Primary Neural Degeneration in the Human Cochlea: Evidence for Hidden Hearing Loss in the Aging Ear.

The noise-induced and age-related loss of synaptic connections between auditory-nerve fibers and cochlear hair cells is well-established from histopathology in several mammalian species; however, its prevalence in humans, as inferred from electrophysiological measures, remains controversial. Here we look for cochlear neuropathy in a temporal-bone study of "normal-aging" humans, using autopsy material from 20 subjects aged 0-89 yrs, with no history of otologic disease. Cochleas were immunostained to allow accurate quantification of surviving hair cells in the organ Corti and peripheral axons of auditory-nerve fibers. Mean loss of outer hair cells was 30-40% throughout the audiometric frequency range (0.25-8.0 kHz) in subjects over 60 yrs, with even greater losses at both apical (low-frequency) and basal (high-frequency) ends. In contrast, mean inner hair cell loss across audiometric frequencies was rarely >15%, at any age. Neural loss greatly exceeded inner hair cell loss, with 7/11 subjects over 60 yrs showing >60% loss of peripheral axons re the youngest subjects, and with the age-related slope of axonal loss outstripping the age-related loss of inner hair cells by almost 3:1. The results suggest that a large number of auditory neurons in the aging ear are disconnected from their hair cell targets. This primary neural degeneration would not affect the audiogram, but likely contributes to age-related hearing impairment, especially in noisy environments. Thus, therapies designed to regrow peripheral axons could provide clinically meaningful improvement in the aged ear.

The predictive value of changes in serologic and cell markers of HIV activity for subsequent clinical outcome in patients with asymptomatic HIV disease treated with zidovudine.

OBJECTIVE: To determine if serologic marker responses to zidovudine treatment during the first year of antiretroviral therapy could predict subsequent HIV disease progression independently of absolute CD4 lymphocyte responses. METHODS: We conducted a case-control study in patients with asymptomatic HIV disease, who were initiating zidovudine therapy in a randomized, prospective trial. A total of 102 patients who progressed to AIDS or advanced AIDS-related complex and 177 randomly selected controls matched by baseline CD4 cell count and duration of follow-up had serum samples (from prior to and at 8, 16, 32 and 48 weeks of zidovudine treatment) assayed for acid-disassociated HIV p24 antigen, beta 2-microglobulin (beta 2M), neopterin, soluble interleukin (IL)-2 receptor, soluble CD4 protein and soluble CD8 protein. RESULTS: Median time to event for cases was 20.2 months; median follow-up on study was 35.4 months for controls. After controlling for absolute CD4 count at baseline, increased baseline serum concentrations of HIV p24 antigen, beta 2M, neopterin, and soluble IL-2 receptor were highly predictive of increased risk of HIV disease progression. In a multiple logistic regression model, controlling for baseline marker values, change in beta 2M consistently added independent value to change in CD4 count in predicting subsequent risk of disease progression. CONCLUSIONS: Monitoring serum immunologic markers, in particular beta 2M, in addition to absolute CD4 lymphocyte counts prior to and within the first 4 months after initiating dideoxynucleoside therapy can increase the accuracy of estimations of subsequent long-term risk of clinical HIV disease progression. This information may be useful to clinicians and patients who are making decisions about initiating or changing antiretroviral therapy.

Recombinant gp160 as a therapeutic vaccine for HIV-infection: results of a large randomized, controlled trial. European Multinational IMMUNO AIDS Vaccine Study Group.

OBJECTIVES: The primary objective of this study was to expand the safety and immunogenicity database of recombinant gp160 as a therapeutic vaccine in the treatment of HIV-infection. Preliminary efficacy data was also sought. DESIGN: This trial was a randomized, double-blind, placebo-controlled study. Two-hundred and eight volunteers, 96 therapy-naive with CD4 cell count >500x10(6)/l (group A) and 112 with CD4 cell count of 200-500x10(6)/l (group B, 51 out of 112 on treatment with one or two nucleoside analogues), received monthly injections of rgp160 IIIB vaccine or placebo for the first 6 months of the study; booster immunizations with rgp160 MN or placebo were given at times 15, 18, and 21 months. METHODS: Safety and immunogenicity data were obtained and measurements of CD4 cell count, plasma viral RNA, and proviral DNA were performed. Clinical outcome was recorded for the 24 months of study. RESULTS: The vaccine was safe and well tolerated. Despite the induction of new rgp160-specific lymphoproliferative responses and the presence of positive delayed type hypersensitivity skin tests to rgp160 at the end of the 24 month study, no effect on the natural history of HIV infection was detected. Within 24 months, AIDS-defining illnesses had occurred in 19 of the vaccinated volunteers and in 18 of the placebo recipients. Persons with higher plasma viral RNA levels and higher proviral DNA had a more rapid decline in CD4 cell count when compared to persons with lower values. Vaccine did not alter viral RNA or proviral DNA levels. CONCLUSION: There was no clinical benefit to therapeutic immunizations with rgp160, despite the induction of new lymphoproliferative responses.

Estimating prevalence of HIV infection: considerations in the design and analysis of a national seroprevalence survey.

A national survey to estimate prevalence of HIV infection would provide a useful addition to available information about the current status and future prospects of the AIDS epidemic in the United States. Both design and interpretation of a prevalence study should make use of existing information about the biology and epidemiology of AIDS. In conjunction with such information, a survey would help increase the accuracy of prevalence estimates and aid in making projections, despite the possibility that participation rates will differ in infected and uninfected individuals.

The conditional latency distribution of AIDS for persons infected by blood transfusion.

Knowledge of the latency period between infection with HIV and the onset of clinical AIDS is important both to establish prognosis for infected individuals and to model the spread of HIV. This paper presents nonparametric analyses of conditional distribution of latency based on data from 1,206 persons who developed AIDS as a result of contaminated blood transfusions. Among persons who develop AIDS within 8 years of infection, there are no significant differences in the distributions of males and females. The conditional latency distribution of infants is significantly shorter than that of other transfusion cases, yet considerably longer than has previously been reported.

Modeling the relationship between survival and CD4 lymphocytes in patients with AIDS and AIDS-related complex.

CD4 lymphocyte and survival data from two completed trials, a double-blind placebo-controlled trial of zidovudine in patients with advanced human immunodeficiency virus type 1 (HIV) disease (BW-02 study) and a randomized trial of two different doses of zidovudine in patients with advanced HIV disease (ACTG-002 study) were used to determine the degree to which CD4 lymphocyte counts reflect zidovudine-associated survival benefit. Proportional hazards models were used, and CD4 lymphocyte counts were smoothed by using empirical Bayes estimates. The geometric mean of the CD4 lymphocyte counts increased by 71 and 46 cells/mm3 for patients in the BW-02 and ACTG-002 studies, respectively, followed by a progressive decline. Higher pretreatment CD4 lymphocyte counts (p = 0.001), greater increases in CD4 lymphocytes at 8 weeks (p = 0.1), and smaller declines in the slope (p = 0.001) were associated with a lower risk of death. The most current CD4 lymphocyte count was most prognostic of death (p = 0.001). The risk of death was greater for patients with lower CD4 lymphocytes and this risk increased sharply when the CD4 lymphocyte counts fell below 50 cells/mm3. The hazard of death was higher for placebo recipients at all levels of CD4 lymphocytes compared with zidovudine recipients. Although higher CD4 lymphocyte counts are associated with improved survival, these increases account for only a small proportion of the survival benefit of zidovudine in these two studies.

A model for the AIDS epidemic in Mexico: short-term projections.

As in many developing countries, the AIDS epidemic in Mexico has become a major public health problem. Given the competition for scarce health resources in Mexico, where hospitals are overcrowded and care for AIDS patients is often unavailable, planning depends on accurate estimates of the incidence of AIDS and the prevalence of HIV-1 infection. This article presents estimates of AIDS incidence in Mexico corrected for delays in reporting and short-term projections based on the corrected AIDS incidence. Trends in incidence cannot be assessed without such correction because only about 50% of AIDS cases are reported within 4 months of diagnosis. In addition to information on AIDS incidence, short-term projections also require estimates of the latency distribution between infection with HIV-1 and onset of AIDS. Latency periods with medians of 8 and 10 years lead to estimates that 22,000 and 24,000 new AIDS cases infected before June 1989 will be diagnosed between 1989 and 1994.

Comparative analysis of HIV type 1 genotypic resistance across antiretroviral trial treatment regimens.

From data on HIV-1 genotypes collected from antiretroviral trial participants who fail virologically, we describe methods for comparing distributions of acquired HIV-1 mutations across different treatment regimens. Given a definition of a "mutational distance" that summarizes the genetic change of a subject's virus in a way that captures the resistance cost of exposure to an antiretroviral regimen, these comparative analyses inform about the relative treatability of emergent virus by next-line therapy directed to the same viral target. The utility of the methods is illustrated by application to data from AIDS Clinical Trials Group (ACTG) Study 241. We find that patients failing zidovudine/didanosine/nevirapine accumulated a 2.41-fold greater nonnucleoside reverse transcriptase inhibitor (RTI) mutational distance than patients failing zidovudine/didanosine [95% confidence interval (1.55, 5.26), p < 0.000001], quantitating expectations that adding a nonnucleoside RTI to a double nucleoside regimen may attenuate future effectiveness of nonnucleoside RTI therapy for nucleoside-experienced patients if viremia is not suppressed. We also find that persons with extensive prior experience with suboptimal nucleoside therapy who were virologically failing zidovudine/didanosine/nevirapine or zidovudine/didanosine accumulated a similar nucleoside RTI mutational distance, implying that the addition of the nonnucleoside RTI did not preserve future nucleoside options.

Assessing and modeling heterosexual spread of the human immunodeficiency virus in the United States.

Epidemiologic investigation of the AIDS epidemic among heterosexuals has consisted chiefly of studies of partners of individuals infected with the human immunodeficiency virus (HIV) and population surveillance. Heterosexual partners of infected individuals appear to be at high risk of infection, but only a small proportion of cases of AIDS have been attributed to heterosexual contact in the United States and Europe. An epidemic model for heterosexual spread of HIV infection is developed and fit to surveillance data. Fitted values are restricted to a range consistent with findings from partner studies. Because, at present, most HIV-infected heterosexuals and bisexuals have been infected through other means (intravenous drug use or homosexual contact), the model considers two interacting populations: a small population of individuals rapidly infected by high-risk activity and a large population of individuals at risk only from heterosexual contact. No precise predictions concerning the AIDS epidemic among heterosexuals are possible now, but current epidemiologic findings neither predict nor preclude a major heterosexual epidemic. Projections depend strongly on the delay between infection and infectivity. The model can also be used to demonstrate how interpretation of results of case-control studies of HIV infection depends on underlying assumptions about the dynamics of the epidemic.

Modelling progression of CD4-lymphocyte count and its relationship to survival time.

The purpose of this article is to model the progression of CD4-lymphocyte count and the relationship between different features of this progression and survival time. The complicating factors in this analysis are that the CD4-lymphocyte count is observed only at certain fixed times and with a high degree of measurement error, and that the length of the vector of observations is determined, in part, by the length of survival. If probability of death depends on the true, unobserved CD4-lymphocyte count, then the survival process must be modelled. Wu and Carroll (1988, Biometrics 44, 175-188) proposed a random effects model for two-sample longitudinal data in the presence of informative censoring, in which the individual effects included only slopes and intercepts. We propose methods for fitting a broad class of models of this type, in which both the repeated CD4-lymphocyte counts and the survival time are modelled using random effects. These methods permit us to estimate parameters describing the progression of CD4-lymphocyte count as well as the effect of differences in the CD4 trajectory on survival. We apply these methods to results of AIDS clinical trials.

Analysis of doubly-censored survival data, with application to AIDS.

This paper proposes nonparametric and weakly structured parametric methods for analyzing survival data in which both the time origin and the failure event can be right- or interval-censored. Such data arise in clinical investigations of the human immunodeficiency virus (HIV) when the infection and clinical status of patients are observed only at several time points. The proposed methods generalize the self-consistency algorithm proposed by Turnbull (1976, Journal of the Royal Statistical Society, Series B 38, 290-295) for singly-censored univariate data, and are illustrated with the results from a study of hemophiliacs who were infected with HIV by contaminated blood factor.

The value of AIDS incidence data in assessing the spread of HIV infection.

Changes over time in the cumulative number of cases of AIDS depend in a complex way on several features of the epidemic, including the distribution of the induction time between infection with the human immunodeficiency virus (HIV) and onset of symptoms of AIDS, heterogeneity in such behaviours as sexual practices, selection of partners, and IV drug use, and changes over time in these behaviours. Consequently, the observed increase in the doubling time in cumulative AIDS incidence from 5 to 13 months, since AIDS was first recognized in 1982, demonstrates neither that the epidemic has begun to 'run its course' nor that behavioural changes have had a major impact in reducing incidence. Even in a homogeneous population with known induction distribution, AIDS incidence data currently are of little value in determining the number of persons infected with HIV unless additional information is available about the shape of cumulative incidence curve of HIV infection.

Characterizing the relationship between HIV-1 genotype and phenotype: prediction-based classification.

This paper establishes a framework for understanding the complex relationships between HIV-1 genotypic markers of resistance to antiretroviral drugs and clinical measures of disease progression. A new classification scheme based on the probabilities of how new patients will respond to antiretroviral therapy given the available data is proposed as a method for distinguishing among groups of viral sequences. This approach draws from existing cluster analysis, discriminant analysis, and recursive partitioning techniques and requires a model relating genotypic characteristics to phenotypic response. A data set of 2,746 sequences and the corresponding Indinavir 50% inhibitory concentrations are described and used for illustrative purposes.

Strategies for cohort sampling under the Cox proportional hazards model, application to an AIDS clinical trial.

In some studies that relate covariates to times of failure it is not feasible to observe all covariates for all subjects. For example, some covariates may be too costly in terms of time, money, or effect on the subject to record for all subjects. This paper considers the relative efficiencies of several designs for sampling a portion of the cohort on which the costly covariates will be observed. Such designs typically measure all covariates for each failure and control for covariates of lesser interest. Control subjects are sampled either from "risk sets" at times of observed failures or from the entire cohort. A new design in which the sampling probability for each individual depends on the amount of information that the individual can contribute to estimated coefficients is shown to be superior to other sampling designs under certain conditions. Primary focus of our designs is on time-invariant covariates, but some methods easily generalize to the time-varying setting. Data from a study conducted by the AIDS Clinical Trials Group are used to illustrate the new sampling procedure and to explore the relative efficiency of several sampling schemes.

AIDS: has the problem been adequately assessed?

Epidemiologic inferences about the epidemic of acquired immunodeficiency syndrome (AIDS) are developed from three different sources: case-control studies, cohort studies, and national data on prevalence and incidence. Together these data imply that reducing the number of sexual partners may in itself provide little protection. Shifting to a "lower-risk" behavior will only be helpful if the cumulative risk of transmitting the virus can be reduced nearly to zero. However, if all members of a minimally affected population made such a shift, the benefit to that population could be dramatic. The emerging realization that latency periods are longer than was first thought implies that the epidemic could be much more severe than has been anticipated. Regional trends give no assurance that it has reached a peak, even in areas of highest prevalence. Much more work needs to be done to establish the actual role of saliva in transmitting HTLV-III because oral contagion has the greatest potential to spread the disease. Efforts to determine the latency period are crucial to predicting the future of the epidemic. Preventive measures--behavior modification and education--hold some hope of retarding spread of the epidemic pending development of effective therapy or a vaccine.

Estimating the proportion of treatment effect explained by a surrogate marker.

In this paper, we measure the extent to which a biological marker is a surrogate endpoint for a clinical event by the proportional reduction in the regression coefficient for the treatment indicator due to the inclusion of the marker in the Cox regression model. We estimate this proportion by applying the partial likelihood function to two Cox models postulated on the same failure time variable. We show that the resultant estimator is asymptotically normal with a simple variance estimator. One can construct confidence intervals for the proportion by using the direct normal approximation to the point estimator or by using Fieller's theorem. Extensive simulation studies demonstrate that the proposed methods are appropriate for practical use. We provide applications to HIV/AIDS clinical trials.

Estimation of HIV dynamic parameters.

Investigation of HIV viral dynamics is important for understanding the HIV pathogenesis and for development of treatment strategies. Perelson et al. demonstrated that simple viral dynamic models fit to data on viral load as measured by plasma HIV-RNA could produce estimates of rates of clearance of virus and of infected CD4+ T-lymphocytes. In this paper we extend the work of Perelson et al. by proposing models with less restrictive assumptions about drug activity. Our models take into account the fact that infectious and non-infectious virions are produced by infected T-cells both before and after the treatment. We also show that direct measurement of infectious virus load provides sufficient information for estimation of antiretroviral drug efficacy parameter. For characterizing viral dynamics of populations and estimation of dynamic parameters, we propose a hierarchical non-linear model. Compared to other methods such as the non-linear least square method used by Perelson et al., we show that the proposed approach has the following advantages: (i) it is more appropriate for modelling within-patient and between-patient variation and to characterize the population dynamics; (ii) it is flexible enough to deal with both rich and sparse individual data; (iii) it has more power to detect model misspecification; (iv) it allows incorporation of covariates for viral dynamic parameters; (v) it makes more efficient use of between-subject information to get better parameter estimates. We give two simulation examples to illustrate the proposed approach and its advantages. Finally, we discuss practical issues regarding the clinical trial design for viral dynamic studies.

Regression analysis of censored and truncated data: estimating reporting-delay distributions and AIDS incidence from surveillance data.

AIDS surveillance provides a vital source of information for health departments to assess the AIDS epidemic and to plan for future health-care needs. However, the use of surveillance data requires proper adjustments for the underreporting of AIDS cases caused by the delay in reporting diagnosed AIDS cases to the surveillance system. The statistical problem of adjusting for this underreporting concerns making inferences about an unobservable random sample of which only a portion is observed in a chronologic time interval defined by the analysis. Most regression methods for making inferences using right-truncated data employ a reverse-time hazard function, which requires that the observed data be transformed so that methods for left-truncated data can be applied. In this paper, we discuss fitting regression models to data that can be truncated and even censored in arbitrary intervals. The proposed methodology was applied to the national AIDS surveillance data provided by the Centers for Disease Control to analyze the trend of delays over chronologic time and variation among different geographic regions as well as across risk groups.