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Objectives: We sought to evaluate associations between CD4 at ART initiation (AI), achieving CD4 >750 cells/mm(3) (CD4 >750), long-term immunological recovery and survival., Methods: This was a prospective observational cohort study. We analysed data from ART-naive patients seen in 1996-2012 and followed ≥3 years after AI. We used Kaplan-Meier (KM) methods and log-rank tests to compare time to achieving CD4 >750 by CD4 at AI (CD4-AI); and Cox regression models and generalized estimating equations to identify factors associated with achieving CD4 >750 and mortality risk., Results: Of 1327 patients, followed for a median of 7.9 years, >85% received ART for ≥75% of follow-up time; 64 died. KM estimates evaluating likelihood of CD4 >750 during 5 years of follow-up, stratified by CD4-AI <50, 50-199, 200-349, 350-499 and 500-750, were 20%, 25%, 56%, 80% and 87%, respectively (log-rank P < 0.001). In adjusted models, CD4-AI ≥200 (versus CD4-AI <200) was associated with achievement of CD4 >750 [adjusted HR (aHR) = 4.77]. Blacks were less likely than whites to achieve CD4 >750 (33% versus 49%, aHR = 0.77). Mortality rates decreased with increasing CD4-AI (P = 0.004 across CD4 strata for AIDS causes and P = 0.009 for non-AIDS death causes). Among decedents with CD4-AI ≥50, 56% of deaths were due to non-AIDS causes., Conclusions: Higher CD4-AI resulted in greater long-term CD4 gains, likelihood of achieving CD4 >750, longer survival and decreased mortality regardless of cause. Over 80% of persons with CD4-AI ≥350 achieved CD4 >750 by 4 years while 75% of persons with CD4-AI <200 did not. These data confirm the hazards of delayed AI and support early AI., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Previous research has demonstrated isolated effects of host genetic factors on the progression of human immunodeficiency virus type 1 (HIV-1) infection. In this paper, the authors present a novel use of multivariable methods for estimating the prevented fraction of acquired immunodeficiency syndrome (AIDS) cases attributable to six restriction genes after accounting for their epidemiologic interactions. The methods presented will never yield a prevented fraction above 1. The study population consisted of a well-characterized cohort of 525 US men with HIV-1 seroconversion documented during follow-up (1984-1996). On the basis of a regression tree approach using a Cox proportional hazards model for times to clinical AIDS, the combinations of genes associated with the greatest protection, relative to the lack of a protective genotype, consisted of: 1) C-C chemokine receptor 5 (CCR5)-Delta 32 and C-C chemokine receptor 2 (CCR2)-64I (relative hazard = 0.44); 2) interleukin 10 (IL10)-+/+ in combination with CCR5-Delta 32 or CCR2-64I (relative hazard = 0.45); and 3) IL10-+/+ in combination with stromal-derived factor (SDF1)-3 'A and CCR5 promoter P1/approximately P1 (relative hazard = 0.37). Overall, 30% of potential AIDS cases were prevented by the observed combinations of restriction genes (95% confidence interval: 7, 47). However, the combined effect was confined to the first 4 years following HIV-1 seroconversion. Additional research is needed to identify AIDS restriction genes with stronger and long-lasting protection to better characterize the genetic epidemiology of HIV-1.

Despite much investigation of zidovudine, little has been reported regarding its effect on the development of most individual AIDS-defining illnesses, including Kaposi's sarcoma (KS). We used observational data from the Multicenter AIDS Cohort Study (MACS) to estimate the effect of zidovudine use on the subsequent incidence of KS. To do this, we examined and adjusted for predictors of zidovudine use. CD4 lymphocyte counts, the development of HIV-related symptoms and AIDS, and changes in these factors were important predictors of zidovudine use. We used these associations to control for confounding by these and other factors with the G-estimation approach. We found no evidence that zidovudine use affected the time to KS in the MACS; the point estimate (95% confidence interval [CI]) for increase in time to KS was zero (-28%-68%). The relative risk was 1.0 (95% CI, 0.54-1.84). Randomized trials suggest that zidovudine may prevent KS. We discuss possible explanations for differences between results.

Higher white blood cell counts in smokers compared with nonsmokers have been well documented, but the longitudinal relation between changes in smoking and changes in white blood cells has not been well described. Since 1984, data have been collected semiannually by the Multicenter AIDS Cohort Study (MACS), a four-center prospective cohort study of acquired immunodeficiency syndrome (AIDS) in homosexual men. The study population includes 2,435 participants who were human immunodeficiency virus (HIV) seronegative as of September 1994 and who contributed 20,918 person-visits for this analysis. For individuals who modified their smoking behavior, changes in white blood cell counts occurred primarily during the first 6 months following changes in the amount of cigarettes smoked. Among former smokers who resumed smoking, the extent of the increase in white blood cell count depended on the number of cigarettes smoked. Specifically, increases of 241, 340, and 740 cells/microliter were observed for smokers who resumed smoking < 1, 1 to < 2, and > or = 2 packs/day, respectively. Conversely, smokers who quit smoking had a decrease of white blood cell count: -32, -629, and -1,122 cells/microliter for men who previously smoked < 1, 1 to < 2, and > or = 2 packs/day, respectively. Long-term ex-smokers, however, still had higher white blood cell counts than did never smokers. There was a high within-individual correlation of white blood cell count in persons who reported a consistent level of smoking (i.e., average correlations between two white blood cell counts 6 years apart were 0.51 for never smokers, 0.48 for ex-smokers, 0.56 for men who smoked < 1 pack/day, and 0.43 for men who smoked > or = 1 pack/day). These analyses indicate an acute effect of changes in smoking on changes in white blood cell count, a residual effect of having been a smoker, and high long-term tracking for white blood cell count.

This paper focuses on 76 human immunodeficiency virus type 1 (HIV-1) seroconverters who concurrently participated in the Chicago, Illinois, component of the Multicenter AIDS Cohort Study (MACS) and the Coping and Change Study (CCS) of homosexual/bisexual men between 1984 and 1992. A nested case-control analysis was performed to assess the critical behavioral risk factors associated with incident HIV-1 infection and the consistency of these relations in early (1984-1988) versus later (1989-1992) phases of the study. Univariate results revealed strong early period associations between seroconversion and various measures of receptive anal intercourse (RAI) that became considerably weaker in the study's later period. The weaker associations reflected the overall decline in levels of RAI among the cohort during the 9 years of observation. In contrast, univariate results revealed stronger later period associations between seroconversion and measures of receptive oral intercourse and insertive anal intercourse. Subsequent multivariate testing did not support the hypothesis that receptive oral intercourse and/or insertive anal intercourse have replaced unprotected RAI as important risk behaviours in the homosexual transmission of HIV-1. In conditional logistic regression models combining intercourse measures with indices of drug and condom use, only the latter variables were consistently associated with HIV-1 seroconversion in both early and later study periods. Adjusted odds ratios (ORs) for nonuse of condoms during RAI were consistently significant throughout the study (ORs = 3.7-4.8), while adjusted odds ratios for recreational drug use variables rose dramatically during the latter half of the study (e.g., for use of cocaine, OR = 81.3 (95% confidence interval 8-824) [corrected], and for use of nitrite "poppers," OR = 9.1 (95% confidence interval 1.8-45.5)). The behavioral intervention applications of these findings, as well as their relation to data from other recent cohort studies of HIV-1 seroconversion among homosexual/bisexual men, are discussed.

To determine whether the excess prevalence of human immunodeficiency virus type 1 (HIV-1) infection in US black and Hispanic homosexual men relative to white men can be explained by differences in sociodemographic factors, history of sexually transmitted diseases, or sexual and drug-use behaviors, the authors conducted a cross-sectional analysis of baseline HIV-1 seroprevalence and HIV-1 risk factors among 4,475 non-Hispanic white, 234 Hispanic white, and 194 black homosexual men from four centers in the United States (Baltimore/Washington, DC, Pittsburgh, Chicago, and Los Angeles). HIV-1 seroprevalence was significantly higher in Hispanic men (50%; odds ratio (OR) = 1.83, 95% confidence interval (CI) 1.41-2.39) and black men (47%; OR = 1.62, 95% CI 1.21-2.16) compared with white men (35%). Both Hispanic and black men more frequently reported a history of sexually transmitted diseases. Overall, Hispanics had the highest risk profile and blacks the lowest risk profile with respect to certain high-risk sexual behaviors (e.g., receptive anal intercourse and use of anonymous sexual partners) and recreational drug use. After multivariate adjustment, black race remained a significant independent risk factor for HIV-1 seropositivity (OR = 1.60, 95% CI 1.13-2.26), but Hispanic ethnicity was no longer statistically significant (OR = 1.17, 95% CI 0.82-1.69). Most of the excess HIV-1 prevalent infection among Hispanics was explained by their predominant recruitment from Los Angeles--the study center with the highest HIV-1 seroprevalence--and their greater prevalence of a history of sexually transmitted diseases and certain high-risk sexual practices. By contrast, adjustment for these same risk behaviors failed to explain the observed black-white differences in HIV-1 seroprevalence, and further studies are needed to elucidate the reasons for these unexplained racial differences. HIV-1 educational programs for homosexual men should take into account the behavioral differences that exist between white and minority racial/ethnic groups.

Serum antibody to p24 (anti-p24) and p24 antigen, alone and in combination with CD4+ lymphocyte number, were evaluated as predictors of progression of human immunodeficiency virus type 1 (HIV-1) infection. Two hundred six HIV-1-prevalent seropositive men in the Multi-center AIDS Cohort Study since 1984-1985 were studied cross-sectionally and 84 seroconverters were evaluated longitudinally. Cross-sectional analyses revealed significant associations among titer of anti-p24, CD4+ cell count, disease status (Centers for Disease Control class), and progression to AIDS. A high titer of anti-p24 was associated with lack of p24 antigenemia. Longitudinal studies of seroconverters demonstrated that a low titer of anti-p24, low CD4+ cell count, and detection of HIV-1 p24 antigen are individually strong predictors of AIDS, but only low CD4+ cell count retains its independent predictive value in multivariate analysis of the three markers during the period immediately after infection with HIV-1.

The authors studied the historical spread of human immunodeficiency virus type 1 (HIV-1) infection in homosexual/bisexual men and projected its future spread in these men using data from an AIDS-free cohort recruited during late 1984 in Baltimore, Maryland; Chicago, Illinois; Los Angeles, California; and Pittsburgh, Pennsylvania. Dates of preentry seroconversion in HIV-1 seroprevalent men were estimated using study entry values of hematologic variables influenced by HIV-1 infection. The authors used survival methods incorporating truncation to determine numbers/dates of seroconversion for men with a pre-1984 AIDS diagnosis who were selectively excluded by design from the 1984 AIDS-free cohort. Overall, the annual seroconversion hazard rose progressively from 0.4% in 1978 to 13.8% in 1983, dropped to 4.6% in 1985, and remained relatively stable at 1.1-2.2% from 1986 to 1990. By January 1990, almost 46% of men who were seronegative in 1978 had seroconverted. The authors estimated historical rates of spread by city, age, education, and ethnicity to examine the effects of these factors in the early and continuing stages of the HIV-1 epidemic. There were striking differences among cities with respect to pre-1985 seroconversion rates but not with respect to post-1985 seroconversion rates. Age, education, and ethnicity were all associated with 1978-1990 seroconversion rates. Future seroconversion among homosexual men was predicted assuming that the "stabilized" 1986-1990 hazards (stratified by age) observed here will be representative of future rates. Truncated Kaplan-Meier methods gave the probability of a seronegative 20-year-old man's remaining seronegative in subsequent years. Such a man has a 20.2% chance of seroconverting before reaching the age of 25 years (a 4.4% yearly hazard). The annual hazard drops to 2.5% between 25 and 30 years, to about 1.5% between 30 and 45 years, and to 1.0% between 45 and 55 years. The overall probability of seroconversion prior to age 55 years is about 50%, with seroconversion still continuing at and after age 55. Given that this cohort consists of volunteers receiving extensive anti-HIV-1 transmission education, the future seroconversion rates of the general homosexual population may be even higher than those observed here.

The HLAs of the major histocompatibility complex in humans have been associated statistically with many diseases [1]. The possibility that recurrent UTIs in women are controlled in part by genotypic traits was suggested by the observation that adherence of Escherichia coli in vitro to both vaginal and buccal cells was greater for patients with such infections than for healthy control subjects and that there was a strong correlation between vaginal cell and buccal cell receptivity [2]. A3 antigen was identified in 12 (34%) of the patients. This frequency was significantly higher in patients than in healthy control subjects, but it was not significantly different from the frequency observed in the reference population. After correction for the number of comparisons made, there was no statistically significant difference between patients and control subjects with any other antigen. These data suggest that HLA A3 may be associated with increased risk of recurrent UTIs.

Clinical and laboratory evaluations of 181 men were performed; the population studied included 131 homosexual or bisexual men (who were stratified into one of three groups on the basis of symptomatology and abnormal findings on physical examination), 39 heterosexual men (who served as controls), and 11 men with acquired immunodeficiency syndrome (AIDS). The presence of specific symptoms and/or lymphadenopathy in homosexual men was associated with perturbation of immunoregulation. A large percentage of asymptomatic, homosexually active men had abnormalities in lymphocyte numbers, subpopulations, and subclasses. Symptomatic individuals had clinical findings, immunologic alterations, and abnormalities of hematopoiesis similar to those found in patients with AIDS. These data suggest that clinical evaluation in conjunction with laboratory studies may serve to identify individuals at increased risk of developing AIDS.

Interviews regarding medical history, life-style, specific drug taking and sexual activities, and physical examinations were administered to 4,955 homosexual men who volunteered for the Multicenter AIDS Cohort Study in Baltimore, Chicago, Los Angeles, and Pittsburgh. Overall, the prevalence of antibodies to human immunodeficiency virus (HIV) in these men was 38.0%. The factor most strongly associated with prevalent HIV infection according to a multiple logistic regression model was rectal trauma, a composite variable which included receptive anal fisting, enemas before sex, reporting of blood around the rectum, and the observation of scarring, fissures or fistulas on rectal examination. Receptive anal intercourse also was strongly associated with HIV infection in the model. The multivariate relative odds for HIV antibody positivity was 7.72 for the highest level of rectal trauma and 3.04 for receptive anal intercourse. Symptoms reported to occur in some persons who subsequently develop acquired immunodeficiency syndrome (AIDS) were frequent among HIV seropositive men (12.9%) but were reported in 8.4% of seronegative men as well. Generalized lymphadenopathy was observed significantly more often in seropositive men (48.8%) compared with seronegative men (11.4%). The prevalence of HIV antibodies was inversely related to the number of T-helper cells and directly related (to a lesser extent) to the number of T-suppressor cells. The results suggest that disruption of the rectal mucosa provides access by HIV to the blood stream and to specific immunologic cells. Since symptoms and generalized lymphadenopathy were often reported among seronegative men, they probably also occur among some seropositive men not currently progressing to AIDS.

To estimate the time interval between human immunodeficiency virus type 1 (HIV-1) seroconversion and acquired immunodeficiency syndrome (AIDS) diagnosis in homosexual men, prospective incident cohorts are difficult to obtain and, if assembled, provide few events owing to the long incubation time. Although seroprevalent cohorts are numerous in size and events, the information is limited due to the unknown times since seroconversion. To combine the information provided by 1,628 seroprevalent men (304 AIDS cases) and 233 seroconverters (12 AIDS cases) being followed in a multicenter study since 1984, the postseroconversion changes in hematologic variables occurring in the incident cohort were used to develop a model that allowed for the imputation of the unknown times since seroconversion for the seroprevalent cohort. Nonparametric life table methods incorporating truncation and censoring were applied for the estimation of the probability distribution of the AIDS-free time after seroconversion. The precision of the estimates was evaluated using bootstrap methods. The analysis suggested that AIDS is unlikely (less than 0.5%) in the first year; 78% of seropositive homosexual men remain AIDS-free 60 months after seroconversion; and the AIDS incidence increases for months 12-36 and levels off at 38 per 1,000 person-semesters for months 42-60. The nonparametric estimate of the incidence rate suggests a median AIDS-free time of 11 years, which is longer than previous estimates based on parametric models.