Can primary prevention or selective screening for melanoma be more precisely targeted through general practice? A prospective study to validate a self administered risk score.

OBJECTIVES: To establish whether a questionnaire incorporating MacKie''s risk factor flow chart can identify patients at high risk for melanoma so that they can be targeted for primary and secondary prevention. To validate the risk score derived from the questionnaire and test the feasibility of self completion by comparing patients'' self reported skin characteristics with a skin examination performed by an experienced general practitioner. DESIGN: Prospective questionnaire survey followed by a comparative study. SETTING: 16 randomly selected group practices in a health district in Cheshire, United Kingdom. SUBJECTS: Questionnaire survey--3105 consecutive patients aged 16 years and over attending for a primary care consultation; comparative study--a self selected subsample of 388 of the 3,105 patients. MAIN OUTCOME MEASURES: MacKie risk group for melanoma. Comparison of high risk skin characteristics reported by patients and those noted during a skin examination by a doctor (kappa statistic). RESULTS: 4.3% of patients (87% women) were in the highest risk group and 4.4% (79% men) were in the second highest risk group, as defined by the MacKie score. Agreement between patients'' self appraisal of skin characteristics and clinical skin examinations was reflected in kappa values of 0.67 for freckles, 0.60 for moles, and 0.43 for atypical naevi. CONCLUSION: This questionnaire helped to identify a group at high risk for melanoma. Furthermore, good agreement was found when the patient''s risk scores were compared with results of the clinical skin examination. This risk score is potentially useful in targeting primary and secondary prevention of melanoma through general practice.     

A major quantitative-trait locus for mole density is linked to the familial melanoma gene CDKN2A: a maximum-likelihood combined linkage and association analysis in twins and their sibs.

Important risk factors for melanoma are densely clustered melanocytic nevi (common moles) and mutations in the p16 (CDKN2A) gene. Nevi may be subclassified as raised or flat. In our sample, raised nevi were 27% of the total, and the two kinds had a correlation of.33. Correlations for total-nevus count (TNC) in 153 MZ and 199 DZ twin pairs were.94 and.60, respectively, which are compatible with a very-high degree of genetic determination. We hypothesized that some of the genetic variance might be due to variation in the p16 gene. Analysis of linkage to a highly polymorphic marker (D9S942), located close to p16, detected quantitative-trait-loci (QTL) effects accounting for 27% of variance in TNC, rising to 33% if flat but not raised moles were considered. Total heritability was higher for raised (.69) than for flat (.42) moles, but QTL linkage was 0 for raised moles, whereas it accounted for 80% of the heritability of flat moles; additionally, family environment accounted for only 15% of variance in raised versus 46% in flat moles. These findings suggest that raised and flat nevi have very different etiologies. Longer alleles at D9S942 were associated with higher flat-mole counts, and a novel modification to a within-sibship association test showed that this association is genuine and not due to population stratification, although it accounts for only 1% of total variance. Since germline mutations in the exons of CDKN2A are rare, it is likely that variants in the noncoding regions of this gene, or in another gene nearby, are responsible for this major determinant of moliness and, hence, of melanoma risk.     

Linkage and association analysis of radiation damage repair genes XRCC3 and XRCC5 with nevus density in adolescent twins.

Previous studies have shown that a deficiency in DNA damage repair is associated with increased cancer risk, and exposure to UV radiation is a major risk factor for the development of malignant melanoma. High density of common nevi (moles) is a major risk factor for cutaneous melanoma. A nevus may result from a mutation in a single UV-exposed melanocyte which failed to repair DNA damage in one or more critical genes. XRCC3 and XRCC5 may have an effect on nevus count through their function as components of DNA repair processes that may be involved directly or indirectly in the repair of DNA damage due to UV radiation. This study aims to test the hypothesis that the frequency of flat or raised moles is associated with polymorphism at or near these DNA repair genes, and that certain alleles are associated with less efficient DNA repair, and greater nevus density. Twins were recruited from schools in south eastern Queensland and were examined close to their 12th birthday. Nurses examined each individual and counted all moles on the entire body surface. A 10cM genome scan of 274 families (642 individuals) was performed and microsatellite polymorphisms in XRCC3 and adjacent to XRCC5 were also typed. Linkage and association of nevus count to these loci were tested simultaneously using a structural-equation modeling approach implemented in MX. There is weak evidence for linkage of XRCC5 to a QTL influencing raised mole count, and also weak association. There is also weak evidence for association between flat mole count and XRCC3. No tests were significant after correction for testing multiple alleles, nor were any of the tests for total association significant. If variation in XRCC3 or XRCC5 influences UV sensitivity, and indirectly affects nevus density, then the effects are small.     

Development of a Melanoma Risk Prediction Model Incorporating MC1R Genotype and Indoor Tanning Exposure: Impact of Mole Phenotype on Model Performance

Background

Identifying individuals at increased risk for melanoma could potentially improve public health through targeted surveillance and early detection. Studies have separately demonstrated significant associations between melanoma risk, melanocortin receptor (MC1R) polymorphisms, and indoor ultraviolet light (UV) exposure. Existing melanoma risk prediction models do not include these factors; therefore, we investigated their potential to improve the performance of a risk model.

Methods

Using 875 melanoma cases and 765 controls from the population-based Minnesota Skin Health Study we compared the predictive ability of a clinical melanoma risk model (Model A) to an enhanced model (Model F) using receiver operating characteristic (ROC) curves. Model A used self-reported conventional risk factors including mole phenotype categorized as “none”, “few”, “some” or “many” moles. Model F added MC1R genotype and measures of indoor and outdoor UV exposure to Model A. We also assessed the predictive ability of these models in subgroups stratified by mole phenotype (e.g. nevus-resistant (“none” and “few” moles) and nevus-prone (“some” and “many” moles)).

Results

Model A (the reference model) yielded an area under the ROC curve (AUC) of 0.72 (95% CI = 0.69, 0.74). Model F was improved with an AUC = 0.74 (95% CI = 0.71–0.76, p<0.01). We also observed substantial variations in the AUCs of Models A & F when examined in the nevus-prone and nevus-resistant subgroups.

Conclusions

These results demonstrate that adding genotypic information and environmental exposure data can increase the predictive ability of a clinical melanoma risk model, especially among nevus-prone individuals.     

Risk attitudes and sun protection behaviour: Can behaviour be altered by using a melanoma genomic risk intervention?

Background: Exposure to ultraviolet radiation from sunlight is directly associated with melanoma skin cancer, however reducing sun-exposure can be difficult to achieve at a population level.Methods: Using a genomic risk information behaviour change trial for melanoma prevention, we classified participants as risk-seeking, risk-neutral or risk-averse for domain-specific risk taking (DOSPERT). One-way ANOVA determined the association between socio-demographic characteristics and risk-taking score, and multivariable linear regression ascertained impact of an individual’s underlying risk propensity on an objective measure of sun-exposure, standard erythemal dose (SED), at 3-months follow-up.Results: Of 119 participants, mean age 53 years; 50% males, 87% had a personal/family history of cancer; 19% were classified risk-seeking, 57% risk-neutral. The mean risk-taking score was significantly higher in younger participants (≤50 years: 13.86 vs. >50 years: 11.11, p = 0.003); and lower in those with a personal/family history of skin cancer versus without (10.55 vs 13.33, p = 0.009). Risk averse individuals had lower weekly mean SEDs at 3-months than risk neutral and risk seeking individuals (2.56, 5.81, 4.81 respectively, p = 0.01). Risk seekers showed fewer sun protective habits (p < 0.001); and higher intentional tanning, (p = 0.01). At 3-months, risk seekers attained 16%–54% lower SEDs in the genomic information group compared with controls, however this was not significantly different across risk groups (interaction p = 0.13).Conclusion: An individual’s underlying risk attitude is likely associated with sun-exposure behaviours, and may modify the effect of a genomic risk information behaviour change intervention. Young people and risk seekers may benefit most from being given information on their genetic risk of melanoma.     

CD4 Cell Count and the Risk of AIDS or Death in HIV-Infected Adults on Combination Antiretroviral Therapy with a Suppressed Viral Load: A Longitudinal Cohort Study from COHERE

Background

Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load.

Methods and Findings

Using data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger), we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements <50 copies/µl and ending with either a measurement >500 copies/µl, the first of two consecutive measurements between 50–500 copies/µl, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell count and a new AIDS event or death or death alone. 75,336 patients contributed 104,265 suppression episodes and were suppressed while on cART for a median 2.7 years. The mortality rate was 4.8 per 1,000 years of viral suppression. A higher CD4 cell count was always associated with a reduced risk of a new AIDS event or death; with a hazard ratio per 100 cells/µl (95% CI) of: 0.35 (0.30–0.40) for counts <200 cells/µl, 0.81 (0.71–0.92) for counts 200 to <350 cells/µl, 0.74 (0.66–0.83) for counts 350 to <500 cells/µl, and 0.96 (0.92–0.99) for counts ≥500 cells/µl. A higher CD4 cell count became even more beneficial over time for patients with CD4 cell counts <200 cells/µl.

Conclusions

Despite the low mortality rate, the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression. A higher CD4 cell count was associated with the greatest benefit for patients with a CD4 cell count <200 cells/µl but still some slight benefit for those with a CD4 cell count ≥500 cells/µl. Please see later in the article for the Editors'' Summary     

Body site‐specific genetic effects influence naevus count distribution in women

Body site is highly relevant for melanoma: it affects prognosis and varies according to the patient's sex. The distribution of naevi, a major risk factor for melanoma, at different body sites also varies according to sex in childhood. Using naevus counts at different body sites in 492 unrelated adults from both sexes, we observed that women have an increased number of naevi on the lower limbs compared to men (p = 8.5 × 10^?5), showing that a high naevus count on this site persists from childhood throughout life. Then, using data from 3,232 twins, we observed, in women, the lowest naevus count heritability on the trunk (26%), and the highest on the lower limbs (69%). Finally, we showed that, in 2,864 women, six genomic loci previously associated with both naevus count and melanoma risk (IRF4, DOCK8, MTAP, 9q31.2, KITLG and PLA2G6) have an effect on naevus count that is body site‐specific, but whose effect sizes are predominantly stronger on the lower limbs. Sex‐specific genetic influence on naevus count at different sites may explain differences in site‐specific melanoma incidence as well as prognosis between sexes.     

Acquired melanocytic nevi as risk factor for melanoma development. A comprehensive review of epidemiological data

Acquired melanocytic nevi (MN) in Caucasian populations are important markers for the risk of melanoma development. The total number of MN on the whole body is the most important independent risk factor for melanoma and the risk of melanoma development increases almost linearly with rising numbers of MN. Additionally, the presence of atypical MN and of actinic lentigines are likewise independent risk factors for melanoma. Atypical mole syndrome should be defined by the presence of many acquired MN and a threshold number of atypical MN. Acquired MN develops mainly during childhood and adolescence in the first two decades of life. The number of acquired nevi seems to be related to hereditary factors and nevus-prone families exist. The amount of sun exposure is the most important environmental risk factor for nevus development, particularly in early childhood. Interestingly, sunburns may play a role in nevus development, but seem not to be required, and even moderate sun exposure promotes the process. Therefore, preventive measures for nevus and melanoma development should target young children and adolescents.     

Effects of self medication programme on knowledge of drugs and compliance with treatment in elderly patients.

OBJECTIVE--To determine whether a programme of self medication for inpatients improves compliance with treatment and knowledge of their drugs after discharge from hospital. DESIGN--Patients were prospectively recruited from four wards: two with a self medication programme and two acting as controls. Ten days after discharge the patients were visited at home. They were questioned about their drugs, and a tablet count was undertaken. SETTING--The pharmacy department and four medical wards with an interest in elderly patients at a district general hospital, and the patients'' homes. PATIENTS--88 patients discharged to their own homes who were regularly taking one or more drugs. INTERVENTION--A hospital self medication programme in which patients are educated about their medicines and given increasing responsibility for taking them in hospital. MAIN OUTCOME MEASURES--Compliance with and knowledge of the purpose of their medicines 10 days after discharge from hospital. RESULTS--The mean compliance score in patients taking part in the self medication programme was 95% compared with 83% in the control group (difference 12%, 95% confidence interval 4% to 21%; P < 0.02). Of the patients in the self medication group, 90% (38/42) knew the purpose of their drugs compared with 46% (17/37) in the control group (difference 44%, 26% to 63%; P < 0.001). CONCLUSION--A self medication programme is an effective aid for improving compliance with and knowledge of patients'' drugs after discharge.     

Enumeration of CD4+ T-cells using a portable microchip count platform in Tanzanian HIV-infected patients

Background

CD4⁺ T-lymphocyte count (CD4 count) is a standard method used to monitor HIV-infected patients during anti-retroviral therapy (ART). The World Health Organization (WHO) has pointed out or recommended that a handheld, point-of-care, reliable, and affordable CD4 count platform is urgently needed in resource-scarce settings.

Methods

HIV-infected patient blood samples were tested at the point-of-care using a portable and label-free microchip CD4 count platform that we have developed. A total of 130 HIV-infected patient samples were collected that included 16 de-identified left over blood samples from Brigham and Women''s Hospital (BWH), and 114 left over samples from Muhimbili University of Health and Allied Sciences (MUHAS) enrolled in the HIV and AIDS care and treatment centers in the City of Dar es Salaam, Tanzania. The two data groups from BWH and MUHAS were analyzed and compared to the commonly accepted CD4 count reference method (FACSCalibur system).

Results

The portable, battery operated and microscope-free microchip platform developed in our laboratory (BWH) showed significant correlation in CD4 counts compared with FACSCalibur system both at BWH (r = 0.94, p<0.01) and MUHAS (r = 0.49, p<0.01), which was supported by the Bland-Altman methods comparison analysis. The device rapidly produced CD4 count within 10 minutes using an in-house developed automated cell counting program.

Conclusions

We obtained CD4 counts of HIV-infected patients using a portable platform which is an inexpensive (<$1 material cost) and disposable microchip that uses whole blood sample (<10 µl) without any pre-processing. The system operates without the need for antibody-based fluorescent labeling and expensive fluorescent illumination and microscope setup. This portable CD4 count platform displays agreement with the FACSCalibur results and has the potential to expand access to HIV and AIDS monitoring using fingerprick volume of whole blood and helping people who suffer from HIV and AIDS in resource-limited settings.     

When We Should Worry More: Using Cognitive Bias Modification to Drive Adaptive Health Behaviour

A lack of behavioural engagement in health promotion or disease prevention is a problem across many health domains. In these cases where people face a genuine danger, a reduced focus on threat and low levels of anxiety or worry are maladaptive in terms of promoting protection or prevention behaviour. Therefore, it is possible that increasing the processing of threat will increase worry and thereby enhance engagement in adaptive behaviour. Laboratory studies have shown that cognitive bias modification (CBM) can increase or decrease anxiety and worry when increased versus decreased processing of threat is encouraged. In the current study, CBM for interpretation (CBM-I) is used to target engagement in sun protection behaviour. The goal was to investigate whether inducing a negative rather than a positive interpretation bias for physical threat information can enhance worry elicited when viewing a health campaign video (warning against melanoma skin cancer), and consequently lead to more adaptive behaviour (sun protection). Participants were successfully trained to either adopt a positive or negative interpretation bias using physical threat scenarios. However, contrary to expectations results showed that participants in the positive training condition reported higher levels of worry elicited by the melanoma video than participants in the negative training condition. Video elicited worry was, however, positively correlated with a measure of engagement in sun protection behaviour, suggesting that higher levels of worry do promote adaptive behaviour. These findings imply that more research is needed to determine under which conditions increased versus decreased processing of threat can drive adaptive worry. Various potential explanations for the current findings and suggestions for future research are discussed.     

Effect of maintenance chemotherapy in childhood on numbers of melanocytic naevi.

OBJECTIVE--(a) To determine whether children given chemotherapy for haematological malignancy have significantly more melanocytic naevi than age matched children in the local population; (b) to establish whether any observed variation in naevus counts from normal is seen at the start of maintenance chemotherapy. DESIGN--Follow up of 29 consecutive children starting maintenance chemotherapy, with parental interview and count of all melanocytic naevi > or = 2 mm on the child''s skin. Assessment repeated three years later after completion of maintenance chemotherapy. Other dermatological problems identified at either visit were also recorded. SETTING--Royal Hospital for Sick Children, Glasgow. RESULTS--At the start of maintenance chemotherapy all children had total body counts of melanocytic naevi within the normal range established for age matched children in the local population. Three years later total body naevus counts were significantly increased, the median increase being 66 naevi per child (95% confidence interval 57 to 94). The only other problem noted in these children was relatively poor regrowth of scalp hair. CONCLUSION--Children on maintenance chemotherapy for haematological malignancies develop an excessive number of melanocytic naevi. Excessive numbers of melanocytic naevi are the most important risk factor for melanoma in the general population. These children should have periodic skin examinations at their follow up visits, and both child and parent should be educated about clinical features of early melanoma.     

Quality Control Methods in Accelerometer Data Processing: Identifying Extreme Counts

Background

Accelerometers are designed to measure plausible human activity, however extremely high count values (EHCV) have been recorded in large-scale studies. Using population data, we develop methodological principles for establishing an EHCV threshold, propose a threshold to define EHCV in the ActiGraph GT1M, determine occurrences of EHCV in a large-scale study, identify device-specific error values, and investigate the influence of varying EHCV thresholds on daily vigorous PA (VPA).

Methods

We estimated quantiles to analyse the distribution of all accelerometer positive count values obtained from 9005 seven-year old children participating in the UK Millennium Cohort Study. A threshold to identify EHCV was derived by differentiating the quantile function. Data were screened for device-specific error count values and EHCV, and a sensitivity analysis conducted to compare daily VPA estimates using three approaches to accounting for EHCV.

Results

Using our proposed threshold of ≥ 11,715 counts/minute to identify EHCV, we found that only 0.7% of all non-zero counts measured in MCS children were EHCV; in 99.7% of these children, EHCV comprised < 1% of total non-zero counts. Only 11 MCS children (0.12% of sample) returned accelerometers that contained negative counts; out of 237 such values, 211 counts were equal to −32,768 in one child. The medians of daily minutes spent in VPA obtained without excluding EHCV, and when using a higher threshold (≥19,442 counts/minute) were, respectively, 6.2% and 4.6% higher than when using our threshold (6.5 minutes; p<0.0001).

Conclusions

Quality control processes should be undertaken during accelerometer fieldwork and prior to analysing data to identify monitors recording error values and EHCV. The proposed threshold will improve the validity of VPA estimates in children’s studies using the ActiGraph GT1M by ensuring only plausible data are analysed. These methods can be applied to define appropriate EHCV thresholds for different accelerometer models.     

High Prevalence of Cryptococcal Antigenemia among HIV-infected Patients Receiving Antiretroviral Therapy in Ethiopia

Background

Cryptococcal disease is estimated to be responsible for significant mortality in Sub-Saharan Africa; however, only scarce epidemiology data exists. We sought to evaluate the prevalence of and risk factors for cryptococcal antigenemia in Ethiopia.

Methods

Consecutive adult HIV-infected patients from two public HIV clinics in Addis Ababa, Ethiopia were enrolled into the study. A CD4 count ≤200 cells/μl was required for study participation. Patients receiving anti-retroviral therapy (ART) were not excluded. A cryptococcal antigen test was performed for all patients along with an interview, physical exam, and medical chart abstraction. Logistic regression analysis was used to assess risk factors for cryptococcal antigenemia.

Results

369 HIV-infected patients were enrolled; mean CD4 123 cells/μl and 74% receiving ART. The overall prevalence of cryptococcal antigenemia was 8.4%; 11% in patients with a CD4 count <100 cells/μl, 8.9% with CD4 100 to 150 cells/μl and 5.7% with CD4150-200 cell/μl. 84% of patients with cryptococcal antigenemia were receiving ART. In multivariable analysis, increasing age, self reported fever, CD4 count <100 cells/μl, and site of screening were associated with an increased risk of cryptococcal antigenemia. No individual or combination of clinical symptoms had optimal sensitivity or specificity for cryptococcal antigenemia.

Conclusion

Cryptococcal antigenemia is high in Ethiopia and rapid scale up of screening programs is needed. Screening should be implemented for HIV-infected patients with low CD4 counts regardless of symptoms or receipt of ART. Further study into the effect of location and environment on cryptococcal disease is warranted.     

Molecular phylogenetic relationships of moles,shrew moles,and desmans from the new and old worlds

A Rich variety of anatomical and physiological specializations has enabled members of the family Talpidae (moles, shrew moles, and desmans) to exploit a diverse range of habitats: terrestrial, semi-aquatic, aquatic/fossorial, semi-fossorial, and fossorial. While numerous morphological and biochemical studies pertaining to the origin and radiation of the Talpidae have been completed, phylogenetic hypotheses remain controversial. To address this shortcoming we sequenced the mitochondrial DNA cytochrome b gene (1140bp) from 29 individuals spanning 12 talpid species. Phylogenetic trees incorporating 12 New and Old World genera (18 species; all 3 extant subfamilies) were then constructed using NJ, MP, ML, and NJ-ML (NJ with ML parameters) methods. Our results provide molecular support for a mononphyletic Talpidae, and suggest that the 12 genera are clustered into seven major clades; (1) Asiatic shrew-like moles (Uropsilus), (2) North American aquatic/fossorial moles (Condylura), (3) North American fossorial moles (Parascalops, Scalopus, and Scapanus), (4) North American semi-fossorial shrew moles (Neurotrichus), (5) Japanese semi-fossorial shrew moles (Dymecodon and Urotrichus), (6) European semi-aquatic desmans (Desmana), and (7) Eurasian fossorial moles (Euroscaptor, Mogera, and Talpa). None of these groupings comprised mole species from both continents. In fact, North American moles and shrew moles do not appear to have specific affinities with Asian moles and shrew moles, respectively. Although low bootstrap support was generally found for evolutionary nodes uniting the major talpid clades, all gene trees constructed identified fossorial North American and Eurasian mole lineages as nonmonophyletic groups, suggesting subterranean specializations arose independently at least twice during the evolution of the Talpidae. Additionally, our data set provides molecular support for a basal divergence and long independent history of Uropsilus from the main talpid line, and refutes the traditional taxonomic status and secondarily basal phylogenetic placement of the subfamily Desmaninae within the Talpidae.     

CD4 and Viral Load Dynamics in Antiretroviral-Na?ve HIV-Infected Adults from Soweto,South Africa: A Prospective Cohort

BackgroundCD4 count is a proxy for the extent of immune deficiency and declines in CD4 count are a measure of disease progression. Decline in CD4 count is an important component: for estimating benefits of ARV treatment; for individual level counselling on the rapidity of untreated disease progression and prognosis; and can be used in planning demand for health services. Our objective is to report CD4 decline and changes in viral load (VL) in a group of HIV-infected adults enrolled in a randomized trial of preventive treatment for TB in South Africa where clade C infection predominates.MethodsHIV-infected, tuberculin skin test positive adults who were not eligible for antiretroviral (ARV) treatment were randomized to a trial of preventive treatment from 2003–2005. VL and CD4 count were assessed at enrollment and CD4 counts repeated at least annually. During follow-up, individuals whose CD4 counts decreased to <200 cells/mm³ were referred for antiretroviral therapy (ART) and were analytically censored.Results1106 ARV naïve adults were enrolled. Their median age was 30 years and male to female ratio was 1∶5. Median baseline CD4 count was 490 cells/mm³ (IQR 351–675). The overall mean decline in CD4 count was 61 cells/mm³ per annum. Adjusting for age, gender, baseline hemoglobin, smoking and alcohol use had little impact on the estimate of CD4 decline. However, VL at baseline had a major impact on CD4 decline. The percent decline in CD4 count was 13.3% (95% CI 12.0%, 14.7%), 10.6% (95% CI 8.8%, 12.4%), and 13.8% (95% CI 12.1%, 15.5%) per annum for baseline VLs of <10,000 (N = 314), 10,001–100,000 (N = 338), >100,000 (N = 122) copies/ml.ConclusionsOur data suggests that six and a half years will elapse for an individual''s CD4 count to decline from 750 to 350 cells/mm³ in the absence of ART.     

Variability in serial CD4 counts and relation to progression of HIV-I infection to AIDS in haemophilic patients. Transfusion Safety Study Group.

OBJECTIVE--To examine the CD4 count and its near term changes relative to progression to AIDS within 30 months and to subsequent CD4 counts. DESIGN--Longitudinal clinical and laboratory study. SETTING--Haemophilia treatment centres in six large American cities. PATIENTS--555 people with congenital clotting disorders who were infected with HIV, initially without AIDS, and seen at follow up for 6-30 months in 1986-9. MAIN OUTCOME MEASURES--Absolute CD4 counts and incidence of AIDS. RESULTS--Outset CD4 count and age were independently related to progression to AIDS (p less than 0.0001 and p less than 0.005 respectively). Patients with CD4 counts of 0.30-0.49 x 10(9) cells/l had an age adjusted risk of AIDS within 30 months of only 9% that of patients with counts less than 0.20 x 10(9)/l. Children under 10 years old had only 16% of the CD4 adjusted risk of AIDS of people aged greater than or equal to 45 years. Analysis of 149 patients'' CD4 counts at the beginning and end of two successive six month intervals showed an average decrease of 11% in each six months regardless of the outset count (greater than or equal to 0.20 x 10(9)/l). For individual patients the decrease in the second six month period was unaffected by the decrease in the first six month period. CONCLUSIONS--Antiviral treatment of asymptomatic people, particularly children, with CD4 counts greater than or equal to 0.3 x 10(9)/l is questionable if predicted on near term progression to AIDS. Because of individual CD4 count variability and the low rate of progression to AIDS near term declines in individual CD4 counts are a poor index for identifying people who will rapidly progress to AIDS.