Biomedical subjects
Publications and source records attributed to D R Hoover.
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OBJECTIVE: To determine whether ejaculate exposure through anoreceptive intercourse is associated with rapid CD4 cell loss. DESIGN: Self-reported behavioral, demographic data and blood samples were gathered longitudinally at ten semiannual visits from individuals participating in the Multicenter AIDS Cohort Study (MACS). PATIENTS/PARTICIPANTS: A group of 937 HIV-seropositive men who were continuously followed for four to ten semiannual visits. OUTCOME MEASURES: A loss of 10% or more in CD4 cells between the first two of any three consecutive semiannual visits that was followed by a 10% or greater loss between the second and third visits. RESULTS: A period of rapid CD4 cell loss over three semiannual visits occurred in 389 of the 937 (42%) HIV-seropositive men studied. Men who reported one or more anoreceptive intercourse partners with whom they were exposed to ejaculate (RAI-E) during the 12 months immediately preceding their visits were more than twice as likely to show this rapid CD4 cell loss compared with men with no such partners. CONCLUSIONS: The association between RAI-E partnerships and rapid CD4 cell loss suggests factors associated with ejaculate exposure (e.g., sexually transmitted diseases) may hasten the clinical progression of HIV disease. It is suggested that infectious diseases, which are known to be associated with ejaculate exposure, may be the causal factor underlying the association between RAI-E partnerships and rapid CD4 cell loss in these men, although the presence of these diseases was not ascertained in these data. HIV-infected individuals should be cautioned against unprotected anoreceptive intercourse.
OBJECTIVE: To examine the association of viral load and CD4 lymphocyte count with mortality among HIV-infected children over one year of age. DESIGN: A prospective study. HIV-infected children were enrolled during the first year of life and followed for more than 2 years at the Queen Elizabeth Central Hospital in Blantyre, Malawi (southeast Africa). METHODS: Morbidity and mortality information was collected every 3 months, and physical examination and blood testing (for viral level and CD4 cell percentage) were performed every 6 months. Kaplan-Meier analyses and proportional hazards models were used to estimate survival and to examine the association of primary predictors with mortality. RESULTS: Of 155 HIV-infected children originally enrolled, 115 (74%) had viral load testing and 82 (53%) had both viral load and CD4 cell percentage testing after their first year. Among children over one year of age, significant associations were found between mortality and the log10 viral load and CD4 cell percentage in both univariate and multivariate models. Independent of the CD4 cell value, a one unit log10 increase in HIV RNA level increased the hazard of child mortality by more than twofold. Children with low CD4 cell counts (< 15%) and high viral loads (> or = 250,000 copies/ml median value) had the worst survival; children with high CD4 cell counts (> or = 15%) and low viral loads (< 250,000 copies/ml) had the best survival. CONCLUSION: As in developed countries, viral load and CD4 cell count are the main predictors of mortality among African children. Making these tests available adds to the challenges to be considered if antiviral therapies were to be adopted in these countries.
To illustrate the importance of adjusting the estimates of cumulative incidence of acquired immunodeficiency syndrome (AIDS) related illnesses for competing risk of other causes of death, we compared unadjusted and adjusted (for competing events) incidence estimates for four AIDS illnesses: pneumocystis cavinii pneumonia (PCP), mycobacterium avium complex (MAC), cytomegalovirus (CMV), and esophageal candidiases. The study population was patients followed by the Johns Hopkins Hospital AIDS Service between 1989 to 1995. Ratios of 4 year unadjusted incidence estimates to 4 year adjusted incidence estimates for the four diseases ranged from 1.38 to 1.86, corresponding to cumulative death rates of 61% to 69%. For CMV, the ratios of 4 year unadjusted to adjusted incidence estimates for five groups of patients ranged from 1.5 to 2.33, corresponding to cumulative death rates of 48% to 78%. We conclude that ignoring the competing risk of death can result in substantial overestimation of disease occurrence, which may give misleading results in estimating and comparing the occurrence of a disease of interest.
BACKGROUND: Although anemia is highly prevalent during pregnancy and is common during human immunodeficiency virus (HIV) infection, anemia and iron status have not been well characterized in HIV-infected pregnant women. OBJECTIVE: To gain insight into iron status in HIV-infected pregnant women using plasma transferrin receptor and related indicators of anemia. STUDY DESIGN: Plasma transferrin receptor, ferritin, alpha1-acid glycoprotein, C-reactive protein and hemoglobin concentrations were measured in pregnant women, gestational age 18-28 weeks, seen in an urban antenatal clinic in Blantyre, Malawi. RESULTS: The prevalence of anemia among 662 HIV-positive and 190 HIV-negative pregnant women was 73.1% and 50.0%, respectively (P<0.0001). Among HIV-positive and HIV-negative women, median plasma transferrin receptor concentrations were 24.4 and 24.1 nmol/l (P=0.5), respectively, and median plasma ferritin concentrations were 17.8 and 20.8 microg/l (P<0.05), respectively. There was a large overlap in plasma transferrin receptor concentrations among women with and without anemia. Using the combination of hemoglobin and ferritin as a standard, the sensitivity and specificity of plasma transferrin receptor in diagnosing iron deficiency anemia was estimated at 45.9% and 68.1%, respectively. CONCLUSION: The use of plasma transferrin receptor concentrations as an indicator of iron deficiency anemia may be limited in pregnant women with chronic inflammation and infection.
Plasma retinol-binding protein (RBP) concentrations have been suggested as surrogate indicators for plasma retinol concentrations in the assessment of vitamin A status in less technologically developed settings. Plasma RBP was measured by radial immunodiffusion and plasma retinol by high performance liquid chromatography in a cross-sectional study of 900 pregnant women at the Queen Elizabeth Central Hospital, Blantyre, Malawi. The Spearman correlation coefficient between plasma RBP and retinol concentrations was 0.95 (p<0.0001). By linear regression, 0.70 micromol l(-1) retinol was equivalent to 21.1 mg l(-1) RBP. With these cut-off points for defining vitamin A deficiency, there was high concordance between categorical descriptions of deficiency using retinol and RBP by chi-square analysis (p<0.001). Measurement of plasma RBP by radial immunodiffusion is simple, inexpensive, and does not require expensive instrumentation. Plasma RBP concentrations measured by radial immunodiffusion are highly correlated with plasma retinol and can be used as a simple surrogate measure for vitamin A concentrations in large field studies.
OBJECTIVE: To assess patterns of morbidity and associated factors in late infancy and early childhood among human immunodeficiency virus (HIV)-infected and -uninfected African children. DESIGN: Prospective study. SETTING: The Queen Elizabeth Central Hospital, Blantyre, Malawi. PARTICIPANTS: Children with known HIV status from an earlier perinatal intervention trial were enrolled during the first year of life and followed to approximately 36 months of age. OUTCOME MEASURES: Morbidity and mortality information was collected every 3 months by a questionnaire. A physical examination was conducted every 6 months. Blood to determine CD4(+) values was also collected. Age-adjusted and Kaplan-Meier analyses were performed to compare rates of morbidity and mortality among infected and uninfected children. RESULTS: Overall, 808 children (190 HIV-infected, 499 HIV-uninfected but born to infected mothers, and 119 born to HIV-uninfected mothers) were included in this study. Of these, 109 died during a median follow-up of 18 months. Rates of childhood immunizations were high among all children (eg, lowest was measles vaccination [87%] among HIV-infected children). Age-adjusted morbidity rates were significantly higher among HIV-infected than among HIV-uninfected children. HIV-infected children were more immunosuppressed than were uninfected children. By 3 years of age, 89% of the infected children died, 10% were in HIV disease category B or C, and only approximately 1% were without HIV symptoms. Among HIV-infected children, median survival after the first occurrence of acquired immunodeficiency syndrome-related conditions, such as splenomegaly, oral thrush, and developmental delay, was <10 months. These same conditions, in addition to frequent bouts of fever, were the main morbidity predictors of mortality. CONCLUSIONS: The frequency of diseases was high, and progression from asymptomatic or symptomatic HIV disease to death was rapid. Management strategies that effectively reduce morbidity for HIV-infected children are needed.
This double-blind, randomized, placebo-controlled clinical trial evaluated the impact on withdrawal symptoms of (i) combining naltrexone with a 4-day buprenorphine taper for short opioid detoxification (NB Group), compared to (ii) using a 4-day buprenorphine taper alone, followed by naltrexone on day 8 (PB Group). Sublingual buprenorphine was administered on days 1-4 (26 mg total). For the NB Group (n = 32) escalating doses of oral naltrexone were given on days 2-8 (placebo day 1). For the PB Group (n = 28) placebo was given on days 1-7 and naltrexone on day 8. Main outcome measures were Observed Opioid Withdrawal scores (OOW, 0-30) and use of medications to treat opioid withdrawal. Of 32 patients in the NB group, 59% experienced clinically relevant withdrawal (defined as OOW > or = 5) on day 2, but, after day 5, none experienced withdrawal. In the PB group, the number of patients experiencing withdrawal increased over time. The first naltrexone dose induced comparable withdrawal in both groups: peak OOW scores were (mean +/- SD) 5.2 +/- 3.3 on day 2 for the NB group, and 4.0 +/- 3.9 on day 8 for the PB group (NS), though, on day 2, 7 patients dropped out in the NB group and none in the PB group, while only one patient dropped out in the PB group on day 8. Throughout the 8-day study, patients in both groups received similar amount of adjunct medication: 0.64 +/- 0.07 mg (NB group) of clonidine vs 0.73 +/- 0.15 mg (PB group; NS). Only 25% of patients required use of sedatives (up to 20 mg diazepam). Starting naltrexone on day 2 appeared to abolish withdrawal symptoms after day 5 and, thus, to shorten the duration of withdrawal symptoms. Peak withdrawal symptoms after naltrexone were of moderate intensity, suggesting that naltrexone combined with buprenorphine is an acceptable and safe treatment for shortened opioid detoxification and induction of naltrexone maintenance.
Disturbances of vaginal flora are common among women of reproductive age. In areas of sub-Saharan Africa where the prevalence of HIV is high, the frequency of bacterial vaginosis (BV) is also high. In this study, we assessed the association of BV and other disturbances of vaginal flora with prevalent HIV infection in two cross-sectional studies among pregnant women in urban Malawi. The prevalence of HIV-1 was 23% in 1990 and 30% in 1993. Overall, 30% of the women had BV, 59% had mild or moderate disturbance of vaginal flora, and only 11% had normal vaginal flora. Increasing prevalence of HIV was significantly associated with increasing severity of disturbance of vaginal flora (p < .00001, chi2 trend test). This trend of increased prevalence persisted after controlling for concurrent sexually transmitted diseases (STDs), sexual activity, and socioeconomic factors. After multivariate adjustment for potential confounders, the odds ratio for the association of BV with prevalent HIV infection was 3.0 (95% confidence interval [CI], 2.4-3.8), that of moderate vaginal disturbance with HIV infection was 2.2 (95% CI, 1.7-2.8), and that of mild vaginal disturbance with HIV infection was 1.6 (95% CI, 1.3-2.1). Among women with BV, HIV infection was higher among younger women than older, implying more recent infection. Although these studies were cross-sectional, our data suggest that BV could be associated with increased susceptibility to HIV infection.
The cytokine soluble CD23 (sCD23) acts as a B cell growth factor and is associated with Epstein-Barr virus (EBV) infection. To elucidate the role sCD23 might play in the pathogenesis of AIDS-related non-Hodgkin's lymphoma (AIDS NHL), 101 AIDS NHL patients from the Multicenter AIDS Cohort Study were studied. Serum sCD23 within 18 months prior to lymphoma diagnosis was measured for all patients and EBV in tumor tissue was ascertained for 49 patients. Tumor morphology and primary site were verified from pathology reports and tumor specimens. Bivariate tests and multivariate regression were employed to determine whether serum sCD23 correlated with tumor EBV, morphology, and primary site. Higher levels of serum sCD23 were associated with the absence of tumor EBV and with small noncleaved cell morphology. Thus, the serum sCD23 level does not appear to be mediated by EBV in these patients, but could be related to a pathogenetic mechanism of small noncleaved cell lymphoma.
Human immunodeficiency virus (HIV) type 1 load in breast milk and mastitis were examined as risk factors for vertical transmission of HIV-1. Six weeks after delivery, HIV-1 load and sodium (an indicator of mastitis) were measured in breast milk from 334 HIV-1-infected women in Malawi. Median breast milk HIV-1 load was 700 copies/mL among women with HIV-1-infected infants versus undetectable (<200 copies/mL) among those with uninfected infants, respectively (P<. 0001). Elevated breast milk sodium levels consistent with mastitis occurred in 16.4% of HIV-1-infected women and were associated with increased vertical transmission of HIV-1 (P<.0001). Median breast milk HIV-1 load was 920 copies/mL among women with versus undetectable among those without elevated breast milk sodium levels, respectively (P<.0001). Mastitis and breast milk HIV-1 load may increase the risk of vertical transmission of HIV-1 through breast-feeding.
BACKGROUND: HIV-infected and uninfected children who survived their first year of life were prospectively followed in Malawi to assess levels of mortality and related risk factors during the second and third years of life. METHODS: Children with known HIV status from an earlier perinatal intervention trial were enrolled. These children [HIV-infected (Group A); HIV-uninfected but born to HIV-seropositive mothers (Group B); and children born to HIV-seronegative mothers (Group C)] were followed every 3 months until age 36 months. Mortality data were collected at each visit. Immunologic data (CD4+ percent) were collected at or immediately after enrollment. RESULTS: Overall 702 children were enrolled and 83 children died during follow-up. The mortality rate per 1000 person years of observation was 339.3 among Group A children, 46.3 among Group B children and 35.7 among Group C children. Among HIV-infected children the cumulative proportion surviving to age 24 months was 70% and those surviving to age 36 months was 55%. By age 32 months none of the severely immunosuppressed (CD4% < 15%) children had survived. The mortality differentials between HIV-infected and uninfected children persisted after adjusting for several risk factors. The major causes of death among infected children (n = 52) were wasting and respiratory conditions. CONCLUSIONS: Although all HIV-infected children had received childhood immunizations, mortality was high. Management of these children should include aggressive antimicrobial treatment, and evaluation of prophylactic regimens should be considered.
Although an elevated sodium concentration in human milk is suggested to be an indicator of mastitis, it is unclear whether elevated sodium concentrations are associated with immunological and inflammatory mediators in human milk. We conducted a cross-sectional study to evaluate the relationships between elevated breast milk sodium concentrations and levels of lactoferrin, lysozyme, secretory leukocyte protease inhibitor (SLPI), interleukin-8 (IL-8), and RANTES (regulated on activation normal T cell expressed and secreted) in human milk at 6 weeks postpartum in 96 lactating women in Blantyre, Malawi. Mastitis, as indicated by an elevated breast milk sodium concentration, was present in 15.6% of the women. Women with and without mastitis had respective median levels of other factors as follows: lactoferrin, 1,230 versus 565 mg/liter (P < 0. 0007); lysozyme, 266 versus 274 mg/liter (P = 0.55); SLPI, 76 versus 15 microg/liter, (P < 0.0002); IL-8, 339 versus 25 ng/liter (P < 0. 0001); and RANTES, 82 versus 3 ng/liter (P < 0.0001). Elevated sodium concentrations in breast milk are associated with an increase in levels of some immunological and inflammatory factors in breast milk.
Human milk contains important immunological factors that protect the breast from infection and are thought to protect infants from infection, including human immunodeficiency virus (HIV) infection. Human milk immunological factors have not been well characterized in HIV-infected lactating women. Lysozyme, secretory leukocyte protease inhibitor (SLPI), sodium (an indicator of mastitis), and HIV were measured in breast milk of 334 HIV-infected women at 6 weeks postpartum. Women with mastitis, as indicated by elevated breast milk sodium concentrations, had higher median levels lysozyme (290 vs 221 mg/L, p < 0.04), SLPI (38 vs 19 mg/L, p < 0.0001) and HIV (920 copies/mL vs undetectable, p < 0.0001) compared with women without mastitis. Lower total plasma carotenoid levels (p < 0.02) and higher maternal HIV load (p < 0.006) by quartile were risk factors for mastitis. Mastitis, as indicated by elevated breast milk sodium levels, is associated with high concentrations of immunological factors and higher HIV load in breast milk.
OBJECTIVE: To characterise the major plasma carotenoids in pregnant women with and without HIV infection attending antenatal clinic in Blantyre, Malawi. DESIGN: A cross sectional study. SETTING: Antenatal clinic of Queen Elizabeth Central Hospital, Blantyre, Malawi. SUBJECTS: Nine hundred women (697 HIV-positive and 203 HIV-negative women) in their second trimester of pregnancy. MAIN OUTCOME MEASURES: Plasma carotenoid levels as related to HIV status and level of disease progression. RESULTS: There were no significant differences in plasma carotenoid levels between HIV-positive and HIV-negative women. Median (25th, 75th percentiles) plasma levels of carotenoids for all women in the study were alpha-carotene, 0.040 (0.23, 0.071) mumol/L; beta-carotene, 0.350 (0.192, 0.595) mumol/L; beta-cryptoxanthin, 0.050 (0.029, 0.091) mumol/L; lutein/zeaxanthin 0.646 (0.426, 0.976) mumol/L; lycopene, 0.088 (0.055, 0.138) mumol/L, and total carotenoids 1.321 (0.884, 1.874) mumol/L. Mothers had higher mean plasma concentrations of alpha-carotene (p < 0.04), beta-carotene (p < 0.0001), lutein/zeaxanthin (p < 0.0001), and total carotenoids (p < 0.0001) in the wet season than the dry season. No seasonality was observed for beta-cryptoxanthin, lycopene, or retinol. CONCLUSION: This study suggests that pregnant women with and without HIV infection in Blantyre, Malawi have relatively low plasma carotenoid levels and poor dietary intake of provitamin A carotenoids.
The cytokine soluble CD23 (sCD23) has been shown to act as a B cell growth factor and to be elevated in serum prior to development of AIDS-related non-Hodgkin's lymphoma (AIDS NHL). To further characterize the elevation of serum sCD23 in AIDS NHL patients and investigate its potential as a diagnostic test, a matched case-control study of AIDS NHL (n = 101) was nested within the Multicenter AIDS Cohort Study. Serum sCD23 was measured in cases' and controls' serum specimens at three different time periods (0-6, 6-12, and 12-18 months) and CD4+ thresholds (0-99, 100-199, and 200-299 cells/microl) prior to the case's NHL diagnosis. Changes in serum sCD23 over time were examined in AIDS NHL cases relative to controls, and t tests were performed to determine whether cases' serum sCD23 exceeded that of controls at each time period and CD4+ threshold. Overall, cases' median serum sCD23 levels were approximately double those of controls. Serum sCD23 concentration was positively correlated with lymphocyte counts for both cases and controls. The difference in cases' and controls' serum sCD23 levels became greater as AIDS NHL diagnosis date approached: in the 18 months preceding the case's NHL diagnosis, serum sCD23 was stable in cases but dropped in controls. Although this difference was statistically significant (P < 0.05), it was not clinically significant. It is unlikely that serum sCD23 would make a useful test for AIDS NHL because the magnitude of the difference between cases and controls was small and there was no change in serum sCD23 in cases that would indicate disease.
BACKGROUND: Host genetic factors, such as HLA alleles, play an important role in mediating the course of HIV-1 disease progression through largely undefined mechanisms. OBJECTIVES: To examine the association of HLA markers with HIV-1 RNA plasma viral load and other factors associated with course of disease progression in HIV-1 infection. DESIGN AND METHODS: A group of 139 HIV-1 seroconverters from the Multicenter AIDS Cohort Study had been typed for a variety of HLA markers. HIV-1 RNA plasma viral load was measured from frozen plasma specimens obtained approximately 9 months following seroconversion. CD4+ cell counts were available from the same study visit. Statistical analysis was performed using survival techniques and linear regression models to quantify the relative associations of an HLA score profile, HIV-1 RNA plasma viral load, CD4+ cell count and age with each other and with rate of progression to AIDS and death. RESULTS: Cox proportional hazards models showed statistically significant differences in time to AIDS by HLA score profile category per unit increase [relative hazard (RH), 0.64; P < 0.0001], HIV-1 RNA plasma viral load per 10-fold increase (RH, 2.04; P = 0.0003), and CD4+ cell count per 100 cell (x 10(6)/l) increase (RH, 0.90; P = 0.02). Multivariate linear regression showed that viral load was 39% lower (P = 0.0001) for each unit increase in HLA score profile and 13% lower (P = 0.002) for each 100 cell (x 10(6)/l) increase in CD4+ cell count. CONCLUSION: The means by which the HLA score profile influences the time to AIDS is probably through immunologic responses that affect the rate of HIV-1 replication, as manifested by the HIV-1 RNA plasma viral load during the first 6-12 months following acute infection.
BACKGROUND: Plasma HIV-1 RNA measurements are used for initiation of antiretroviral treatments. Whether the viral-load association with prognosis is similar in women and men is unknown. METHODS: We studied 812 specimens from 650 injection-drug users (IDUs) participating in a continuous observational study of patients based in a community clinic. HIV-1 load was measured by branched-chain DNA on samples from 527 IDUs from the baseline visit, and by reverse-transcriptase PCR and quantitative microculture on samples from 285 IDUs at a follow-up visit 3 years later. FNDINGS: Women had lower median viral-load measurements than men by branched-chain DNA (3365 vs 8907 copies/mL; p=0.001), reverse-transcriptase PCR (45416 vs 93130 copies/mL; p=0.02), and quantitative microculture (5 vs 8 infectious units per million peripheral blood mononuclear cells; p=0.015). This association remained even after adjustment for CD4 cell count, race, and drug use within the previous 6 months. Time to AIDS was statistically similar for men and women in a univariate proportional-hazards model and in a model adjusting for CD4 cell count. Proportional-hazards models showed that women with the same viral load as men had a 1.6-fold higher risk of AIDS (95% CI 1.10-2.32); or, equivalently, that women with half the viral load of men had a similar time to AIDS as men. INTERPRETATION: Although a biological mechanism remains unclear, these data suggest that current recommendations for HIV-1 viral-load thresholds to initiate antiretroviral therapy should be revised downwards for women.