Acquired Immunodeficiency Syndrome Cohort Research Articles

Genetic factors associated with age-related macular degeneration modulating plasma inflammatory biomarker levels in patients with AIDS

ABSTRACT Introduction Patients with the acquired immunodeficiency syndrome (AIDS) have an increased prevalence and incidence of intermediate-stage age-related macular degeneration (AMD). Several elevated plasma inflammatory biomarkers are associated with increased incidence of intermediate-stage AMD in this population. We evaluated the association between AMD risk alleles and plasma inflammatory biomarker levels in persons with AIDS. Materials and Methods Cryopreserved plasma specimens of 229 non-Hispanic White and 252 non-Hispanic blacks from the Longitudinal Study of the Ocular Complications of AIDS cohort were assayed for plasma levels of soluble tumor necrosis factor receptor (sTNFR) 2, interleukin (IL)-18, C × 3motif chemokine ligand 1 (CX3CL1), C-reactive protein (CRP), and soluble CD14 (sCD14). Genotyping included AMD-associated variants rs10801553 and rs800292 for complement factor H (CFH) rs9332739 and rs547154 for complement factor 2 (C2), rs2230199 for C3, rs2285714 for CFI, and rs3732379 and rs3732378 for C × 3motif chemokine receptor 1 (CX3CR1). Results In Whites, AMD low-risk CX3CR1 variants (V249I and T280M) were associated with reduced plasma levels of IL-18. In Blacks, AMD low-risk C3 R102G and low-risk CX3CR1 T280M variants were associated with reduced CRP levels. Conclusions Genetic variants in AMD-associated immune genes may influence AMD-associated systemic plasma inflammatory biomarker levels in patients with AIDS.

Impact of Human Immunodeficiency Virus on Postoperative Outcomes following Osteonecrosis-Indicated Total Hip Arthroplasty

AbstractOsteonecrosis (ON) of the femoral head in human immunodeficiency virus (HIV)-positive patients is often treated with total hip arthroplasty (THA). The purpose of this study was to determine the effect that HIV positive status and acquired immunodeficiency syndrome (AIDS) have on postoperative complication rates and outcomes in patients with ON treated with THA. Patients who underwent primary ON-indicated THA with a minimum of 2-year follow-up were identified in a national database (PearlDiver Technologies) using Current Procedural Terminology and International Classification of Diseases codes. These patients were stratified into two cohorts: those who were HIV-positive and those who were HIV-negative (control). The HIV-positive cohort was further stratified into those with AIDS and those with asymptomatic HIV at the time of THA. Univariate and multivariate analyses were conducted to determine associations between the three cohorts and their 90-day, and 2-year outcomes were each compared with HIV-negative patients. In this study, 1,163 patients were in the HIV-positive cohort and 34,288 were in the HIV-negative cohort. In the HIV-positive cohort, there were significantly higher 90-day rates of renal failure (odds ratio [OR] = 1.874; p < 0.001), pneumonia (OR = 1.682; p = 0.002), and sepsis (OR = 1.975; p < 0.001). The asymptomatic HIV cohort and AIDS cohort followed similar associations as the HIV cohort; however, the AIDS cohort also had significantly higher rate of blood transfusion (OR = 1.692; p = 0.012) and deep vein thrombosis (OR = 1.765; p = 0.036). HIV infection, whether symptomatic or not, and AIDS are associated with a higher risk of short-term complications after THA. Physicians must consider this risk and discuss with their patients to reduce future complications.

Toxoplasmic Encephalitis in an AIDS Cohort at Puerto Rico before and after Highly Active Antiretroviral Therapy (HAART)

Highly active antiretroviral therapy (HAART) significantly reduced the toxoplasmic encephalitis (TE) incidence in acquired immunodeficiency syndrome (AIDS) patients. The TE incidence and mortality were evaluated in an AIDS cohort followed in Puerto Rico before, during, and after HAART implementation in the Island. Of the 2,431 AIDS studied patients 10.9% had TE diagnosis, with an incidence density that decreased from 5.9/100 person-years to 1.1/100 person-years after HAART. Cox proportional hazard analysis showed substantial mortality reduction among TE cases who received HAART. No mortality reduction was seen in those cases who received TE prophylaxis. Although this study shows a TE incidence and mortality reduction in the AIDS cohort after HAART, the incidence was higher than those reported in the United States AIDS patients. Poor TE prophylaxis compliance might explain the lack of impact of this intervention. Strengthening the diagnostic and opportune TE diagnosis and prompt initiation of HAART in susceptible patients is important to control this opportunistic infection.

Cancer incidence in the multicenter aids cohort study before and during the HAART era

The incidence of Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) among human immunodeficiency virus (HIV)-infected individuals declined after 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. Cancer incidence among HIV-infected and HIV-uninfected participants in the Multicenter AIDS (acquired immunodeficiency syndrome) Cohort Study (MACS) between 1984 and 2007 was compared with the expected incidence using US population-based data from the Surveillance, Epidemiology, and End Results (SEER) program. Age- and race-adjusted cancer incidence rates were also compared HIV by status and over time within the MACS. Exact statistical methods were used for all analyses. A total of 933 incident cancers were observed during 77,320 person-years of follow-up. Compared with SEER, MACS HIV-infected men had significantly (P<.05) elevated rates of KS (standardized incidence ratio [SIR], 139.10), NHL (SIR, 36.80), Hodgkin lymphoma (HL)(SIR, 7.30), and anal cancer (SIR, 25.71). Within MACS, HIV infection was found to be 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 found to be 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), the incidence of anal cancer increased (IRR, 5.84), and the incidence of HL remained statistically unchanged (IRR, 0.75) from the pre-HAART to the HAART era. Cancer risk remains elevated among HIV-infected men who have sex with men, highlighting the continuing need for appropriate cancer screening in this population.

Cytokine signaling pathway polymorphisms and AIDS-related non-Hodgkin lymphoma risk in the multicenter AIDS cohort study

Cytokine stimulation of B-cell proliferation may be an important causative mechanism for acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). The Epstein-Barr virus (EBV) may be a co-factor, particularly for primary central nervous system (CNS) tumors, which are uniformly EBV-positive in the setting of AIDS. Thus, we examined associations of genetic variation in IL10 and related cytokine-signaling molecules (IL10RA, CXCL12, IL13, IL4, IL4R, CCL5 and BCL6) with AIDS-related NHL risk and evaluated differences between primary CNS and systemic tumors. We compared 160 Multicenter AIDS Cohort Study (MACS) participants with incident lymphomas, of which 90 followed another AIDS diagnosis, to HIV-1-seropositive controls matched on duration of lymphoma-free survival post-HIV-1 infection (N = 160) or post-AIDS diagnosis (N = 90). We fit conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Carriage of at least one copy of the T allele for the IL10 rs1800871 (as compared to no copies) was associated with decreased AIDS-NHL risk specific to lymphomas arising from the CNS (CC vs. CT/TT: OR = 0.3; 95% CI 0.1, 0.7) but not systemically (CC vs. CT/TT: OR = 1.0; 95% CI 0.5, 1.9) (Pheterogeneity = 0.03). Carriage of two copies of the 'low IL10' haplotype rs1800896_A/rs1800871_T/rs1800872_A was associated with decreased lymphoma risk that varied by number of copies (Ptrend = 0.02). None of the ORs for the other studied polymorphisms was significantly different from 1.0. Excessive IL10 response to HIV-1 infection may be associated with increased risk of NHL, particularly in the CNS. IL10 dysregulation may be an important causative pathway for EBV-related lymphomagenesis.

Persistent GB virus C infection and survival in HIV-infected men.

GB virus C (GBV-C), which is not known to be pathogenic in humans, replicates in lymphocytes, inhibits the replication of human immunodeficiency virus (HIV) in vitro, and has been associated with a decreased risk of death among HIV-positive persons in some, but not all, studies. Previous studies did not control for differences in the duration of HIV or GBV-C infection. We evaluated 271 men who were participants in the Multicenter Acquired Immunodeficiency Syndrome Cohort Study for GBV-C viremia (by means of a reverse-transcriptase-polymerase-chain-reaction assay) or E2 antibody (by means of an enzyme-linked immunosorbent assay) 12 to 18 months after seroconversion to positivity for HIV (the early visit); a subgroup of 138 patients was also evaluated 5 to 6 years after HIV seroconversion (the late visit). GBV-C infection was detected in 85 percent of men with HIV seroconversion on the basis of the presence of E2 antibody (46 percent) or GBV-C RNA (39 percent). Only one man acquired GBV-C viremia between the early and the late visit, but 9 percent of men had clearance of GBV-C RNA between these visits. GBV-C status 12 to 18 months after HIV seroconversion was not significantly associated with survival; however, men without GBV-C RNA 5 to 6 years after HIV seroconversion were 2.78 times as likely to die as men with persistent GBV-C viremia (95 percent confidence interval, 1.34 to 5.76; P=0.006). The poorest prognosis was associated with the loss of GBV-C RNA (relative hazard for death as compared with men with persistent GBV-C RNA, 5.87; P=0.003). GBV-C viremia was significantly associated with prolonged survival among HIV-positive men 5 to 6 years after HIV seroconversion, but not at 12 to 18 months, and the loss of GBV-C RNA by 5 to 6 years after HIV seroconversion was associated with the poorest prognosis. Understanding the mechanisms of interaction between GBV-C and HIV may provide insight into the progression of HIV disease.

Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Multicenter AIDS Cohort Study Investigators.

Time to development of acquired immunodeficiency syndrome (AIDS) and time to death have been extended with the increased use of combination therapy and protease inhibitors. Cohort studies following up persons with human immunodeficiency virus (HIV) infection in periods characterized by different therapies offer the opportunity to estimate therapy effectiveness at the population level. To assess the effectiveness of self-reported, long-term potent antiretroviral therapy in a cohort of 536 men whose duration of HIV infection was known (seroconverters). Cohort study. The cohort was compared for time to development of AIDS and time to death in 1984 to 1990, 1990 to 1993, 1993 to July 1995, and July 1995 to July 1997 when the major treatments were no therapy, monotherapy, combined therapy, and potent antiretroviral therapy, respectively. Survival analysis methods with time zero set as the date of seroconversion and incorporating staggered entries into each period were used. Mean CD4 cell change, stratified by infection duration, was determined for each period using a random effects model. The Multicenter AIDS Cohort Study (MACS) in 4 urban areas (Baltimore, Md; Chicago, III; Los Angeles, Calif; and Pittsburgh, Pa). A total of 5622 men who were 18 years or older were enrolled into MACS. Of the 5622, there were 2191 HIV-positive individuals at enrollment. Of the 3431 men who were HIV-negative, 536 were observed to seroconvert and were followed up for up to 13 years. The group of 536 who seroconverted constituted the study population. Time from seroconversion to development of AIDS and to death and change in CD4 cell count. A total of 231 seroconverters developed AIDS, and 200 men died. Using 1990 to 1993 as the reference period, the relative hazard of AIDS was 1.04 (95% confidence interval [CI], 0.73-1.48) during 1993 to July 1995 and 0.35 (95% CI, 0.20-0.61) during July 1995 to July 1997. Relative hazards of death were 0.87 (95% CI, 0.58-1.31) and 0.62 (95% CI, 0.38-1.01 ) for the same periods. The relative time (the factor by which times are contracted or expanded) to development of AIDS was 0.97 (95% CI, 0.86-1.09) for 1993 to July 1995 and 1.63 (95% CI, 1.40-1.89) for July 1995 to July 1997. Relative survival time for 1993 to July 1995 was 1.01 (95% CI, 0.91-1.12) and for July 1995 to July 1997 was 1.21 (95% CI, 1.07-1.36) relative to 1990 to 1993. The rate of CD4 cell count decline in July 1995 to July 1997 was significantly lower (P<.05) compared with the previous 2 periods. In the calendar period when potent antiretroviral therapy was introduced, the time to development of AIDS and time to death were extended, and rate of CD4 cell count decline was arrested.

Protective effect of an SDF-1 variant in HIV disease: abstract and commentary.

Stromal-derived factor (SDF-1) is the principal ligand for CXCR4, a coreceptor with CD4 for T lymphocyte cell line–tropic human immunodeficiency virus–type 1 (HIV-1). A common polymorphism, SDF1-3′A, was identified in an evolutionarily conserved segment of the 3′ untranslated region of the SDF-1 structural gene transcript. In the homozygous state, SDF1-3′A/3′A delays the onset of acquired immunodeficiency syndrome (AIDS), according to a genetic association analysis of 2857 patients enrolled in five AIDS cohort studies. The recessive protective effect of SDF1-3′A was increasingly pronounced in individuals infected with HIV-1 for longer periods, was twice as strong as the dominant genetic restriction of AIDS conferred by CCR5 and CCR2 chemokine receptor variants in these populations, and was complementary with these mutations in delaying the onset of AIDS.

Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE Study, Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC)

Stromal-derived factor (SDF-1) is the principal ligand for CXCR4, a coreceptor with CD4 for T lymphocyte cell line-tropic human immunodeficiency virus-type 1 (HIV-1). A common polymorphism, SDF1-3'A, was identified in an evolutionarily conserved segment of the 3' untranslated region of the SDF-1 structural gene transcript. In the homozygous state, SDF1-3'A/3'A delays the onset of acquired immunodeficiency syndrome (AIDS), according to a genetic association analysis of 2857 patients enrolled in five AIDS cohort studies. The recessive protective effect of SDF1-3'A was increasingly pronounced in individuals infected with HIV-1 for longer periods, was twice as strong as the dominant genetic restriction of AIDS conferred by CCR5 and CCR2 chemokine receptor variants in these populations, and was complementary with these mutations in delaying the onset of AIDS.

Serum hormones in men with human immunodeficiency virus-associated wasting.

Weight loss is commonly associated with increased morbidity and mortality in individuals with human immunodeficiency virus (HIV) infection. We performed a nested case-control study of 26 HIV-infected subjects recruited from a cohort of gay men enrolled in the Multicenter Acquired Immunodeficiency Syndrome Cohort Study. To test the hypothesis that hormonal changes precede and may induce the wasting syndrome, we performed a nested case-control study and analyzed serum gonadal steroids and GH in samples of HIV-infected men with or without weight loss, uncomplicated by diarrhea or ever having an opportunistic infection. We studied 13 cases (mean age +/- SD, 45 +/- 7.2 yr) with a mean weight loss of 13 +/- 3.6%, considered to have the wasting syndrome by Centers for Disease Control criteria (weight loss of > 10%) and 13 controls matched for age and duration of follow-up. Serum bioavailable testosterone (T) levels decreased in the case group (P < 0.05) before the definition of wasting was attained, although weight loss had already begun. More impressive declines occurred in serum T (P = 0.012), free T (P = 0.0025), and bioavailable T (P < 0.0001) during the 6 months immediately before documentation of wasting. These changes were concurrent with an increase in serum FSH (P = 0.0135) without a change in serum LH. We conclude that a decline in bioavailable T occurs early in the course of events leading to wasting, suggesting that changes in gonadal hormones may contribute to the multifactorial etiology of the wasting syndrome.

Replacing time since human immunodeficiency virus infection by marker values in predicting residual time to acquired immunodeficiency syndrome diagnosis. Multicenter AIDS Cohort Study.

It is widely assumed that the time since human immunodeficiency virus (HIV) infection is an important indicator of HIV disease stage, yet for most infected individuals the date of infection is unknown. We consider whether marker values, such as CD4 lymphocyte number or percent and levels of serum beta2 microglobulin or serum neopterin, render time since infection unimportant for predicting the residual time to acquired immunodeficiency syndrome (AIDS) diagnosis. The Multicenter AIDS Cohort Study (MACS) contains a subsample of homosexual men whose date of HIV seroconversion is known within +/-6 months and who provide data for this analysis. From this subsample, we extract two overlapping data subsets. The first subset consists of 370 persons whose 3,723 study visits include complete data on the cellular markers CD4 lymphocyte number and percent for a period of 9 years. The second consists of 272 persons whose 1,593 visits include complete information on cellular markers and on the serological markers beta2-microglobulin and neopterin for a period of 5 1/2 years. We model the residual time to AIDS diagnosis with a regression model, in which cellular and serologic markers are the explanatory covariates (independent variables) and the residual time to AIDS is the responses variable (dependent variable). A robust estimate of the variance-covariance matrix corrects for the dependence of repeated measurements in the same individual. In the case of CD4 number and percent, the results indicate that time since infection is of none or at most little importance if the marker value is known, suggesting that time since infection can be adequately replaced by the combination of marker values. However, the serological markers alone do not eliminate the importance of the time since infection.

Effects of Micronutrient Intake on Survival in Human Immunodeficiency Virus Type 1 Infection

The authors examined the relation between dietary and supplemental micronutrient intake and subsequent mortality among 281 human immunodeficiency type 1 (HIV-1)-infected participants at the Baltimore, Maryland/Washington, DC, site of the Multicenter Acquired Immunodeficiency Syndrome Cohort Study. Subjects completed a semiquantitative food frequency questionnaire at their baseline visit in 1984. Levels of daily micronutrient intake were examined in relation to subsequent mortality over the 8-year follow-up period by using multivariate Cox models, adjusting for age, symptoms, CD4+ count, energy intake, and treatment. The highest quartile of intake for each B-group vitamin was independently associated with improved survival: B1 (relative hazard (RH) = 0.60, 95% confidence interval (CI) 0.38-0.95), B2 (RH = 0.59, 95% CI 0.38-0.93), B6 (RH = 0.45, 95% CI 0.28-0.73), and niacin (RH = 0.57, 95% CI 0.36-0.91). In a final model, the third quartile of beta-carotene intake (RH = 0.60, 95% CI 0.37-0.98) was associated with improved survival, while increasing intakes of zinc were associated with poorer survival. Intakes of B6 supplements at more than twice the recommended dietary allowance were associated with improved survival (RH = 0.60, 95% CI 0.39-0.93), while intakes of B1 and B2 supplements at levels greater than five times the recommended dietary allowance were associated with improved survival (B1: RH = 0.61, 95% CI 0.38-0.98; B2:RH = 0.60, 95% CI 0.37-0.97). Any intake of zinc supplements, however, was associated with poorer survival (RH = 1.49, 95% CI 1.02-2.18). These data support the performance of clinical trials to assess the effects of B-group vitamin supplements on HIV-1-related survival. Further studies are needed to determine the optimal level of zinc intake in HIV-1-infected individuals.

Clinical manifestations of AIDS in the era of pneumocystis prophylaxis. Multicenter AIDS Cohort Study.

Among patients infected with human immunodeficiency virus type 1 (HIV-1), early and widespread use of prophylactic regimens against Pneumocystis carinii is changing the pattern of illnesses related to the acquired immunodeficiency syndrome (AIDS). We conducted a subcohort analysis of 844 men with AIDS (87 percent of whom have since died) from a prospectively followed cohort of 2592 HIV-1-infected homosexual men. A total of 138 men received prophylaxis before the diagnosis of AIDS, but 39 (28 percent) nevertheless had P. carinii pneumonia at some time. Only four illnesses occurred more frequently in men who received P. carinii prophylaxis before the onset of AIDS: Mycobacterium avium complex disease, which developed in 33.4 percent, as compared with 17.3 percent of the 706 men who did not receive early prophylaxis; wasting syndrome (18.4 percent vs. 6.4 percent); cytomegalovirus disease (44.9 percent vs. 24.8 percent); and esophageal candidiasis (21.3 percent vs. 12.8 percent). Collectively, these four diseases accounted for the initial AIDS-related illness in 42.7 percent of those who received prophylaxis before the onset of AIDS, as compared with 10.7 percent of those who did not. During the three six-month periods before the diagnosis of AIDS (0 to 6, > 6 to 12, and > 12 to 18 months), the geometric mean CD4+ cell counts were 48, 87, and 147 per cubic millimeter, respectively, in men who received prophylaxis against P. carinii, as compared with 118, 211, and 279 per cubic millimeter in those who did not. M. avium complex disease, esophageal candidiasis, wasting syndrome, and cytomegalovirus disease are more common in HIV-infected patients who have received prophylaxis against P. carinii than in those who have not. Prophylaxis may delay the first AIDS illness for 6 to 12 months.

Depressive Symptoms as Predictors of Medical Outcomes in HIV Infection

Objective. —To ascertain whether depressive symptoms as determined by the Center for Epidemiologic Studies—Depression scale (CES-D) predict accelerated mortality and worse medical outcomes in patients infected with human immunodeficiency virus (HIV). Design. —Eight-year cohort study with semiannual follow-up. Setting. —Community volunteers. Participants. —A total of 1809 HIV-seropositive homosexual men without the acquired immunodeficiency syndrome (AIDS) who entered the Multicenter AIDS Cohort Study in 1984 or 1985. Eight-year follow-up data were available on 75% of eligible participants. Outcome Measures. —Times to AIDS, death, and prophylactic treatment, and slopes describing the decline in CD4 count for each individual participant. Results. —Using a conventional definition of depression (CES-D ≥16 at the first study visit), 21.3% of participants were classified as depressed. Depressed participants had lower CD4 counts and reported more AIDS-related symptoms. There were no significant differences between depressed and nondepressed participants on any of the outcome measures ( P >.05 in all cases). In contrast, men reporting AIDS-related symptoms had shorter times to AIDS and to death even after adjusting for CD4 counts ( P Conclusions. —We find no evidence that depressive symptoms independently prognosticate worse outcomes in HIV infection. Because of associations of depression with symptom reports, CD4 counts, and indicators of socioeconomic status, future studies of the relationship between depression and HIV outcome should consider these variables as confounders. ( JAMA . 1993;270:2563-2567)

Depressive symptoms as predictors of medical outcomes in HIV infection. Multicenter AIDS Cohort Study

To ascertain whether depressive symptoms as determined by the Center for Epidemiologic Studies-Depression scale (CES-D) predict accelerated mortality and worse medical outcomes in patients infected with human immunodeficiency virus (HIV). Eight-year cohort study with semiannual follow-up. Community volunteers. A total of 1809 HIV-seropositive homosexual men without the acquired immunodeficiency syndrome (AIDS) who entered the Multicenter AIDS Cohort Study in 1984 or 1985. Eight-year follow-up data were available on 75% of eligible participants. Times to AIDS, death, and prophylactic treatment, and slopes describing the decline in CD4 count for each individual participant. Using a conventional definition of depression (CES-D > or = 16 at the first study visit), 21.3% of participants were classified as depressed. Depressed participants had lower CD4 counts and reported more AIDS-related symptoms. There were no significant differences between depressed and nondepressed participants on any of the outcome measures (P > .05 in all cases). In contrast, men reporting AIDS-related symptoms had shorter times to AIDS and to death even after adjusting for CD4 counts (P < .01). The analyses were repeated, with similar results, using different definitions of depression based on the CES-D. We find no evidence that depressive symptoms independently prognosticate worse outcomes in HIV infection. Because of associations of depression with symptom reports, CD4 counts, and indicators of socioeconomic status, future studies of the relationship between depression and HIV outcome should consider these variables as confounders.

Survival and Mortality Patterns of an Acquired Immunodeficiency Syndrome (AIDS) Cohort in New York State

The survival experience and causes of death of acquired immunodeficiency syndrome (AIDS) patients were studied using a cohort of 3,699 AIDS patients in New York State, excluding New York City, whose illness was diagnosed before January 1990 at age 13 years or older. The median length of survival for all cases was 11.5 months, and survival increased over time from 5.3 months pre-1984 to 9.3 months in 1984-1986 and to 13.2 months in 1987-1989. In a Cox proportional hazards model, risk of dying was higher for persons aged 35 years or more at diagnosis and for persons with a diagnosis other than Pneumocystis carinii pneumonia or Kaposi's sarcoma whose illness was diagnosed before 1986. In this AIDS cohort, 2,834 (77 percent) persons died before 1991; 87 percent of the death certificates listed human immunodeficiency virus (HIV)/AIDS or an AIDS indicator disease as one of the multiple causes of death. The finding that 13 percent of the death certificates did not mention AIDS/HIV suggests that use of death certificates alone to count HIV-related deaths would result in an undercount. The recent expansion of the federal AIDS case definition is expected to add HIV-infected persons who die from conditions, such as recurrent pneumonia, that were not included in the earlier definition.

The spectrum of acquired immunodeficiency syndrome (AIDS)-associated malignancies in San Francisco, 1980-1987.

Population-based disease registries for acquired immunodeficiency syndrome (AIDS) and cancer were linked for San Francisco residents to study the pattern of AIDS-associated malignancies diagnosed during the time period 1980-1987. A total of 1,756 newly diagnosed malignancies were identified during these years among members of the AIDS cohort. Of these, 1,752 (99.7%) occurred in males, 1,454 (83%) were Kaposi's sarcoma, 235 (13%) were non-Hodgkin's lymphoma, and 16 (1%) were Hodgkin's disease. The distributions of AIDS patients with cancer differed significantly from those without cancer by race and by risk group. Malignancies known to be human immunodeficiency virus (HIV)-associated, and now diagnostic of AIDS (Kaposi's sarcoma, non-Hodgkin's lymphoma), were, as would be expected, dramatically in excess among AIDS patients. Some malignancies not traditionally thought to be HIV-associated appear to have occurred more often than expected in the study cohort. These include Hodgkin's disease, rare non-melanoma skin cancers, and cancers of the rectum, anus, and nasal cavity. Malignancies known to be HIV-associated were more likely to be diagnosed concurrent with or subsequent to first AIDS diagnosis. Conversely, malignancies not known to be HIV-associated were more likely to be diagnosed before AIDS diagnosis. Compared with the concurrent reference population of the San Francisco Bay Area, there was little or no increase in Kaposi's sarcoma over the time interval of this study. For non-Hodgkin's lymphoma, and suggestively for Hodgkin's disease, however, the temporal increase has been quite dramatic.

Increasing Viral Burden in CD4+ T Cells from Patients with Human Immunodeficiency Virus (HIV) Infection Reflects Rapidly Progressive Immunosuppression and Clinical Disease

To determine over time the relation between viral burden and immunologic decline in patients with asymptomatic human immunodeficiency virus (HIV) infection. Blind analysis of cell samples from matched cohorts for HIV proviral DNA by polymerase chain reaction, retrospective analysis of clinical data on patients, and prospective follow-up of patients seropositive for the human immunodeficiency virus type 1 (HIV-1). National research clinic and academic medical centers. Cohort 1 included 12 healthy HIV-1-seropositive patients (average follow-up, 14 months): Six patients had stable disease and 6 developed rapidly progressive disease. Cohort 2 included 15 healthy HIV-1-seropositive patients from the Multi-center AIDS Cohort Study (average follow-up, 32 months): Eight patients had stable disease and 7 developed rapidly progressive disease. LABORATORY STUDIES: Quantitative polymerase chain reaction was done to determine the HIV-1 viral burden in sort-purified CD4+ T cells obtained from patients at various timepoints. In patients who remained asymptomatic, frequencies of HIV-infected CD4+ T cells were low (less than 1/10,000 to 1/1000) at study entry and increased only minimally (none higher than 1/1000). In contrast, among patients who developed HIV-related symptoms including the acquired immunodeficiency syndrome (AIDS) despite having similar CD4 counts, frequencies of HIV-infected CD4+ T cells were higher at entry (greater than 1/1000) and increased substantially (greater than 1/100) in most within 3 months of developing progressive disease. This increase in HIV burden coincided with a significant decline over time in the percent of T4 cells (31% to 16%), whereas the percent of T4 cells was unchanged in persons who remained asymptomatic (33% to 34%). Increasing viral burden in peripheral blood CD4+ T-cells is directly associated with a progressive decline in CD4+ T cells and deteriorating clinical course in HIV-infected patients.