Effects of α-tocopherol and ß-carotene supplementation on liver cancer incidence and chronic liver disease mortality in the ATBC study.

BACKGROUND: Recent data suggest the possible benefits of α-tocopherol and ß-carotene supplementation on liver cancer and chronic liver disease (CLD), but the long-term trial data are limited. METHODS: We evaluated the efficacy of supplemental 50 mg day(-1) α-tocopherol and 20 mg day(-1) ß-carotene on incident liver cancer and CLD mortality in a randomised trial of 29,105 Finnish male smokers, who received supplementation for 5-8 years and were followed for 16 additional years for outcomes. RESULTS: Supplemental α-tocopherol, ß-carotene, or both, relative to placebo, did not reduce the risk of liver cancer or CLD, either overall, during the intervention or during the post-intervention period. CONCLUSIONS: Long-term supplemental α-tocopherol or ß-carotene had no effect on liver cancer or CLD mortality over 24 years of follow-up.

Fecal microbiota diversity in survivors of adolescent/young adult Hodgkin lymphoma: a study of twins.

BACKGROUND: Adolescent/young adult Hodgkin lymphoma (AYAHL) survivors report fewer exposures to infections during childhood compared with controls, and they have functional lymphocyte aberrations. The gut microbiota plays a central role in immunity. METHODS: We investigated whether fecal microbial diversity differed between 13 AYAHL survivors and their unaffected co-twin controls. Pyrosequencing of fecal bacterial 16S rRNA amplicons yielded 252 943 edited reads that were assigned to species-level operational taxonomic units (OTUs) and standardised for sequencing depth by random sampling. Microbial diversity was compared within vs between twin pairs and by case-control status. RESULTS: The number of unique OTUs was more similar within twin pairs compared with randomly paired participants (P=0.0004). The AYAHL cases had fewer unique OTUs compared with their co-twin controls (338 vs 369, P=0.015); this difference was not significant (169 vs 183, P=0.10) when restricted to abundant OTUs. CONCLUSION: In this small study, AYAHL survivors appear to have a deficit of rare gut microbes. Further work is needed to determine if reduced microbial diversity is a consequence of the disease, its treatment, or a particularly hygienic environment.

Two criteria for evaluating risk prediction models.

We propose and study two criteria to assess the usefulness of models that predict risk of disease incidence for screening and prevention, or the usefulness of prognostic models for management following disease diagnosis. The first criterion, the proportion of cases followed PCF (q), is the proportion of individuals who will develop disease who are included in the proportion q of individuals in the population at highest risk. The second criterion is the proportion needed to follow-up, PNF (p), namely the proportion of the general population at highest risk that one needs to follow in order that a proportion p of those destined to become cases will be followed. PCF (q) assesses the effectiveness of a program that follows 100q% of the population at highest risk. PNF (p) assess the feasibility of covering 100p% of cases by indicating how much of the population at highest risk must be followed. We show the relationship of those two criteria to the Lorenz curve and its inverse, and present distribution theory for estimates of PCF and PNF. We develop new methods, based on influence functions, for inference for a single risk model, and also for comparing the PCFs and PNFs of two risk models, both of which were evaluated in the same validation data.

Physicochemical differences between fragments of plasma membrane and endoplasmic reticulum.

Specific turbidities, densities, and refractive indices of fragments of plasma membrane (PM) and endoplasmic reticulum (ER) from Ehrlich ascites carcinoma have been measured. A spherical shell model of specified dimensions and refractive index was established for PM fragments. The ionic composition of the dispersion medium was varied systematically. Increases in Gamma/2 caused increases in the turbidity of both PM and ER suspensions, the greatest effects being observed with Ca(2+) and Mg(2+). In the case of PM this effect is attributable mainly to aggregation, whereas "structural" changes account for most of the turbidity increase with ER. The pH was also varied systematically to obtain pH- density and turbidity profiles and to establish the isoelectric pH of the two membrane types (PM-3.6; ER-4.35). Turbidity was maximum at "isoelectric" pH, which corresponds in each case to the region of minimum charge on the particle surfaces. Both PM and ER show large increases of density at the "isoelectric" pH, but only ER shows substantial structurally based turbidity increase under these conditions. Both PM and ER show operation of electrostatic attractions near "isoelectric" pH. PM has been shown to have ionically distinctive inner and outer surfaces while ER shows no such dissymmetry. The necessary theoretical background for interpretation of turbidity and density measurements is included, as well as a discussion of the limitations of our conclusions and the biological importance of our results.

Risk of human immunodeficiency virus (HIV-1) infection among laboratory workers.

In a prospective cohort study of 265 laboratory and affiliated workers, one individual with no recognized risk factors for human immunodeficiency virus type 1 (HIV-1) infection was HIV-1 seropositive at the time of entry into the study. Molecular analyses of two HIV-1 isolates derived in two independent laboratories from a blood sample from this worker showed that the isolates were indistinguishable from a genotypic form of HIV-1 present in the H9/HTLV-IIIB cell line. Exposure to this strain of virus most probably occurred during work with concentrated virus or culture fluids from virus-producing cell lines under standard Biosafety Level 3 containment. Although no specific incident leading to this infection has been identified, undetected skin contact with virus culture supernatant might have occurred. This worker was the only one found to be positive among the subgroup of 99 workers who shared a work environment involving exposure to concentrated virus. The incidence rate of 0.48 per 100 person-years exposure indicates that prolonged laboratory exposure to concentrated virus is associated with some risk of HIV-1 infection, which is comparable to the risk for health care workers experiencing a needle stick exposure. While none of the ten workers with parenteral exposure to HIV-1 in this cohort became infected, a worker in another laboratory did seroconvert following an injury with a potentially contaminated needle. Strict Biosafety Level 3 containment and practices should be followed when working with concentrated HIV-1 preparations, and further refinement of the procedures may be necessary.

Probability that a two-stage genome-wide association study will detect a disease-associated snp and implications for multistage designs.

Large two-stage genome-wide association studies (GWASs) have been shown to reduce required genotyping with little loss of power, compared to a one-stage design, provided a substantial fraction of cases and controls, pi(sample), is included in stage 1. However, a number of recent GWASs have used pi(sample) < 0.2. Moreover, standard power calculations are not applicable because SNPs are selected in stage 1 by ranking their p-values, rather than comparing each SNP's statistic to a fixed critical value. We define the detection probability (DP) of a two-stage design as the probability that a given disease-associated SNP will have a p-value among the lowest ranks of p-values at stage 1, and, among those SNPs selected at stage 1, at stage 2. For 8000 cases and 8000 controls available for study and for odds ratios per allele in the range 1.1-1.3, we show that DP is substantially reduced for designs with pi(sample)

Methods for projecting course of acquired immunodeficiency syndrome epidemic.

Three methods for projecting the short-term course of the acquired immunodeficiency syndrome (AIDS) epidemic are discussed: (a) empirical extrapolation, (b) the method of "back calculation," and (c) projections based on compartmental models. Extrapolation, which requires only data on AIDS incidence, is based on an assumed functional form and on the supposition that previous trends will continue. The method of back calculation incorporates both information on previous AIDS incidence and knowledge about the incubation period distribution. These calculations provide some evidence of how many infections occurred during previous time intervals. Although this information is not precise, particularly for the recent past, it is sufficient to produce stable short-term projections. Compartmental models can be used to project future prevalence of infection as well as future AIDS incidence. However, such projections are very dependent on assumptions about initial numbers of individuals infected, rates of transmission, changes in high-risk behaviors over time, and assumptions about transmission among subpopulations with differing transmission rates and initial prevalence of infection. Thus, compartmental models offer insights into the trends in an epidemic but do not currently provide a practical tool for obtaining quantitative projections. We present projections for various risk groups based on the method of back calculation and discuss the use of additional epidemiologic data to obtain accurate projections a decade in advance.

Use of circulating pregnancy-specific beta 1 glycoprotein as a marker in carcinoma of the breast in women.

Pregnancy-specific beta 1 glycoprotein (SP1) was determined by radioimmunoassay in sera from 27 normal women, 33 women with benign breast disease, and 191 women with carcinoma of the breast, staged for extent of the disease. All diagnostic groups exhibited substantial overlap in SP1 values. Those with benign breast diseases tended to have values at least as high as those with cancer. Normal patients tended to have slightly lower values, but this difference may well have been due to the younger ages of the normal patients in our sample, because SP1 values tended to increase with age. Immunochemical dilutions of SP1 in the serum with the highest value (10.2 ng/ml) did not differ significantly from standard placental SP1.

Screening geographic areas for unusual survival experience or stage at diagnosis with application to breast and colon cancer.

An approach was devised for the problem of detecting geographic areas with poor survival for cancer patients. Methods were proposed to deal with the two major sources of variability in summary survival measures for geographic areas: the distribution of prognostic factors for individuals within an area and random variation. In addition, small geographic areas often had to be combined so that a sufficient number of cases could be obtained in each area for calculation of survival statistics, and a procedure for doing so was developed. Then stage-specific and overall 5-year survival estimates for each geographic area were converted to standardized normal deviates so that outlying observations could be detected using the theory of normal-order statistics. A similar approach was used to determine which geographic areas had unusually high proportions of advanced disease at diagnosis. Our outlier detection procedure was designed for screening available data for geographic areas possibly deserving further study rather than for concluding that survival or staging was substandard in those areas. Methods were applied to data from the Surveillance, Epidemiology, and End Results (SEER) Program for breast and colon cancer. For each cancer site, some geographic areas were identified with unusual survival or stage distributions.

Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer.

BACKGROUND: In response to findings from the Breast Cancer Prevention Trial that tamoxifen treatment produced a 49% reduction in the risk of invasive breast cancer in a population of women at elevated risk, the National Cancer Institute sponsored a workshop on July 7 and 8, 1998, to develop information to assist in counseling and in weighing the risks and benefits of tamoxifen. Our study was undertaken to develop tools to identify women for whom the benefits outweigh the risks. METHODS: Information was reviewed on the incidence of invasive breast cancer and of in situ lesions, as well as on several other health outcomes, in the absence of tamoxifen treatment. Data on the effects of tamoxifen on these outcomes were also reviewed, and methods were developed to compare the risks and benefits of tamoxifen. RESULTS: The risks and benefits of tamoxifen depend on age and race, as well as on a woman's specific risk factors for breast cancer. In particular, the absolute risks from tamoxifen of endometrial cancer, stroke, pulmonary embolism, and deep vein thrombosis increase with age, and these absolute risks differ between white and black women, as does the protective effect of tamoxifen on fractures. Tables and aids are developed to describe the risks and benefits of tamoxifen and to identify classes of women for whom the benefits outweigh the risks. CONCLUSIONS: Tamoxifen is most beneficial for younger women with an elevated risk of breast cancer. The quantitative analyses presented can assist health care providers and women in weighing the risks and benefits of tamoxifen for reducing breast cancer risk.

Projections of the incidence of non-Hodgkin's lymphoma related to acquired immunodeficiency syndrome.

Advances in antiretroviral therapy and treatment or prophylaxis against opportunistic infection have resulted in prolongation of the survival of patients with acquired immunodeficiency syndrome (AIDS). Previous research has demonstrated an association between AIDS and risk of non-Hodgkin's lymphoma (NHL). In addition to the approximately 3% of individuals found to have NHL at the time of AIDS onset, others continue to develop NHL following AIDS diagnosis. Data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute demonstrated a sharply increasing incidence of NHL among men in the age range 20-49 years since 1983 in the United States. Based on new data on the risk of NHL following AIDS diagnosis, on estimates of improved survival following AIDS diagnosis, and on projections of future AIDS incidence, we considered four sets of assumptions and estimated the number of AIDS-related NHL cases in 1992 to be between 2900 and 9800. Three of these projections were higher than the estimate of 4700 cases obtained by linear extrapolation of SEER incidence trends. These projections of AIDS-related NHL incidence suggest that between 8% and 27% of all NHL cases that occur in the United States in 1992 will arise as a consequence of infection with the human immunodeficiency virus (HIV), imposing a substantial health care burden. More research into the pathogenesis of lymphoma and new approaches to antiretroviral and antilymphoma therapy will be necessary to prevent and treat this formidable complication of infection with HIV.

Multiple markers for lung cancer diagnosis: validation of models for localized lung cancer.

Sera from 71 patients with localized lung cancer, from 70 normal controls, and from 73 patients with benign lung diseases were analyzed for 10 substances to detect lung cancer: ferritin, lipid-bound sialic acid, total sialic acid, beta 2-microglobulin, lipotropin, the alpha and beta subunits of human chorionic gonadotropin, calcitonin (two assays), parathyroid hormone, and carcinoembryonic antigen (CEA). Individual markers were studied, and optimal combinations of markers were sought for discriminating patients with localized lung cancer from normal controls and from patients with benign lung disease. Both logistic regression and recursive partitioning methods for discrimination were tried. The best rules involved only CEA and ferritin for discriminating patients with lung cancer from normal controls, and CEA and age for discriminating patients with lung cancer from those with benign lung diseases. The performance of these rules was validated on an independent serum panel containing sera from 56 patients with localized lung cancer, 75 normal controls, and 75 patients with benign lung diseases. Three rules designed to achieve 95% specificity against normal controls attained 14%-36% sensitivity for localized lung cancer in the validation panels, whereas three rules designed to achieve 95% specificity against benign lung diseases attained 30%-39% sensitivity. Some aspects of potential clinical applications are discussed.

Projecting individualized probabilities of developing breast cancer for white females who are being examined annually.

To assist in medical counseling, we present a method to estimate the chance that a woman with given age and risk factors will develop breast cancer over a specified interval. The risk factors used were age at menarche, age at first live birth, number of previous biopsies, and number of first-degree relatives with breast cancer. A model of relative risks for various combinations of these factors was developed from case-control data from the Breast Cancer Detection Demonstration Project (BCDDP). The model allowed for the fact that relative risks associated with previous breast biopsies were smaller for women aged 50 or more than for younger women. Thus, the proportional hazards models for those under age 50 and for those of age 50 or more. The baseline age-specific hazard rate, which is the rate for a patient without identified risk factors, is computed as the product of the observed age-specific composite hazard rate times the quantity 1 minus the attributable risk. We calculated individualized breast cancer probabilities from information on relative risks and the baseline hazard rate. These calculations take competing risks and the interval of risk into account. Our data were derived from women who participated in the BCDDP and who tended to return for periodic examinations. For this reason, the risk projections given are probably most reliable for counseling women who plan to be examined about once a year.

Validation studies for models projecting the risk of invasive and total breast cancer incidence.

BACKGROUND: In 1989, Gail and colleagues developed a model for estimating the risk of breast cancer in women participating in a program of annual mammographic screening (designated herein as model 1). A modification of this model to project the absolute risk of developing only invasive breast cancer is referred to herein as model 2. We assessed the validity of both models by employing data from women enrolled in the Breast Cancer Prevention Trial. METHODS: We used data from 5969 white women who were at least 35 years of age and without a history of breast cancer. These women were in the placebo arm of the trial and were screened annually. The average follow-up period was 48.4 months. We compared the observed number of breast cancers with the predicted numbers from the models. RESULTS: In terms of absolute risk, the ratios of total expected to observed numbers of cancers (95% confidence intervals [CIs]) were 0.84 (0. 73-0.97) for model 1 and 1.03 (0.88-1.21) for model 2, respectively. Within the age groups of 49 years or less, 50-59 years, and 60 years or more, the ratios of expected to observed numbers of breast cancers (95% CIs) for model 1 were 0.91 (0.73-1.14), 0.96 (0.73-1. 28), and 0.66 (0.52-0.86), respectively. Thus, model 1 underestimated breast cancer risk in women more than 59 years of age. For model 2, the risk ratios (95% CIs) were 0.93 (0.72-1.22), 1.13 (0.83-1.55), and 1.05 (0.80-1.41), respectively. Both models exhibited a tendency to overestimate risk for women classified in the higher quintiles of predicted 5-year risk and to underestimate risk for those in the lower quintiles of the same. CONCLUSION: Despite some limitations, these methods provide useful information on breast cancer risk for women who plan to participate in an annual mammographic screening program.

Multiple markers for lung cancer diagnosis: validation of models for advanced lung cancer.

Sera from 171 patients with advanced lung cancer, from 110 normals, and from 123 subjects with benign respiratory diseases were analyzed for 10 substances to detect lung cancer: ferritin, lipid-bound sialic acid, total sialic acid, beta 2-microglobulin, lipotropin, the alpha and beta subunits of human chorionic gonadotropin, calcitonin (two assays), parathyroid hormone, and carcinoembryonic antigen. Individual markers were studied, and optimal combinations of markers were sought for discriminating lung cancer patients from normals and from patients with benign lung disease. Numerous methods for combining the markers were examined, but the methods of logistic regression and recursive partitioning were finally adopted. The best discrimination rules we could find used only carcinoembryonic antigen (CEA) and total sialic acid (TSA). The performance of these rules was validated on an independent serum panel containing sera from 68 patients with advanced lung cancer, from 40 normals, and from 52 patients with benign respiratory disease. The combination rules based on TSA and CEA performed better than a rule based on CEA alone. Logistic discrimination rules with TSA and CEA that were designed to have 95% specificity achieved 54% sensitivity for discriminating advanced lung cancer from normal controls and 52% sensitivity for discriminating advanced lung cancer from controls with benign disease. Some aspects of clinical applicability are discussed, including planned studies for localized lung cancer and the requirement for further testing in specific clinical settings.

Gastric dysplasia and gastric cancer: Helicobacter pylori, serum vitamin C, and other risk factors.

BACKGROUND: Gastric cancer is generally thought to arise through a series of gastric mucosal changes, but the determinants of the precancerous lesions are not well understood. To identify such determinants, we launched a follow-up study in 1989-1990 among 3433 adults in Linqu County, China, a region with very high rates of gastric cancer. METHODS: Data on cigarette smoking, alcohol consumption, and other characteristics of the participants were obtained by interview in 1989-1990, when an initial endoscopy was taken. At study entry, antibodies to Helicobacter pylori were assayed in 2646 adults (77% of people screened), and levels of serum micronutrients were measured in approximately 450 adults. Follow-up endoscopic and histopathologic examinations were conducted in 1994. Antibodies to H. pylori, levels of serum micronutrients, and other baseline characteristics were compared between subjects whose condition showed progression to dysplasia or gastric cancer from study entry to 1994 and subjects with no change or with regression of their lesions over the same time frame. All P: values are two-sided. RESULTS: The presence of H. pylori at baseline was associated with an increased risk of progression to dysplasia or gastric cancer (odds ratio [OR] = 1.8; 95% confidence interval [CI] = 1.2-2.6). The risk of progression to dysplasia or gastric cancer also was moderately increased with the number of years of cigarette smoking. In contrast, the risk of progression was decreased by 80% (OR = 0.2; 95% CI = 0.1-0.7) among subjects with baseline ascorbic acid levels in the highest tertile compared with those in the lowest tertile, and there was a slightly elevated risk in those individuals with higher levels of alpha-tocopherol. CONCLUSIONS: H. pylori infection, cigarette smoking, and low levels of dietary vitamin C may contribute to the progression of precancerous lesions to gastric cancer in this high-risk population.

Graphs to estimate an individualized risk of breast cancer.

PURPOSE: Clinicians who counsel women about their risk for developing breast cancer need a rapid method to estimate individualized risk (absolute risk), as well as the confidence limits around that point. The Breast Cancer Detection Demonstration Project (BCDDP) model (sometimes called the Gail model) assumes no genetic model and simultaneously incorporates five risk factors, but involves cumbersome calculations and interpolations. This report provides graphs to estimate the absolute risk of breast cancer from the BCDDP model. PATIENTS AND METHODS: The BCDDP recruited 280,000 women from 1973 to 1980 who were monitored for 5 years. From this cohort, 2,852 white women developed breast cancer and 3,146 controls were selected, all with complete risk-factor information. The BCDDP model, previously developed from these data, was used to prepare graphs that relate a specific summary relative-risk estimate to the absolute risk of developing breast cancer over intervals of 10, 20, and 30 years. RESULTS: Once a summary relative risk is calculated, the appropriate graph is chosen that shows the 10-, 20-, or 30-year absolute risk of developing breast cancer. A separate graph gives the 95% confidence limits around the point estimate of absolute risk. Once a clinician rules out a single gene trait that predisposes to breast cancer and elicits information on age and four risk factors, the tables and figures permit an estimation of a women's absolute risk of developing breast cancer in the next three decades. CONCLUSION: These results are intended to be applied to women who undergo regular screening. They should be used only in a formal counseling program to maximize a woman's understanding of the estimates and the proper use of them.

Radiation-induced thyroid neoplasms: evidence for familial susceptibility factors.

To determine if there is a familial component to susceptibility to radiation-induced thyroid neoplasms, we studied 572 individuals who were members of 286 sibpairs who received childhood radiation treatment and for whom follow-up information was obtained. Of these 572 individuals, 240 (42.0%) had thyroid neoplasms (benign and malignant), and 75 (13.1%) had surgically confirmed thyroid cancer. To test the null hypothesis, that neoplasm occurred without regard to family membership, it was necessary to take into account each individual's years at risk and known risk factors. These risk factors, analyzed by the proportional hazards model of Cox, were sex, age at time of radiation treatment, and treatment dose. For each individual, we calculated the cumulative hazard that a neoplasm would occur from that individual's specific risk factors and years at risk. Each individual was also assigned an indicator, D = 1 or 0, according to whether a neoplasm had occurred. Finally, for each individual we computed a residual, D minus the cumulative hazard. In the absence of familial effects, positive and negative residuals would be distributed without regard to family membership, whereas residuals would tend to have concordant signs and magnitudes within families if familial effects were present. Permutational methods, therefore, were used to determine whether the sum among families of the products of residuals within sibpairs was too large, compared to random pairing. For all thyroid neoplasms (both benign and malignant), within-family concordance was significant (P = 0.05, the observed sum among families of the products of residuals was larger than 9468 of 9999 permutations). For thyroid cancer considered alone, the same analysis did not demonstrate familial concordance conclusively, but the results were suggestive (P = 0.18). We conclude that in addition to the previously described risk factors of female sex, younger age at radiation exposure, and higher dose, it is likely that there are independent familial risk factors for developing thyroid neoplasms. Whether these are genetic or environmental factors remains to be determined.

Kin-cohort designs for gene characterization.

BACKGROUND: In the kin-cohort design, a volunteer with or without disease (the proband) agrees to be genotyped, and one obtains information on the history of a disease in first-degree relatives of the proband. From these data, one can estimate the penetrance of an autosomal dominant gene, and this technique has been used to estimate the probability that Ashkenazi Jewish women with specific mutations of BRCA1 or BRCA2 will develop breast cancer. METHODS: We review the advantages and disadvantages of the kin-cohort design and focus on dichotomous outcomes, although a few results on time-to-disease onset are presented. We also examine the effects of violations of assumptions on estimates of penetrance. We consider selection bias from preferential sampling of probands with heavily affected families, misclassification of the disease status of relatives, violation of Hardy-Weinberg equilibrium, violation of the assumption that family members' phenotypes are conditionally independent given their genotypes, and samples that are too small to ensure validity of asymptotic methods. RESULTS AND CONCLUSIONS: The kin-cohort design has several practical advantages, including comparatively rapid execution, modest reductions in required sample sizes compared with cohort or case-control designs, and the ability to study the effects of an autosomal dominant mutation on several disease outcomes. The design is, however, subject to several biases, including the following: selection bias that arises if a proband's tendency to participate depends on the disease status of relatives, information bias from inability of the proband to recall the disease histories of relatives accurately, and biases that arise in the analysis if the conditional independence assumption is invalid or if samples are too small to justify standard asymptotic approaches.

Therapy may explain recent deficits in AIDS incidence.

Since the middle of 1987, fewer consistently defined AIDS cases have been reported than expected among homosexual and bisexual men in the United States. This "AIDS deficit" was greater among homosexual and bisexual men in New York City, San Francisco, and Los Angeles, but was also striking among all homosexual and bisexual men in the United States. Deficits were virtually absent among intravenous drug users (IVDUs) in the United States. Three independent sources of data--placebo-controlled trials, pharmaceutical company reports, and the San Francisco Men's Health Study--were used to demonstrate that the amounts of zidovudine (AZT) given prophylactically to those at highest risk of AIDS since March 1987 have been sufficient to account for most of the observed AIDS deficits. Other advances in the medical care of pre-AIDS patients may have combined with AZT to produce the deficits. Other hypothesized explanations were examined and found insufficient to account for the observed AIDS deficits, including: (a) a sudden halt in new human immunodeficiency virus (HIV) infections during the early or mid-1980s; (b) misspecification of the distribution of AIDS incubation times following HIV infection; (c) increasing delays in the reporting of AIDS cases; (d) changes in the surveillance definition of AIDS in 1987; and (e) evolution of attenuated HIV strains. The hypothesis that therapy is affecting national AIDS rates has important implications. Failure to take the effects of therapy into account can lead to serious underestimates by back-calculation of the cumulative numbers infected with HIV and of AIDS incidence over the longer term. Moreover, it appears that AIDS incidence could be retarded in underserved groups, such as IVDUs, by making AZT and other state-of-the-art treatments readily available to AIDS-free patients with advanced immunodeficiency.