Joan S. Chmiel

Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study.

Background: AIDS-related death and disease rates have declined in the highly active antiretroviral therapy (HAART) era and remain low; however, current causes of death in HAART-treated patients remain ill defined. Objective: To describe mortality trends and causes of death among HIV-infected patients in the HAART era. Design: Prospective, multicenter, observational cohort study of participants in the HIV Outpatient Study who were treated from January 1996 through December 2004. Measurements: Rates of death, opportunistic disease, and other non-AIDS-defining illnesses (NADIs) determined to be primary or secondary causes of death. Results: Among 6945 HIV-infected patients followed for a median of 39.2 months, death rates fell from 7.0 deaths/100 person-years of observation in 1996 to 1.3 deaths/100 person-years in 2004 (P = 0.008 for trend). Deaths that included AIDS-related causes decreased from 3.79/100 person-years in 1996 to 0.32/100 person-years in 2004 (P = 0.008). Proportional increases in deaths involving liver disease, bacteremia/sepsis, gastrointestinal disease, non-AIDS malignancies, and renal disease also occurred (P = <0.001, 0.017, 0.006, <0.001, and 0.037, respectively.) Hepatic disease was the only reported cause of death for which absolute rates increased over time, albeit not significantly, from 0.09/100 person-years in 1996 to 0.16/100 person-years in 2004 (P = 0.10). The percentage of deaths due exclusively to NADI rose from 13.1% in 1996 to 42.5% in 2004 (P < 0.001 for trend), the most frequent of which were cardiovascular, hepatic, and pulmonary disease, and non-AIDS malignancies in 2004. Mean CD4 cell counts closest to death (n = 486 deaths) increased from 59 cells/&mgr;L in 1996 to 287 cells/&mgr;L in 2004 (P < 0.001 for trend). Patients dying of NADI causes were more HAART experienced and initiated HAART at higher CD4 cell counts than those who died with AIDS (34.5% vs 16.8%, respectively, received HAART for 4 of more years, P < 0.0001; 22.4% vs 7.8%, respectively, initiated HAART with CD4 cell counts of more than 350 cells/&mgr;L, P < 0.001). Conclusions: Although overall death rates remained low through 2004, the proportion of deaths attributable to non-AIDS diseases increased and prominently included hepatic, cardiovascular, and pulmonary diseases, as well as non-AIDS malignancies. Longer time spent receiving HAART and higher CD4 cell counts at HAART initiation were associated with death from non-AIDS causes. CD4 cell count at time of death increased over time.

Cancer of the stomach. A patient care study by the American College of Surgeons.

OBJECTIVE The major purpose of this study was to document the modes of presentation, diagnostic methods, clinical management, and outcome of gastric cancer as reported by tumor registries of US hospitals and cancer programs approved by the American College of Surgeons. SUMMARY BACKGROUND DATA Gastric cancer continues to diminish in the US, but the stage of disease and survival outcome after surgical resection is unchanged despite increased availability and sophistication of diagnostic techniques. This is in contrast to the marked improvement in survival outcome in Japanese and other Eastern series over the last decades. Possible reasons for the improved Japanese results have been earlier detection secondary to active diagnostic surveillance of the population and widespread adoption of aggressive surgical resection emphasizing wide-field node (R2) dissection. Although selected US centers using the Japanese approach report better survival data, the approach has not been widely adapted by US treatment centers. METHODS Tumor registries at American College of Surgeons (ACS) approved hospitals were mailed a study protocol in 1987. They were instructed to review 25 consecutive patients with gastric cancer treated in 1982 (long-term study) and 25 patients treated in 1987 (short-term study). A detailed protocol included significant history, diagnostic results, staging, pathology findings, and treatment results. The data forms on 18,365 patients were returned and analyzed (11,264 patients in the long-term study and 7101 patients in the short-term study). RESULTS Of 18,365 patients, 63% were males. The median ages were 68.4 years in males and 71.9 years in females. There was a history of gastric ulcer in 25.5% of the patients. Lesion location was upper third in 31%, middle third in 14%, distal third in 26%, and entire stomach in 10% of patients (and the site was unknown in 19%). Gastric resection was performed for 80% of upper third cancers and 85% of distal third cancers; 50% of patients with total gastric involvement had gastric resection. The extent of gastric resection varied according to location. For lower third lesions, subtotal gastrectomy was done in 55% of the cases, extended resection in 21%, and total gastrectomy in 6%. For proximal lesions, 29% had subtotal, 4.6% had total, and 41% had extended gastrectomies (including esophagus), and 13.6% had dissection of celiac nodes. The operative mortality rate was 7.2%. Staging (American Joint Committee on Cancer [AJCC]) was as follows: I, 17%; II, 17%; III, 36%; and IV, 31%. The overall survival rate reflecting deaths from all causes was 14% among 10,891 patients diagnosed in 1982, and it was 19% in patients having resection. The disease specific survival rate was 26%. The survival rate after resection was 19% and 21% for lower and mid third cancers, 10% for upper third cancers, and 4% if the entire stomach was involved. The stage-related survival rates were 50% (stage I), 29% (stage II), 13% (stage III), and 3% (stage IV). Among patients with pathologically clear margins, the survival rate was 35% versus 13% in those with microscopically involved margins, and it was 3% in those with grossly involved margins. CONCLUSION This report of gastric cancer treatment by American College of Surgeons approved institutions in the US provides an overview of the disease as commonly treated throughout the US. Although the results are less favorable than those reported by centers with large institutional experiences with this disease and are inferior to those of the Japanese and other Eastern centers, they suggest potential for increasing survival by upstaging through earlier diagnosis and using resectional techniques demonstrated to more adequately control local regional disease.

Survival Benefit of Initiating Antiretroviral Therapy in HIV-Infected Persons in Different CD4+ Cell Strata

Context When to start antiretroviral therapy (ART) for HIV infection is controversial. Starting too early exposes patients to side effects and uncertain benefits. Starting too late deprives patients of benefits. Contribution In this cohort study, HIV-infected patients with baseline CD4+ cell counts between 0.201 and 0.350 109 cells/L who began ART immediately had lower mortality rates than those who started therapy after their CD4+ cell count decreased to less than 0.201 109 cells/L. Optimal timing of therapy is unclear when the CD4+ cell count is greater than 0.350 109 cells/L. Cautions A randomized, controlled trial is the best way to identify the optimal timing of ART. The Editors Optimal timing of antiretroviral therapy (ART) initiation for persons with HIV infection is of great clinical and public health importance. Therapy reduces HIV-related mortality and morbidity for patients with substantial CD4+ cell depletion (<0.100 109 cells/L) who initiate treatment (1). Although data demonstrate the viral suppressive and immunologic (CD4+ cell count) benefits of therapy in persons with higher CD4+ cell counts (2-8), long-term improvements in disease-associated morbidity and mortality with earlier therapy are less clear (9, 10). In such patients, the potential benefits of ART and highly active ART (HAART) will probably be weighed against possible untoward sequelae of earlier treatment, including the development of metabolic abnormalities; emergence of drug-resistant virus, with resultant exhaustion of effective remaining therapies; cost; and access (9, 11-13). Current treatment guidelines allowing for the delay of ART until a lower CD4+ thresholdusually 0.350 109 cells/L or, for some patients, 0.200 109 cells/Lreflect a lack of consensus on the benefits of earlier initiation of therapy (13, 14). Sparse data exist on which to base specific recommendations for the initiation of ART relative to CD4+ cell count. Longitudinal data comparing ART recipients to appropriate comparison groups not receiving ART (especially patients with CD4+ cell counts > 0.200 109 cells/L) are limited (10, 15). Analyses that include extended follow-up data on such patients are critical because these patients are unlikely to develop or die of an HIV-related condition over the short term, in contrast to those who start therapy with lower CD4+ cell counts. Another challenge is related to the relatively brief time that HAART has been available (since early 1996), making comparative longitudinal studies of sufficient duration difficult. We compare mortality rates among ambulatory HIV-infected patients who initiated ART and those who delayed ART in various CD4+ strata. Patients were enrolled in the HIV Outpatient Study (HOPS), a dynamic cohort of ambulatory HIV-infected patients demographically representative of treated HIV-infected patients in the United States. Methods HOPS HOPS is an ongoing prospective observational cohort study into which patients have been continuously recruited and followed since 1993 (1, 16). Study sites are 10 clinics (8 private, 2 public) in 8 U.S. cities that provide care for more than 2400 HIV-infected patients per year. Participating physicians have extensive experience treating HIV-infected patients. Information is abstracted from outpatient charts at each visit and entered electronically by trained staff; it is then compiled centrally and reviewed and edited before being analyzed. Information abstracted includes demographic characteristics and risk factors for HIV infection; symptoms; diagnosed diseases (both definitive and presumptive); medications prescribed, including dose and duration; and laboratory values, including CD4+ cell counts and measurements of plasma HIV-1 RNA (viral load). Selection of Patients for Analysis We identified HOPS participants who had at least two CD4+ measurements and reliable data on ART initiation and use for at least 30 consecutive days from January 1994 through March 2001. We defined HAART as the use of at least three drugs simultaneously, including one protease inhibitor or non-nucleoside reverse-transcriptase inhibitor, or any regimen with at least two full-dose protease inhibitors. Three patient subgroups were analyzed: those observed to have a pre-ART CD4+ cell count of 0.501 to 0.750 109 cells/L, those with a pre-ART CD4+ cell count of 0.351 to 0.500 109 cells/L, and those with a pre-ART CD4+ cell count of 0.201 to 0.350 109 cells/L. Patients could be in more than one subgroup if they had a pre-ART CD4+ cell count in more than one of the defined ranges. Thus, analyses within a subgroup are distinct from analyses in other subgroups. We then stratified patients in each subgroup into one of three treatment groups: those who began ART while still in the same CD4+ subgroup range (subsequently called patients who initiated ART), those who began ART after their CD4+ cell count decreased to less than the CD4+ subgroup range (subsequently called patients who delayed ART), and those who never received ART (untreated patients). The closest (in time) CD4+ cell count available within 6 months before or 2 weeks after ART initiation was used to define the CD4+ cell count at the start of therapy. By definition, because patients who delayed ART had to have at least 1 additional CD4+ measurement during follow-up, patients who initiated ART and those who were untreated were also required to have at least 1 additional CD4+ measurement during follow-up to reduce potential bias in the analysis as a result of differential time under observation. For all treatment groups, time under observation began with the date of the earliest CD4+ cell count within the CD4+ stratum in which the patient was analyzed. Patients included in the analyses of the CD4+ subgroups of 0.201 to 0.350 109 cells/L and 0.351 to 0.500 109 cells/L were those whose earliest CD4+ cell count within the subgroup-defined range was observed after 1 January 1994. The analysis of the CD4+ subgroup of 0.501 to 0.750 109 cells/L was limited to those whose earliest CD4+ cell count within this range was observed between January 1994 and December 1995. This allowed longer elapsed time to observe clinical events. For analysis, the observation period for each patient ended at 6 months after the last contact with a HOPS clinic or at death. We analyzed all deaths, including those not directly due to AIDS or indirectly from conditions exacerbated by HIV infection (such as hepatic, renal, or cardiac disease). Causes of death were ascertained through review of clinic and hospital charts, death certificates, and national AIDS surveillance data. Deaths from suicide (one patient in the CD4+ subgroup of 0.201 to 0.350 109 cells/L who delayed ART and one patient in the CD4+ subgroup of 0.501 to 0.750 109 cells/L who initiated treatment) were treated as censored. Statistical Analysis We used SAS software, version 8.0 (SAS Institute, Inc., Cary, North Carolina), for all analyses. Patient characteristics were compared by chi-square test or the Fisher exact test for categorical variables and the Wilcoxon rank-sum test or t-test for continuous variables. We analyzed mortality rates per 1000 person-years and calculated the relative risk for death, 95% CIs, and approximate two-sided P values for each subgroup (17). Cox proportional-hazards regression was used to estimate hazard ratios, adjusted for age, sex, race, insurance status, viral load (log scale) at time of first ART (a dummy variable was used to include patients missing viral load data), receipt of HAART, and CD4+ cell count at the time of first observation within each stratum. Role of the Funding Source The funding source participated in the design, conduct, analysis, and reporting of the study and in the decision to submit the manuscript for publication. Results We evaluated data from 1464 HIV-infected HOPS participants. Of these patients, 596 who initiated ART had at least one additional CD4+ measurement after ART initiation, and 175 who delayed ART had at least one additional recorded CD4+ cell count in a higher stratum before ART initiation. We compared the demographic and baseline characteristics of patients described in this report to those of the larger overall group of HOPS participants and found no meaningful differences (data not shown). We analyzed data from 399 patients (340 who initiated and 59 who delayed ART) with pre-ART CD4+ cell counts between 0.201 and 0.350 109 cells/L, 327 patients (240 who initiated and 87 who delayed ART) with pre-ART CD4+ cell counts between 0.351 and 0.500 109 cells/L, and 122 patients (55 who initiated and 67 who delayed ART) with pre-ART CD4+ cell counts between 0.501 and 0.750 109 cells/L. Median years of follow-up for patients who initiated and those who delayed ART, by CD4+ subgroup, were as follows: 3.8 and 3.9 years for the subgroup of 0.201 to 0.350 109 cells/L, 4.1 and 4.2 years for the subgroup of 0.351 to 0.500 109 cells/L, and 5.4 and 5.3 years for the subgroup of 0.501 to 0.750 109 cells/L, respectively. Table 1 shows the demographic, immunologic, virologic, and care characteristics of patients who initiated ART and those who delayed ART, by CD4+ subgroup. Across subgroups, at least 69% of patients were men, 64% were younger than 40 years of age, 62% were white, and 35% had private health care insurance. Patients who initiated ART and those who delayed ART did not differ significantly except for the following: Patients in the CD4+ subgroup of 0.351 to 0.500 109 cells/L with private insurance tended to initiate rather than delay ART, and men in the CD4+ subgroup of 0.501 to 0.750 109 cells/L tended to delay therapy. Table 1. Characteristics of the HIV Outpatient Study Patients Who Initiated or Delayed Antiretroviral Therapy, by Preantiretroviral CD4+ Cell Count Stratum In general, most patients in a CD4+ subgroup who delayed ART initiated therapy in the next lowest CD4+ subgroup, that is, those who did not start in one subgroup started approximat

RISK FACTORS FOR SEROCONVERSION TO HUMAN IMMUNODEFICIENCY VIRUS AMONG MALE HOMOSEXUALS: Results from the Multicenter AIDS Cohort Study

2507 homosexual men who were seronegative for human immunodeficiency virus (HIV) at enrollment were followed for six months to elucidate risk factors for seroconversion to HIV. 95 (3.8%) seroconverted. Of men who did not engage in receptive anal intercourse within six months before baseline and in the six-month follow-up period, only 0.5% (3/646) seroconverted to HIV. By contrast, of men who engaged in receptive anal intercourse with two or more partners during each of these successive six-month intervals, 10.6% (58/548) seroconverted. No HIV seroconversions occurred in 220 homosexual men who did not practise receptive or insertive anal intercourse within twelve months before the follow-up visit. On multivariate analysis receptive anal intercourse was the only significant risk factor for seroconversion to HIV, the risk ratio increasing from 3-fold for one partner to 18-fold for five or more partners. Furthermore, data for the two successive six-month periods show that men who reduced or stopped the practice of receptive anal intercourse significantly lowered their risk of seroconversion to 3.2% and 1.8%, respectively. Receptive anal intercourse accounted for nearly all new HIV infections among the homosexual men enrolled in this study, and the hazards of this practice need to be emphasised in community educational projects.

Incidence and epidemiology of anal cancer in the multicenter AIDS cohort study.

Objective:To examine the incidence and risk factors for anal cancer in a multicenter cohort of human immunodeficiency virus (HIV) positive and HIV-negative men who have sex with men followed between 1984 and 2006 (Multicenter AIDS Cohort Study). Methods:Prospective analysis using Poisson regression and Cox proportional hazard models and a nested case-control study using conditional logistic regression. Results:There were 28 cases of anal cancer among the 6972 men who were evaluated. The incidence rate was significantly higher in HIV-positive men than in HIV-negative men (incidence rate = 69 vs 14 per 100,000 person-years). Among HIV-positive men, anal cancer incidence was higher in the highly active antiretroviral therapy (HAART) era than the pre-HAART era (incidence rate = 137 vs 30 per 100,000 person-years). In multivariate analysis restricted to the HAART era, anal cancer risk increased significantly with HIV infection (relative hazard = 4.7, 95% confidence interval = 1.3 to 17) and increasing number of unprotected receptive anal sex partners at the first 3 study visits (P trend = 0.03). Among HIV-positive men, current HAART use did not decrease anal cancer risk. Conclusions:HIV-positive men had increased risk of anal cancer. Improved survival of HIV-positive individuals after HAART initiation may allow for sufficient time for human papillomavirus-associated anal dysplasias to develop into malignancies, thus explaining the increased incidence of anal cancer in the HAART era.

AIDS-defining opportunistic illnesses in US patients, 1994-2007: a cohort study.

Objectives:To assess the incidence and spectrum of AIDS-defining opportunistic illnesses in the highly active antiretroviral therapy (cART) era. Design:A prospective cohort study of 8070 participants in the HIV Outpatient Study at 12 U.S. HIV clinics. Methods:We calculated incidence rates per 1000 person-years of observation for the first opportunistic infection, first opportunistic malignancy, and first occurrence of each individual opportunistic illness during 1994–2007. Using stratified Poisson regression models, and adjusting for sex, race, and HIV risk category, we modeled annual percentage changes in opportunistic illness incidence rates by calendar period. Results:Eight thousand and seventy patients (baseline median age 38 years; median CD4 cell count 298 cells/μl) experienced 2027 incident opportunistic illnesses during a median of 2.9 years of observation. During 1994–1997, 1998–2002, and 2003–2007, respectively, rates of opportunistic infections (per 1000 person-years) were 89.0, 25.2 and 13.3 and rates of opportunistic malignancies were 23.4, 5.8 and 3.0 (P for trend <0.001 for both). Opportunistic illness rate decreases were similar for the subset of patients receiving cART. During 2003–2007, there were no significant changes in annual rates of opportunistic infections or opportunistic malignancies; the leading opportunistic illnesses (rate per 1000 person-years) were esophageal candidiasis (5.2), Pneumocystis pneumonia (3.9), cervical cancer (3.5), Mycobacterium avium complex infection (2.5), and cytomegalovirus disease (1.8); 36% of opportunistic illness events occurred at CD4 cell counts at least 200 cells/μl. Conclusions:Opportunistic illness rates declined precipitously after introduction of cART and stabilized at low levels during 2003–2007. In this contemporary cART era, a third of opportunistic illnesses were diagnosed at CD4 cell counts at least 200 cells/μl.

Cumulative exposure to nucleoside analogue reverse transcriptase inhibitors is associated with insulin resistance markers in the Multicenter AIDS Cohort Study

Objective:To estimate insulin resistance and its relationship to antiretroviral therapy (ART) in a cohort of HIV-infected persons with comparison to HIV-seronegative controls. Design:Prospective cohort of 533 HIV-infected and 755 HIV-seronegative men in the Multicenter AIDS Cohort Study evaluated at 6-month intervals between 1999 and 2003. Methods:Recent ART exposure was assessed by type of treatment in the preceding 6 months [i.e., no ART, monotherapy, combination ART, or highly active antiretroviral therapy (HAART) with and without a protease inhibitor (PI)]. Cumulative exposure was determined for the three major ART classes and for individual medications within each class. Two endpoints, a modified QUICKI index, 100 × 1/[log10(glucose) + log10(insulin)] and fasting hyperinsulinemia (insulin > 15 μU/ml), were assessed. All statistical models were adjusted for age, body mass index, race, nadir CD4 cell count, hepatitis C serostatus and family history of diabetes mellitus. Results:Each of the HIV-infected groups had higher odds of hyperinsulinemia and lower mean QUICKI than the HIV-seronegative men. Each additional year of exposure to nucleoside analogue reverse transcriptase inhibitors (NRTI) was associated with increased odds of hyperinsulinemia [odds ratio (OR), 1.08; 95% confidence interval (CI), 1.02–1.13) and a lower QUICKI (−0.04; 95% CI, −0.07 to −0.01). Cumulative exposure to non-nucleoside analogue reverse transcriptase inhibitors or PI drugs was not associated with either insulin resistance marker. Of individual medications examined, stavudine was associated with the highest risk of hyperinsulinemia (OR, 1.2; 95% CI, 1.2–1.3). Conclusions:Fasting surrogate markers suggest increased insulin resistance in HIV-infected men, which is related to cumulative NRTI exposure.

Prevention of Thromboembolism after Spinal Cord Injury Using Low-Molecular-Weight Heparin

OBJECTIVE To examine the safety and effectiveness of a low-molecular-weight heparin in the prevention of thromboembolism in patients with recent spinal cord injury and complete motor paralysis. DESIGN Randomized evaluation of two heparin regimens in 41 consecutive patients meeting eligibility requirements for anticoagulant prophylaxis. Daily bedside examinations were supplemented by serial venous flow studies; suspicious or positive tests were confirmed by venography. INTERVENTION Standard heparin, 5000 units subcutaneously three times a day; low-molecular-weight heparin 3500 anti-Xa units subcutaneously once daily. MEASUREMENTS AND MAIN RESULTS Five patients in the standard heparin group had thrombotic events, including two patients with fatal pulmonary embolism; two other patients had bleeding severe enough to necessitate withdrawing the heparin. The cumulative event rate was 34.7% (95% CI, 13.7% to 55.2%). None of the patients treated with low-molecular-weight heparin had thrombosis or bleeding (CI, 0% to 14%). The difference between the two groups was significant (P = 0.006, log-rank test). CONCLUSIONS Low-molecular-weight heparin is safe and effective in the prevention of thromboembolism in selected patients with spinal cord injury and complete motor paralysis, and is superior to standard heparin in fixed doses of 5000 units three times a day.

Low CD4+ T Cell Count Is a Risk Factor for Cardiovascular Disease Events in the HIV Outpatient Study

BACKGROUND Traditional cardiovascular disease (CVD) risk factors, human immunodeficiency virus (HIV) infection, and antiretroviral (ARV) agents have been associated with CVD events in HIV-infected patients. We investigated the association of low CD4(+) T lymphocyte cell count with incident CVD in a cohort of outpatients treated in 10 HIV specialty clinics in the United States. METHODS We studied patients who were under observation from 1 January 2002 (baseline), categorized them according to National Cholesterol Education Program guidelines into 10-year cardiovascular risk score (10-y CVR) groups , and observed them until CVD event, death, last HIV Outpatient Study contact, or 30 September 2009. We calculated rates of incident CVD events and identified associated baseline risk factors using Cox proportional hazard models. We also performed a nested case-control study to examine the association of latest CD4(+) cell count with CVD events. RESULTS Among 2005 patients, 148 experienced incident CVD events. CVD incidence increased steadily from 0.4 to 3.0 events per 100 person-years from lowest to highest 10-y CVR group (P < .001). In multivariable Cox analyses adjusted for 10-y CVR, CD4(+) cell count <350 cells/mm(3) was associated with incident CVD events (hazard ratio, 1.58 [95% confidence interval, 1.09-2.30], compared with >500 cells/mm(3)), suggesting an attributable risk of approximately 20%. In the multivariable case-control analyses, traditional CVD risk factors and latest CD4(+) cell count <500 cells/mm(3), but not cumulative use of ARV class or individual drugs, were associated with higher odds of experiencing CVD events. CONCLUSION CD4(+) count <500 cells/mm(3) is an independent risk factor for incident CVD, comparable in attributable risk to several traditional CVD risk factors in the HIV Outpatient Study cohort.

Health-related quality of life among people with HIV disease: results from the multicenter AIDS Cohort Study.

To examine the effect of HIV status, symptomatology and CD4+ lymphocyte level on health-related quality of life, the Medical Outcomes Study Short-Form Health Survey (SF-36) was administered to 2,295 gay men enrolled in the Multicenter AIDS Cohort Study (MACS) in 1994. Distinct physical and mental health factors of the SF-36 were found. Seropositive asymptomatic individuals and seropositive individuals with CD4+ lymphocytes ≥ 500/mm3 scored as well as seronegative participants on all of the mental health domain scales, but lower on the general health perceptions and physical health composite score. Seropositive individuals with at least one symptom or with CD4+ lymphocytes below 200/mm3 scored significantly lower on all of the SF-36 scales and summary scores than seronegative controls. The SF-36 was found to exhibit similar mental and physical health factors for an adult gay male population to that previously seen in general population samples and in patient groups with other diseases. In conclusion, HIV-positive men who are asymptomatic or have CD4+ lymphocytes above 500/mm3 have similar perceived mental health but worse perceived physical health than seronegative men. HIV-positive men who are symptomatic or have CD4+ lymphocytes below 200/mm3 have worse perceived mental and physical health than seronegative men.