. 1, 1994, and Dec. 31, 1996; all patients were from British Columbia. Rates of progression from the initiation of antiretroviral therapy to death or to diagnosis of primary AIDS were determined for patients who initially received an ERA-II regimen (2 nucleoside analogue reverse transcriptase inhibitors [NRTIs] including lamivudine or stavudine, or both) and for those who initially received an ERA-III regimen (triple-drug regimen consisting of 2 NRTIs and a protease inhibitor [indinavir, ritonavir or saquinavir] or a non-NRTI [nevirapine]). RESULTS: A total of 500 men and women (312 receiving an ERA-III regimen and 188 an ERA-III regimen) were eligible. Patients in the ERA-III group survived significantly longer than those in the ERA-II group. As of Dec. 31, 1997, 40 patients had died (35 in the ERA-II group and 5 in the ERA-III group), for a crude mortality rate of 8.0%. The cumulative mortality rates at 12 months were 7.4% (95% confidence interval [CI] 5.9% to 8.9%) for patients in the ERA-II group and 1.6% (95% CI 0.7% to 2.5%) for those in the ERA-III group (log rank p = 0.003). The likelihood of death was more than 3 times higher among patients in the ERA-II group (mortality risk ratio 3.82 [95% CI 1.48% to 9.84], p = 0.006). After adjustment for prophylaxis for Pneumocystis carinii pneumonia or Mycobacterium avium infection, AIDS diagnosis, CD4+ cell count, sex and age at initiation of therapy, the likelihood of death among patients in the ERA-II group was 3.21 times higher (95% CI 1.24 to 8.30, p = 0.016) than in the ERA-III group. Cumulative rates of progression to AIDS or death at 12 months were 9.6% (95% CI 7.7% to 11.5%) in the ERA-II group and 3.3% (95% CI 1.8% to 4.8%) in the ERA-III group (log rank p = 0.006). After adjustment for prognostic variables (prophylaxis for P. carinii pneumonia or M. avium infection, CD4+ cell count, sex and age at initiation of treatment), the likelihood of progression to AIDS or death at 12 months among patients in the ERA-II group was 2.37 times higher (95% CI 1.04 to 5.38, p = 0.040) than in the ERA-III group. INTERPRETATION: This population-based cohort study confirms that patients initially treated with a triple-drug antiretroviral regimen comprising 2 NRTIs plus protease inhibitor or a non-NRTI have a lower risk of morbidity and death than patients treated exclusively with 2 NRTIs.
PMCID: PMC1230111  PMID: 10102000
20.  Trends in Mortality and Causes of Death among Women with HIV in the US: A Ten-year Study 
Background
To assess trends in mortality and cause of death for women with HIV, we studied deaths over a 10 year period among participants in the Women’s Interagency HIV Study (WIHS), a representative US cohort.
Methods
Deaths were ascertained by National Death Index-Plus match and causes of death determined by death certificate.
Results
From 1995 through 2004, 710 of 2792 HIV-infected participants died. During this interval the standardized mortality ratio (SMR) fell from a high of 24.7 in 1996 to a plateau with a mean of 10.3 from 2001–2004. Over the decade, deaths from non-AIDs causes increased and accounted for the majority of deaths by 2001–2004. The most common non-AIDS causes of death were trauma or overdose, liver disease, cardiovascular disease and malignancy. Independent predictors of mortality besides HIV-associated variables were depressive symptoms, and active hepatitis B or C. Women who were overweight or obese were significantly less likely to die of AIDS than women of normal weight.
Conclusion
In the WIHS, the death rate has plateaued in recent years. While HIV-associated factors predicted AIDS and non-AIDS deaths, other treatable conditions predicted mortality. Further gains in reducing mortality among HIV-infected women may require broader access to therapies for depression, viral hepatitis and HIV itself.
doi:10.1097/QAI.0b013e3181acb4e5
PMCID: PMC2769934  PMID: 19487953
HIV; mortality; women; viral hepatitis; non-AIDs mortality
21.  Cancer incidence in the Multicenter AIDS Cohort Study before and during the HAART era: 1984–2007 
Cancer  2010;116(23):5507-5516.
Background
The incidence of Kaposi’s sarcoma (KS) and non-Hodgkin’s lymphoma (NHL) among human immunodeficiency virus (HIV)-infected individuals declined following the introduction of highly active antiretroviral therapy (HAART) in the mid 1990s, but the cancer risk associated with HIV infection during the HAART era remains to be clarified.
Methods
We compared cancer incidence among HIV-infected and -uninfected participants in the Multicenter AIDS Cohort Study (MACS) between 1984 and 2007 to the expected incidence using US population-based data from the Surveillance, Epidemiology, and End Results (SEER) Program, and we compared age and race adjusted cancer incidence rates by HIV status and over time within the MACS. Exact statistical methods were used for all analyses.
Results
933 incident cancers were observed during 77,320 person-years of follow-up. Compared to SEER, MACS HIV-infected men had significantly (p<0.05) elevated rates of KS (standardized incidence ratio (SIR)=139.10), NHL (SIR=36.80), Hodgkin’s lymphoma (HL) (SIR=7.30), and anal cancer (SIR=25.71). Within MACS, HIV infection was independently associated with each of these cancers across the entire follow-up period, and KS (incidence rate ratio (IRR)=54.93), NHL (IRR=11.18), and anal cancer (IRR=18.50) were each significantly elevated among HIV-infected men during the HAART era. Among these men, the incidence of KS and NHL declined (IRR=0.13 and 0.23, respectively), anal cancer incidence increased (IRR=5.84), and HL incidence remained statistically unchanged (IRR=0.75) from the pre-HAART to the HAART era.
Conclusion
Cancer risk remains elevated among HIV-infected men who have sex with men, highlighting the continuing need for appropriate cancer screening in this population.
doi:10.1002/cncr.25530
PMCID: PMC2991510  PMID: 20672354
HIV infection; cancer incidence; malignancy; AIDS-defining malignancy; HAART
22.  HIV stroke risk: evidence and implications 
An estimated 34 million men, women, and children are infected with human immunodeficiency virus type 1 (HIV-1), the virus that causes acquired immunodeficiency syndrome (AIDS). Current technology cannot eradicate HIV-1, and most patients with HIV-1-infection (HIV+) will require lifelong treatment with combined antiretroviral therapy (cART). Stroke was recognized as a complication of HIV-1 infection since the early days of the epidemic. Potential causes of stroke in HIV-1 include opportunistic infections, tumors, atherosclerosis, diabetes, hypertension, autoimmunity, coagulopathies, cardiovascular disease, and direct HIV-1 infection of the arterial wall. Ischemic stroke has emerged as a particularly significant neurological complication of HIV-1 and its treatment due to the aging of the HIV+ population, chronic HIV-1 infection, inflammation, and prolonged exposure to cART. New prevention and treatment strategies tailored to the needs of the HIV+ population are needed to address this issue.
doi:10.1177/2040622312471840
PMCID: PMC3610259  PMID: 23556125
atherosclerosis; cerebrovascular; human immunodeficiency virus type 1; infection; inflammation; stroke
23.  HIV-Associated Hodgkin's Lymphoma: Prognosis and Therapy in the Era of cART 
Advances in Hematology  2012;2012:507257.
Patients with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) are at increased risk for developing Hodgkin's lymphoma (HL), a risk that has not decreased despite the success of combination antiretroviral therapy (cART) in the modern era. HIV-associated HL (HIV-HL) differs from HL in non-HIV-infected patients in that it is nearly always associated with Epstein-Barr virus (EBV) and more often presents with high-risk features of advanced disease, systemic “B” symptoms, and extranodal involvement. Before the introduction of cART, patients with HIV-HL had lower response rates and worse outcomes than non-HIV-infected HL patients treated with conventional chemotherapy. The introduction of cART, however, has allowed for the delivery of full-dose and dose-intensive chemotherapy regimens with improved outcomes that approach those seen in non-HIV infected patients. Despite these significant advances, HIV-HL patients remain at increased risk for treatment-related toxicities and drug-drug interactions which require careful attention and supportive care to insure the safe administration of therapy. This paper will address the modern diagnosis, risk stratification, and therapy of HIV-associated HL.
doi:10.1155/2012/507257
PMCID: PMC3261478  PMID: 22272202
24.  Copy-Years Viremia as a Measure of Cumulative Human Immunodeficiency Virus Viral Burden 
American Journal of Epidemiology  2009;171(2):198-205.
Plasma human immunodeficiency virus type 1 (HIV-1) viral load is a valuable tool for HIV research and clinical care but is often used in a noncumulative manner. The authors developed copy-years viremia as a measure of cumulative plasma HIV-1 viral load exposure among 297 HIV seroconverters from the Multicenter AIDS Cohort Study (1984–1996). Men were followed from seroconversion to incident acquired immunodeficiency syndrome (AIDS), death, or the beginning of the combination antiretroviral therapy era (January 1, 1996); the median duration of follow-up was 4.6 years (interquartile range (IQR), 2.7–6.5). The median viral load and level of copy-years viremia over 2,281 semiannual follow-up assessments were 29,628 copies/mL (IQR, 8,547–80,210) and 63,659 copies × years/mL (IQR, 15,935–180,341). A total of 127 men developed AIDS or died, and 170 survived AIDS-free and were censored on January 1, 1996, or lost to follow-up. Rank correlations between copy-years viremia and other measures of viral load were 0.56–0.87. Each log10 increase in copy-years viremia was associated with a 1.70-fold increased hazard (95% confidence interval: 0.94, 3.07) of AIDS or death, independently of infection duration, age, race, CD4 cell count, set-point, peak viral load, or most recent viral load. Copy-years viremia, a novel measure of cumulative viral burden, may provide prognostic information beyond traditional single measures of viremia.
doi:10.1093/aje/kwp347
PMCID: PMC2878100  PMID: 20007202
acquired immunodeficiency syndrome; HIV; HIV infections; viral load; viremia
25.  HIV infection, aging, and immune function: implications for cancer risk and prevention 
Current opinion in oncology  2012;24(5):506-516.
Purpose of review
Combination antiretroviral therapy (ART) has turned HIV infection into a complex chronic disease. This article documents cancer risk among HIV-infected persons, reviews immune system effects of HIV infection in relation to cancer risk, discusses implications for cancer prevention, and suggests future research directions.
Recent findings
There has been a shift in the cancer spectrum from AIDS-defining cancers (ADC) to non-ADC, although the burden of ADC remains high. Although a high prevalence of non-HIV cancer risk factors among HIV-infected persons contributes to cancer risk, substantial evidence has accumulated in favor of an independent association between HIV-induced immunodeficiency and elevated risk of many specific cancer types, most of viral cause, although further work is needed to disentangle immunodeficiency and smoking effects for lung cancer, and immunodeficiency and hepatitis virus effects for liver cancer. Relationships between cancer risk and two other immune system hallmarks of HIV infection, chronic inflammation, and immune dysfunction/senescence, remain poorly understood.
Summary
Early, sustained ART is a crucial component of cancer prevention. Continued epidemiologic monitoring is needed to detect possible effects on cancer risk of specific ART classes or medications, long-term exposure to systemic inflammation or immune dysfunction, or earlier or more effective ART.
doi:10.1097/CCO.0b013e328355e131
PMCID: PMC3695478  PMID: 22759737
aging; cancer; HIV; immune system; inflammation

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