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S L Welles

Publications and source records attributed to S L Welles.

At least 19 recordsLinked to original sources
PubMed2000

HIV-1 genotypic zidovudine drug resistance and the risk of maternal--infant transmission in the women and infants transmission study. The Women and Infants Transmission Study Group.

OBJECTIVES: Although the treatment of pregnant women and their infants with zidovudine (ZDV) has been remarkably effective in preventing the perinatal transmission of human HIV-1, many potentially preventable infections still occur. To examine whether the risk of perinatal infection is increased among women who carry ZDV-resistant HIV-1, the role of genotypic ZDV resistance in perinatal transmission was evaluated. METHODS: The reverse transcriptase (RT) region of clinical isolates from culture supernatants of 142 HIV-1-infected women enrolled in the Women and Infants Transmission Study (WITS), who had been treated with ZDV during pregnancy was sequenced. Results from genotypic sequencing were linked to demographic, laboratory, and obstetrical databases, and the magnitude of association of having consensus drug-resistant HIV-1 RT mutations with transmission was estimated. RESULTS: Twenty-five per cent (34/142) of maternal isolates had at least one ZDV-associated resistance mutation. A lower CD4 cell percentage and count (P= 0.0001) and higher plasma HIV-1 RNA (P=0.006) were associated with having any ZDV resistance mutation at delivery. Having any RT resistance mutation [odds ratio (OR): 5.16; 95% confidence interval (CI): 1.40, 18.97; P=0 0.01], duration of ruptured membranes [OR: 1.13 (1.02, 1.26) per 4 h duration; P= 0.02], and total lymphocyte count [OR: 1.06 (1.01, 1.10) per 50 cells higher level; P=0.009] were independently associated with transmission in multivariate analysis. CONCLUSION: Maternal ZDV resistant virus was predictive of transmission, independent of viral load, in these mothers with moderately advanced HIV-1 disease, many of whom had been treated with ZDV before pregnancy.

Anti-HIV Agents↗
PubMed2000

The Minnesota DARE PLUS Project: creating community partnerships to prevent drug use and violence.

The research community has criticized Drug Abuse Resistance Education (D.A.R.E.) because the extant literature indicates a lack of evidence that the elementary school program prevents drug use. Yet D.A.R.E. continues to be the most widely implemented drug use prevention program in the United States and has considerable community support. To date, the junior high D.A.R.E. program has not been evaluated. The Minnesota DARE PLUS Project is a randomized trial of 24 schools and communities. During 1999-2001, students in eight schools will receive the junior high D.A.R.E. curriculum in 7th grade; eight schools also will receive the curriculum as well as additional parent involvement, peer leadership, and community components in the 7th and 8th grades; and eight schools will serve as controls. This article describes the background and conceptualization, the curriculum and additional intervention components, and the evaluation methods of the DARE PLUS Project.

Adolescent↗
PubMed1999

A study of adult T-cell leukemia/lymphoma incidence in central Brooklyn.

Adult T-cell leukemia/lymphoma (ATL), a rare outcome of infection with human T-lymphotropic virus (HTLV-I), is endemic in central Brooklyn, which has a large Caribbean migrant population. Previous studies have suggested that HTLV-I prevalence in central Brooklyn may be similar to that recorded in the Caribbean islands. We established a pilot 1-year surveillance program to identify cases of ATL in 7 of 10 hospitals serving the residents of 18 zip codes of central Brooklyn with a combined population of 1,184,670. Of the 6,198 in-patient beds in the catchment area, approximately 83% were covered. Twelve incident cases of ATL were ascertained, all among persons of Afro-Caribbean descent, indicating an annual incidence in African-Americans in this community of approximately 3.2/100,000 person-years. Unexplained hypercalcemia was the most useful screening method, identifying 3 of 5 patients not referred for possible ATL by a local hematologist. The female:male ratio was 3:1. The age pattern was different from that reported in the Caribbean Basin and closer to the pattern seen in Japan. Our study supports evidence that HTLV-I infection and ATL are endemic in central Brooklyn and suggests that a more intensive surveillance program for this disease coupled with intervention efforts to reduce HTLV-I transmission are warranted.

Adult↗
PubMed1999

Quantitative proviral DNA and antibody levels in the natural history of HTLV-I infection.

The pathogenesis of human T-cell lymphotropic virus type I (HTLV-I) in adult T-cell leukemia/lymphoma (ATL) and HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) is poorly understood. We prospectively followed up and evaluated the virologic correlates of infection in transfusion recipients after seroconversion, in asymptomatic carriers, and in ATL and HAM/TSP patients. Proviral DNA levels (copies/105 lymphocytes) were determined by real-time automated polymerase chain reaction and antibody titers by end-point dilution by use of an HTLV-I enzyme-linked immunoassay. In early infection, proviral load was initially elevated (median, 212 copies/105 lymphocytes at time 1) and later decreased (median, 99 copies at time 2, and 27 copies at time 3). Corresponding antibody titers were low at time 1 (1:2154), had significantly increased by time 2 (1:12312), and were stable by time 3 (1:4694). These viral markers were significantly lower in asymptomatic carriers than in HAM/TSP or ATL patients. Therefore, proviral load and antibody titers may be useful as predictive markers of disease among carriers.

Adolescent↗
PubMed1998

Selective vertical transmission of HIV-1 antiretroviral resistance mutations.

OBJECTIVE: To examine the patterns of vertical transmission of zidovudine (ZDV) resistance mutations. DESIGN: HIV-1 reverse transcriptase codons 10-250 were sequenced from 24 pairs of ZDV-exposed women and their HIV-infected infants as part of the Women and Infants Transmission Study. METHODS: Viral RNA was extracted from tissue culture supernatants and sequenced using fluorescent dye-primer chemistry and an automated sequencer. RESULTS: For 17 of these pairs, maternal and infant sequences were identical to one another and lacking known ZDV resistance mutations. The remaining seven maternal sequences contained known mutations associated with ZDV resistance at reverse transcriptase codons 70, 210, 215 and 219. In each case where the maternal HIV isolate showed a pure mutant species, the infant sequence was identical. When the maternal sequence showed the presence of a sequence mixture at codon 70 or 219, the infant's virus showed only wild-type sequence even when the ZDV-resistant mutant was quantitatively dominant in the mother. The single maternal HIV isolate showing mixed sequence at codon positions 210 and 215 transmitted an unmixed mutant to the infant at both positions. When maternal mixtures were present at sites not associated with ZDV resistance, only the dominant species appeared in the infant. CONCLUSIONS: When maternal HIV isolates contained mixed wild-type and ZDV-resistant subpopulations, only a single component of the mixture could be detected in the infected infants. Resistance mutants without the codon 215 mutation were not transmitted from mixtures, even when the mutants formed the majority of circulating maternal virus. In perinatal HIV transmission, specific ZDV-resistant HIV genotypes circulating in the maternal virus pool may influence whether infection in the infant will be established by a wild-type or ZDV-resistant HIV strain.

Anti-HIV Agents↗
PubMed1998

Statistical issues for HIV surrogate endpoints: point/counterpoint. An NIAID workshop.

This paper summarizes the proceedings of an NIAID-sponsored workshop on statistical issues for HIV surrogate endpoints. The workshop brought together statisticians and clinicians in an attempt to shed light on some unresolved issues in the use of HIV laboratory markers (such as HIV RNA and CD4+ cell counts) in the design and analysis of clinical studies and in patient management. Utilizing a debate format, the workshop explored a series of specific questions dealing with the relationship between markers and clinical endpoints, and the choice of endpoints and methods of analysis in clinical studies. This paper provides the position statements from the two debaters on each issue. Consensus conclusions, based on the presentations and discussion, are outlined. While not providing final answers, we hope that these discussions have helped clarify a number of issues, and will stimulate further consideration of some of the highlighted problems. These issues will be critical in the proper assessment and use of future therapies for HIV disease.

Biomarkers↗
PubMed1998

Association between serum total cholesterol and HIV infection in a high-risk cohort of young men.

Low serum total cholesterol (TC) is associated with a variety of nonatherosclerotic diseases, but the association of TC with infectious disease has been little studied. In this study, we examined the relationship between serum TC and HIV infection in members of a large health maintenance organization in Northern California. The cohort consisted of 2446 unmarried young men 15 to 49 years of age at high risk of HIV infection, defined as self-reported history of sexually transmitted disease or liver disease. Baseline measurements were taken between 1979 and 1985, and subjects were passively followed for HIV infection until the end of 1993 (average length of follow-up, 7.7 years). From a multivariate-adjusted Cox regression, the rate ratio (RR) of HIV infection was 1.66 (95% CI = 1.07, 2.56) for men with serum TC levels <160 mg/dl compared with those with TC levels between 160 and 199 mg/dl. Similar excess risk of AIDS and AIDS-related death was observed. These findings suggest that low serum TC levels should be considered a marker of increased risk of HIV infection in men already at heightened risk of HIV infection.

Adolescent↗
PubMed1998

The inter-relation of maternal immune competence, HIV-1 viral load, and nutritional status in preventing vertical transmission: an alternative to chemoprophylaxis?

As the human immunodeficiency virus (HIV) global pandemic moves towards the end of its second decade, women of reproductive age throughout the world have been shown to be increasingly at risk for acquiring HIV-1 infection. Recently, the focus for preventive measures has expanded to include preventing the perinatal transmission of HIV-1 to fetuses and newborns. This manuscript reviews the available literature that examines risk factors for perinatal transmission, immunopathogenesis of HIV-1 infection, and the role that antioxidant micronutrients play in modulating immune response to HIV-1 disease progression. The available information provides a compelling case for the design of studies that evaluate the extent to which maternal HIV-1 viremia and disease progression are modulated by her nutritional status. Should results from these studies confirm that antioxidant micronutrient status is inversely related to HIV-1 RNA load, particularly in economically vulnerable populations, carefully designed and executed supplementation trials would be warranted.

Anti-HIV Agents↗
PubMed1996

Prognostic value of plasma human immunodeficiency virus type 1 (HIV-1) RNA levels in patients with advanced HIV-1 disease and with little or no prior zidovudine therapy. AIDS Clinical Trials Group Protocol 116A/116B/117 Team.

The association of plasma human immunodeficiency virus type 1 (HIV-1) RNA level at study entry and over time with clinical progression was evaluated in 187 patients from AIDS Clinical Trials Group protocol 116A who had little or no prior zidovudine treatment. Three-fold-higher HIV-1 RNA levels at study entry and 3-fold increases by week 8 were associated with progression (relative hazard [RH], 1.67; 95% confidence limits [CL], 1.20, 2.32; and RH, 1.45; CL, 1.02, 2.05, respectively). Having 3-fold-higher CD4 cell count at entry was independently associated with a 52% reduction in risk for progression (adjusted RH, 0.48; CL, 0.33, 0.70). When stratified by length of prior zidovudine therapy, RNA level was predictive in drug-naive patients (adjusted RH, 1.87; CL, 1.23, 2.85) but not predictive in patients with up to 16 weeks of prior therapy (adjusted RH, 1.11; CL, 0.70, 1.76). Analysis suggests that the acquisition of mutations at HIV-1 reverse transcriptase codons 215 and 74 is associated with subsequent increases in HIV-1 RNA level (relative risk, 7.00; CL, 0.86, 56.90).

Acquired Immunodeficiency Syndrome↗
PubMed1996

Association of plasma human immunodeficiency virus type 1 RNA level with risk of clinical progression in patients with advanced infection. AIDS Clinical Trials Group (ACTG) 116B/117 Study Team. ACTG Virology Committee Resistance and HIV-1 RNA Working Groups.

Human immunodeficiency virus (HIV)-1 RNA level in plasma was evaluated as a surrogate marker for disease progression in a clinical trial of advanced HIV-1 infection. Baseline HIV-1 RNA level was an independent predictor of disease progression (relative hazard [RH] for each doubling of HIV-1 RNA level, 1.26; 95% confidence interval [CI], 1.03-1.54; P = .02), after adjusting for the week 4 change in HIV-1 RNA level, baseline CD4 cell count, syncytium-inducing phenotype, clinical status at study entry, and therapy randomization. A 50% reduction in HIV-1 RNA level was associated with a 27% decrease in the adjusted risk of disease progression during the study (RH, 0.73; 95% CI, 0.52-1.02; P = .07). The partial validation of HIV-1 RNA as a predictor for clinical end points has implications for the use of HIV-1 RNA in clinical trials and practice.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Zidovudine resistance and HIV-1 disease progression during antiretroviral therapy. AIDS Clinical Trials Group Protocol 116B/117 Team and the Virology Committee Resistance Working Group.

OBJECTIVE: To evaluate the association between resistance of human immunodeficiency virus type 1 (HIV-1) to zidovudine and clinical progression. DESIGN: Retrospective analysis of specimens from patients in the AIDS Clinical Trials Group (ACTG) protocol 116B/117, a randomized comparison of didanosine with continued zidovudine therapy in patients with advanced HIV-1 disease who had received 16 weeks or more of previous zidovudine therapy. SETTING: Participating ACTG virology laboratories. PATIENTS: 187 patients with baseline HIV-1 isolates. MEASUREMENTS: Zidovudine susceptibility testing and assays for syncytium-inducing phenotype were done on baseline HIV-1 isolates. Relative hazards for clinical progression or death associated with baseline clinical, virologic, and immunologic factors were determined from Cox proportional hazards regression models. RESULTS: Compared with other patients, 15% (26 of 170) with isolates showing high-level zidovudine resistance (50% inhibitory zidovudine concentration > or = 1.0 microM) had 1.74 times the risk for progressing to a new AIDS-defining event or death (95% CI, 1.00 to 3.03) and 2.78 times the risk for death (CI, 1.21 to 6.39) in analyses that controlled for baseline CD4+ T-lymphocyte count, syncytium-inducing HIV-1 phenotype, disease stage, and randomized treatment assignment. The clinical benefit of didanosine was not limited to patients with highly zidovudine-resistant baseline HIV-1 isolates. CONCLUSIONS: High-level resistance of HIV-1 to zidovudine predicted more rapid clinical progression and death when adjusted for other factors. However, patients with advanced HIV-1 disease may benefit from a change in monotherapy from zidovudine to didanosine whether high-level HIV-1 resistance to zidovudine is present or absent, and laboratory assessment of zidovudine resistance is not necessary for deciding when to switch monotherapy from zidovudine to didanosine.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Length of incubation time for human immunodeficiency virus cultures.

Qualitative human immunodeficiency virus culture is a slow, labor-intensive, and expensive procedure, yet critical for the diagnosis of infants born to human immunodeficiency virus-seropositive mothers. We report that the cultures can be terminated at day 21 with minimal false-negative results but with considerable savings in both time and money.

Child↗
PubMed1995

Evaluating surrogate markers.

We discuss approaches for efficiently evaluating potential surrogate markers; in particular, we focus on case-cohort designs in which marker evaluation is undertaken only for a random sample of subjects within a randomized trial and for all other subjects who develop a major clinical outcome. These designs will be useful in clinical trials in which a highly significant treatment difference on clinical outcome has been obtained. In addition, we describe a method for using data from all available studies using a meta-analysis to explore the association of treatment effects on the potential marker and on clinical outcome. This may be the most effective approach for marker evaluation because it uses data from both large and small trials and incorporates information from trials in which nonsignificant treatment differences on the major clinical outcome are obtained.

Biomarkers↗
PubMed1994

Decreased reactivity to PPD among HTLV-I carriers in relation to virus and hematologic status.

Data on human T-cell lymphotropic-virus-type-I (HTLV-I) status and hematology from 528 individuals were analyzed for associations with low reactivity to the purified protein derivative (PPD) of Mycobacterium tuberculosis recall antigen. Subjects were classified as HTLV-I carriers with abnormal lymphocytes (Ably), carriers without Ably, and seronegatives. All carriers had a significant 2.6-fold risk of being low responders to PPD compared with the seronegatives, carriers with Ably having the highest relative risk. Carriers with HTLV-I-antibody titer > or = 1:256, or with other detectable markers of virus status such as antibody to tax and proviral DNA, had increased risk for low response to PPD similar to the estimate for HTLV-I seropositivity alone, compared with the seronegatives. Subjects with a low lymphocyte count had 3.5 times the risk for being low responders to PPD, compared with subjects with high counts. Similarly, subjects with a low monocyte count had 2.0 times the risk for low reactivity of those with a moderate to high count. Results were not confounded by age, sex, smoking or alcohol drinking. Using multiple logistic regression, only HTLV-I seropositivity and low lymphocyte and monocyte counts were predictive of low reactivity to PPD. Analysis indicates that suppression of delayed-type hypersensitivity is associated with HTLV-I infection per se, and not with viral replication or load. Furthermore, this effect may occur in part via changes in the number and function of lymphocytes and monocytes. Such a mechanism may involve altered cytokine production in carriers and concomitant changes in cell populations involved in delayed-type hypersensitivity.

Carrier State↗
PubMed1994

An enhanced surveillance program for adult T-cell leukemia in central Brooklyn.

The Brooklyn Adult T-cell Leukemia/Lymphoma (ATL) study was developed to estimate the incidence of the human T-cell lymphotropic virus type I (HTLV-I)-associated ATL in the Crown Heights/Bedford Stuyvesant community. This central Brooklyn black community is an area which has already been shown in earlier reports to be endemic for HTLV-I-associated ATL. Surveillance has been conducted at seven area hospitals that serve this community, with surveillance already completed at five hospitals. Potential study subjects who are 20 years or older are identified by the review of admission records, discharge summaries, pathology and clinical chemistry reports, or physician referrals. Diagnoses of leukemia or lymphoma, or the presence of leukocytosis or hypercalcemia are used as criteria to identify the subjects. Participating subjects give a sample of blood for the determination of HTLV-I infection by serologic tests. At the time of enrollment, subjects provide demographic information including age, sex and birthplace. After one year of surveillance at five hospitals (39.5% of inpatient beds in the catchment), we have identified 12 cases of HTLV-I-associated ATL. The mean age of the ATL patients was 50 years, with patients being predominantly female (83.3%) and often Caribbean immigrants (83.3%). Interestingly, 42% of our cases were identified solely by findings of hypercalcemia from clinical chemistry reports. The remaining ATL cases were identified by physician referral. This enhanced surveillance program that uses both clinical and laboratory criteria for ATL case ascertainment can serve as a prototype for similar surveillance in other areas endemic for HTLV-I-associated ATL--an important effort because of the strong potential for disease prevention.

Adult↗
PubMed1994

The distribution of T-cell subsets among HTLV-I carriers in Japan.

Data on T-cell subsets from 89 human T-cell lymphotropic virus-I (HTLV-I) carriers and 25 seronegative people were analyzed to identify differences in T-cell subset values among three subgroups: HTLV-I carriers with abnormal lymphocytes (Ably; n = 24), carriers without Ably (n = 65), and HTLV-I seronegatives (n = 25). Estimates of mean values were adjusted for age, sex, smoking, and alcohol drinking, as appropriate. The percentage of CD25+ T cells was elevated in carriers with Ably (mean, 16.7 +/- 1.0) compared with the seronegatives (11.4 +/- 1.4; p = 0.0002); individuals with CD25 T-cell percentages above the median for the seronegatives had a corresponding 5.4-fold risk for being a carrier with Ably. Similarly, the percentage of CD4 T cells was elevated in carriers with Ably. Conversely, the percentage of CD8 T cells was lower among both groups of HTLV-I carriers than in the seronegatives. There was a corresponding significant increase (p = 0.0004) of the CD4/CD8 ratio among carriers with Ably (1.57 +/- 0.12) compared with the seronegatives (1.22 +/- 0.12). Among subjects with CD4/CD8 ratios above the median for the seronegatives, there were 6.8- and 4.5-fold risks for being carriers with or without Ably, respectively. The percentage of CD7 was lower among carriers with Ably (75.6 +/- 1.6) than among seronegatives (78.9 +/- 1.5; p = 0.13). The percentage of beta-interleukin-2-receptor-positive T cells did not vary among the three subgroups.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMed1994

Changes in hematologic parameters among Japanese HTLV-I carriers.

Hematologic data from 1,039 persons who participated in the Miyazaki Cohort study on human T-cell lymphotropic virus type-I (HTLV-I) infection were analyzed. Individuals were classified by HTLV-I antibody status and the presence of abnormal lymphocytes (Ably). We identified several differences in selected leukocyte populations: lymphocyte percent was higher among the HTLV-I carriers with Ably (36.5 +/- 2.0%, n = 29) compared with the carriers without Ably (33.1 +/- 0.6%, n = 299) and the seronegatives 36.4 +/- 0.4%, n = 711) (p = 0.04). Conversely, there was a trend of decreasing eosinophil percent among both carrier groups with the lowest percent among carriers with Ably (1.8 +/- 0.5%) compared with the seronegatives (2.8 +/- 0.1%) (p = 0.05). Mean basophil percent was decreased among both carriers groups (p = 0.09). Additionally, red cell count was elevated among the carriers with Ably (461 +/- 7 x 10(4)/mm3) compared with the seronegatives (446 +/- 2 x 10(4)/mm3) (p = 0.03). The HTLV-I carriers with Ably had lower serum albumin (4.39 +/- 0.05 g%) compared with the seronegatives (4.47 +/- 0.01 g%) (p = 0.10). These alterations may be a consequence of HTLV-I infection, with the greatest changes among carriers with Ably, a subset thought to be at risk for developing adult T-cell leukemia.

Alanine Transaminase↗