Longitudinal evaluation of markers of inflammation in HIV-positive and HIV-negative Rwandan women.

OBJECTIVES: African women are disproportionately affected by HIV infection and may experience non-AIDS-related complications associated with inflammation. High-sensitivity C-reactive protein (hsCRP), d-dimer and transthyretin have been examined as inflammatory markers elsewhere, but it is unclear how they change over time in HIV-negative or HIV-positive African women with or without antiretroviral therapy (ART) initiation. METHODS: We examined hsCRP, d-dimer and transthyretin levels at baseline and at follow-up of ≥2 years in 185 HIV-negative and 510 HIV-positive Rwandan women who were ART naïve at study entry. Generalized estimating equations for each marker were used to investigate the association with HIV infection/CD4 count, ART and follow-up time. RESULTS: Compared with HIV-negative women, HIV-positive women had higher hsCRP and d-dimer and lower transthyretin concentrations, with greater differences at lower CD4 counts. After adjusting for CD4 count and other factors, ART was not significantly associated with log hsCRP (P = 0.36) at follow-up, but was independently associated with lower log d-dimer (P = 0.03) and higher transthyretin (P = 0.0008) concentrations. At ≥ 2 years of follow-up, hsCRP had not significantly changed in any group but log d-dimer had decreased significantly in all groups. Transthyretin declined significantly over time in HIV-negative women and HIV-positive non-ART initiators, but increased significantly in HIV-positive ART initiators. CONCLUSIONS: HIV infection and advanced immune suppression were associated with higher hsCRP and d-dimer and lower transthyretin concentrations. ART (independently of CD4 changes) was significantly associated with decreases in d-dimer and increases in transthyretin, but, in contrast to other studies, was not associated with decreases in hsCRP. We found no change in hsCRP over time in any group.

Bone quality assessed using quantitative ultrasound at the distal radius does not differ in antiretroviral therapy-naïve HIV-positive and HIV-negative Rwandan women.

OBJECTIVES: The incidence of fractures appears to be increased in HIV-infected individuals. METHODS: We assessed bone quality using quantitative ultrasound (QUS) in HIV-infected and uninfected Rwandan women. A Sunlight Omnisense 7000 QUS was used to measure the speed of ultrasound (SOS) at the distal radius in 646 antiretroviral therapy (ART)-naïve HIV-infected women and 211 HIV-uninfected women. The Z-scores for SOS were based on data for women of the same age from the manufacturer's reference material. RESULTS: The mean CD4 cell count was 285 (± 166) cells/µL in the HIV-positive women. SOS Z-scores adjusted and unadjusted for body mass index did not differ between the groups. SOS did not differ by CD4 count (< 200 vs. ≥ 200 cells/µL: 4016 (± 117) vs. 4028 (± 107) m/s, respectively; p=0.19. CONCLUSIONS: In HIV-positive ART-naïve Rwandan women with advanced HIV disease, bone quality at the distal radius was similar to that in HIV-negative controls.

Frailty-Related Factors among Women Living with and without HIV Aged 40 Years and Older. The Women's Interagency HIV Study.

BACKGROUND: Frailty is a clinical, geriatric syndrome linked to disability and mortality; and may be associated with a variety of factors among underrepresented and underserved women living with HIV (WLWH) and without HIV (WLWOH) transitioning through the adult life course. OBJECTIVES: Determine whether a published set of factors associated cross-sectionally with frailty in WLWH and similar WLWOH at average age 39 years in 2005/2006 were associated with frailty in 2018/2019 among women who initiated frailty assessments at age ≥40 years, or whether a new set of factors were associated with frailty. DESIGN: Cross-sectional analyses within a longitudinal cohort study. SETTING: The multi-center Women's Interagency HIV Study (WIHS). PARTICIPANTS: 1285 participants (951 WLWH, 334 WLWOH), median age 53 years (interquartile range 47-58 years). MEASUREMENTS: The Fried Frailty Phenotype (FFP) in association with 23 factors representing HIV serostatus, other infections, sociodemographic factors, health behaviors, and chronic diseases. RESULTS: Frailty prevalence was 11.1% in 2018/2019 (12.6% among WLWOH, 9.6% among WLWH, p=0.121). The published 2005/2006 final multivariable stepwise regression model contained 9 predictors of frailty. When refit to women in 2018/2019, only age ≥50 years and annual income ≤$12,000 were independently positively associated with frailty; other significant 2005/2006 factors, HIV serostatus, CD4+ count <500 cells/mL among WLWH, smoking, drinking, FIB-4 and eGFR, were not. A newly-derived stepwise model considering all 23 predictors measured in 2018/2019, showed independent positive associations between frailty and age ≥50 years, annual income ≤$12,000, obesity (body mass index (BMI) ≥30kg/m2), and history of tuberculosis and cancer. CONCLUSION: Different chronic and infectious disease factors were associated with frailty among WLWH and WLWOH over the adult life course. Understanding factors associated with frailty by adult life stage, allows identification and implementation of novel, temporal interventions to alleviate frailty-associated outcomes and enhance quality of life among WLWH and WLWOH.

Depression in the first year of stay for elderly long-term nursing home residents in the USA.

BACKGROUND: Understanding the prevalence, incidence and cofactors of depression among long-term elderly nursing home (LTNH) residents domiciled for eight months or more may help optimize depression treatment in this vulnerable group. We quantified first year depression in American LTNH residents and the associations between depression and resident/facility characteristics. METHODS: Data were obtained from the Minimum Data Set and Online Survey Certification and Reporting for 634,060 LTNH residents admitted from 1999 to 2005 in 4,216 facilities. Depression first diagnosed at admission and at subsequent quarterly intervals through the first year of stay was examined. Logistic regressions modeled correlates of newly identified depression in each time-period. RESULTS: Recorded depression at admission and during the first year increased from 1999 to 2005. By 2005, 54.4% of LTNH residents had depression diagnosed over the first year; 32.8% at admission and a further 21.6% later during the first year. Antidepressant use was reported prior to depression diagnosis for 48% of those first identified depressed after admission. Men, non-Hispanic blacks, never married, and severely-cognitively impaired LTNH residents were less often identified with depression, particularly at admission. Pain and physical comorbidity were positively associated with depression identified throughout the first year. Prior institutionalization was associated with depression at admission, but not new depression after admission. Facility characteristics had weaker associations with depression. CONCLUSIONS: High depression rates at admission and during the first year indicate a need to monitor and treat large numbers of American LTNH residents for depression. Reduced associations between demographics and depression as stays progress suggest other factors have increased roles in depression etiology.

Simple Power and Sample Size Estimation for Non-Randomized Longitudinal Difference in Differences Studies.

Intervention effects on continuous longitudinal normal outcomes are often estimated in two-arm pre-post interventional studies with b≥1 pre- and k≥1 post-intervention measures using "Difference-in-Differences" (DD) analysis. Although randomization is preferred, non-randomized designs are often necessary due to practical constraints. Power/sample size estimation methods for non-randomized DD designs that incorporate the correlation structure of repeated measures are needed. We derive Generalized Least Squares (GLS) variance estimate of the intervention effect. For the commonly assumed compound symmetry (CS) correlation structure (where the correlation between all repeated measures is a constantρ) this leads to simple power and sample size estimation formulas that can be implemented using pencil and paper. Given a constrained number of total timepoints (T), having as close to possible equal number of pre-and post-intervention timepoints (b=k) achieves greatest power. When planning a study with 7 or less timepoints, given large ρ(ρ≥0.6) in multiple baseline measures (b≥2) or ρ≥0.8 in a single baseline setting, the improvement in power from a randomized versus non-randomized DD design may be minor. Extensions to cluster study designs and incorporation of time invariant covariates are given. Applications to study planning are illustrated using three real examples with T=4 timepoints and ρ ranging from 0.55 to 0.75.

The association of blood pressure levels and change in renal function in hypertensive and nonhypertensive subjects.

We compared the changes in serum creatinine levels over time after a mean follow-up of 9.8 years in essential hypertensive (EH, n = 56) and control (n = 59) male veteran subjects. All subjects had normal serum creatinine levels (62 to 124 mumol/L) and "normal" urinalysis results on entry into the study. Subjects with comorbid renal diagnoses and diabetes mellitus were eliminated from the analysis. Although not statistically significant, the rate of change in the serum creatinine concentration over time was greater in the EH cohort compared with the control cohort (1.08 +/- 4.8 vs 0.027 +/- 3.5 mumol/L per year). The difference was especially marked in black EH subjects vs black control subjects (1.60 +/- 6.2 mumol/L per year vs -0.21 +/- 3.3 mumol/L per year). When age, race, body mass index, and a diagnosis of EH were entered into a logistic regression analysis, EH subjects had a statistically significantly greater rate of decline in renal function than did control subjects (1.5 +/- 8.3 mumol/L per year). When mean time-averaged systolic blood pressure for each subject was also included in the logistic regression analysis, only systolic time-averaged blood pressure was statistically significant (0.063 +/- 0.029 mumol/L per year). We conclude that in the absence of clinically detected parenchymal renal disease, EH subjects have a greater rate of decline in renal function than do nonhypertensive subjects. Time-averaged blood pressure is predictive of the change in serum creatinine concentration not only in EH subjects but also in nonhypertensive subjects. Thus, preservation of renal function may require a blood pressure lower than the currently accepted normotensive range.

Risk Factors for the Development of BK Virus Nephropathy in Renal Transplant Recipients.

The BK polyoma virus has, in recent years, become a significant cause of renal allograft dysfunction and failure. Among 260 adult kidney transplant recipients, those with biopsy-proven BK virus nephropathy (BKVN) were compared with those without BKVN with regard to gender, age, race, rejection episodes, time on dialysis, number of organs transplanted, HLA match, live donor versus deceased donor, cold ischemia time, delayed graft function, cytomegalovirus (CMV) serostatus of donor and recipient, induction therapy, and maintenance immunosuppression. Episodes of rejection (35.7% of patients with BKVN vs 8.5% of patients without BKVN; P = .01), transplantation of >1 organ (35.7% of patients with BKVN vs 9.0% of patients without BKVN; P = .01), positive CMV serology in both donor and recipient (71.4% of patients with BKVN vs 41.1% of patients without BKVN; P = .03), and a greater cumulative dose of daclizumab use at the time of induction (2.24 ± 0.05 mg/kg in patients with BKVN vs 2.03 ± 0.14 mg/kg in patients without BKVN; P = .04) were statistically significant risk factors for the development of BKVN. Those who developed BKVN received a higher mean cumulative dose of rabbit antithymoglobulin for induction therapy, but that difference failed to achieve statistical significance (P = .07).

Long-term survival without clinical AIDS after CD4+ cell counts fall below 200 x 10(6)/l.

OBJECTIVE: Quantify and study cofactors of long-term survival without AIDS in HIV-1-infected individuals with CD4+ cell counts < 200 x 10(6)/l. DESIGN: Comparison of 579 participants who could be longitudinally evaluated for at least 3 years after the earliest date of first reaching a CD4+ cell count < 200 x 10(6)/l or an AIDS-defining illness (1987 Centers for Disease Control and Prevention definition). SETTING: Ongoing 9-year cohort study with data collected at 6-month intervals. PATIENTS: HIV-1-infected homosexual men. MEASUREMENTS AND MAIN RESULTS: Of the men, 20% did not develop an AIDS illness within 3 years following a confirmed CD4+ cell count < 200 x 10(6)/l; 29 and 28% were diagnosed with a first clinical AIDS illness from 1-3 and < 1 years, respectively, beyond their first CD4+ cell count < 200 x 10(6)/l; 23% were diagnosed with a clinical AIDS illness prior to their first CD4+ cell count < 200 x 10(6)/l. Slower decline of CD4+ cell count (P < 0.001) and presence of higher body-mass index during the period prior to the first CD4+ cell count < 200 x 10(6)/l (P < 0.001) predicted longer time to an AIDS illness once this threshold was reached. Most men had rapid loss of CD4+ cells, total T cells, and hemoglobin during the period after CD4+ cells declined below 200 x 10(6)/l. However, those remaining free of AIDS illnesses the longest arrested their decline in CD4+ cell counts and hemoglobin levels and increased total T cells during this period. Although antiretroviral therapy and Pneumocystis carinii prophylaxis extend AIDS-free survival, 45% of the group who were AIDS-free > or = 3 years after CD4+ cells fell below 200 x 10(6)/l had not used these treatments. CONCLUSIONS: Significant numbers of individuals remain free of illnesses and AIDS symptoms > or = 3 years after CD4+ cell counts drop below 200 x 10(6)/l. This occurs even in the absence of treatment. The associations seen here suggest that host and viral factors play important roles. Thus, further studies are needed to determine the biological basis of long-term survival without AIDS illnesses in HIV-1-immunosuppressed patients.

Racial differences in rate of CD4 decline in HIV-1-infected homosexual men.

OBJECTIVE: To determine whether racial differences exist in the rate of CD4 lymphocyte decline in HIV-1-infected homosexual men. DESIGN: Prospective cohort study. STUDY POPULATION: Non-Hispanic white (n = 321) and black (n = 102) HIV-1-seropositive homosexual and bisexual men were recruited from the Baltimore/Washington, DC metropolitan areas between 1984-1985 and 1987-1990, and evaluated semiannually. MAIN MEASUREMENTS: Changes in CD4 lymphocyte count and CD4 percentage over time were analysed using linear regression methods for the 271 white and 69 black participants who had at least four semiannual CD4 lymphocyte measurements. RESULTS: Rate of decline in CD4 lymphocyte count over 6 months was much slower among black than white seroprevalent men at all levels of baseline CD4 count (baseline 201-400 x 10(6)/l: + 0.24 versus -17.7 x 10(6)/l; 401-600 x 10(6)/l: -11.3 versus -23.9 x 10(6)/l; 601-800 x 10(6)/l: -15.1 versus -35.2 x 10(6)/l; > 800 x 10(6)/l: -4.3 versus -42.7 x 10(6)/l for black versus white, respectively), although this was only statistically significant for the lowest and highest strata of baseline CD4 count. These racial differences persisted after adjustment for recruitment period (1984-1985 or 1987-1990), follow-up duration, age and zidovudine therapy or Pneumocystis carinii pneumonia prophylaxis. Similar findings were observed among the 70 white and 11 black seroconverters. Black participants were also less likely than a subgroup of white participants matched on baseline CD4 lymphocyte count to be HIV-1 p24 antigen-positive. However, after acid dissociation of samples initially p24 antigen-negative, there were no significant differences in the prevalence of p24 antigenemia at enrollment or after 1 year of follow-up. CONCLUSIONS: This analysis suggests a more gradual decline in CD4 lymphocyte count among black than white Americans. The clinical significance of and reasons for this are unclear, but the lower prevalence of p24 antigenemia due to immune complexing among black Americans suggests that racial differences in the immune response to HIV may exist. Additional studies are needed to validate these findings in a larger cohort of non-whites, and to assess their relationship with other measures of cell-mediated immune function.

Solar ultraviolet radiation exposure does not appear to exacerbate HIV infection in homosexual men. The Multicenter AIDS Cohort Study.

OBJECTIVE: To determine the effect of sun exposure on HIV progression. DESIGN: Cross-sectional survey nested within a longitudinal cohort study. SETTING: The Multicenter AIDS Cohort Study. PARTICIPANTS: A total of 1155 white HIV-seronegative and 496 white HIV-seropositive homosexual men, of whom 142 seroconverted during the study. MAIN OUTCOME MEASURES: T-helper lymphocyte decline and AIDS. RESULTS: No positive correlation was found between the development of AIDS or loss of T-helper lymphocytes and (i) phenotypic characteristics associated with enhanced ultraviolet radiation (UVR) sensitivity (hair or eye color, skin type), or (ii) reported UVR exposure (sun lamp/tanning bed use, frequency of beach vacations, sunscreen use), or (iii) composite score of UVR sensitivity and exposure history. The composite scores and individual measures of risk were not correlated with rate of T-helper lymphocyte decline (slope) based upon rank correlation (correlation coefficient, 0.04; P = 0.32). In fact, individuals purposefully seeking the sun had slower T-helper lymphocyte declines. Sensitivity to UVR was also not significantly associated with AIDS [odds ratio (OR), 1.11 per unit of higher composite score; 95% confidence interval (CI), 0.66-1.88; P = 0.63]. Among individuals who were HIV-infected at baseline, those who have been purposely seeking sun exposure were less likely to have AIDS (OR, 0.67; 95% CI, 0.39-1.11; P = 0.12). CONCLUSIONS: These data suggest that phenotypic characteristics of high UVR sensitivity and exposure are not highly correlated with decline in T-helper lymphocyte count or with progression to AIDS.

The influence of drug use patterns on the rate of CD4+ lymphocyte decline among HIV-1-infected injecting drug users.

OBJECTIVES: To assess the relationship between various injecting drug use patterns and the rate of CD4+ lymphocyte decline in HIV-1-infected injecting drug users in Baltimore, Maryland, USA. METHODS: A cohort of 605 HIV-1-infected injecting drug users was recruited between 1988 and early 1989 in East Baltimore using extensive community outreach techniques. The participants were interviewed semi-annually to collect information on drug use practices. The outcome measure of interest was the rate of CD4+ lymphocyte decline between pairs of CD4+ lymphocyte counts. A mixed model was used to evaluate the relationship between the change in CD4+ lymphocyte count per month and previous CD4+ lymphocyte count and various drug use variables. RESULTS: The 605 HIV-infected injecting drug users had a median initial CD4+ lymphocyte count of 513 cells x 10(6)/l. Using 3209 paired observations, the mean change in CD4+ lymphocyte count was -3.2 cells x 10(6)/l per month. The rate of decline was higher in those with a higher level of CD4+ lymphocytes (P < 0.01) and length of drug use (P < 0.01), but did not vary by injection frequency or injection intensity of specific drug types. Although animal studies have suggested that the pattern of drug administration (continuous versus intermittent) and episodes of withdrawal or overdose might impact the rate of CD4+ lymphocyte decline, this was not observed in the present study. CONCLUSION: Patterns of injecting drug use, based on self-report, were not associated with the rate of decline in CD4+ lymphocytes.

Trends of HIV-1 and sexually transmitted diseases among pregnant and postpartum women in urban Malawi.

OBJECTIVES: To examine rates of HIV-1 and sexually transmitted disease (STD) among pregnant and postpartum women in urban Malawi, Africa. DESIGN: Serial cross-sectional surveys and a prospective study. METHODS: Three major surveys were conducted in 1990, 1993 and 1994/1995. Consecutive first-visit antenatal women and women giving birth at the Queen Elizabeth Central Hospital were tested for HIV and STD after counseling and obtaining informed consent. Unlinked, anonymous HIV testing was also conducted on smaller samples of antenatal women in the same hospital to provide annual prevalence data. HIV-seronegative postpartum women from the 1990 and 1993 surveys were enrolled in a prospective study to determine HIV incidence. RESULTS: HIV seroprevalence rose from 2.0% in 1985 to 32.8% in 1996, a 16-fold increase. The highest age-specific HIV prevalence was in the following age-groups: 20-24 years during 1990, 25-29 years during 1993, and 30-34 years during 1996. Among 1173 women followed for a median of 30.9 months, HIV incidence was 5.98 per 100 person-years in women aged < 20 years and declined steadily in older women. The prevalence of STD significantly declined among both HIV-positive and negative women. This decline in STD prevalence, however, was not accompanied by increased condom use over time. CONCLUSIONS: Among urban childbearing women in Malawi, incidence of HIV is highest among young women while, currently, prevalence is highest among older women. Recent declines in STD prevalence suggest that HIV prevention programs are having an impact either through improved STD diagnosis and treatment or reduced risk behaviors. Sequential cross-sectional STD prevalence measures may be useful in monitoring effectiveness of STD and HIV prevention activities.

PIP: Prevalence rates of HIV-1 and other sexually transmitted diseases (STDs) among pregnant and postpartum women were investigated in sequential, cross-sectional studies (1990, 1993, and 1994-95) conducted at Queen Elizabeth Central Hospital in Blantyre, Malawi. Annual anonymous, unlinked testing revealed a linear increase in HIV-1 prevalence among antenatal patients from 2.0% in 1985 to 32.8% in 1996. Analysis of demographic attributes of women enrolled in the 1990 and 1993 surveys of consecutive, first-visit antenatal women (n = 6603 and 2161, respectively) and the 1994-95 study of all women giving birth at the hospital during a 6-month period (n = 6964) indicated that HIV-infected women were most likely to be young, with fewer pregnancies, and be more educated. The highest age-specific HIV prevalence shifted from 20-24 years in 1990 to 30-34 years in 1996, indicating an aging cohort of women who became infected at a younger age. Reported lifetime use of condoms increased from 5.6% in 1990 to 17.5% in 1993, then declined to 4.9% in 1995; condom use was consistently higher among HIV-positive than HIV-negative women. The prevalence of all STDs (syphilis, trichomoniasis, gonorrhea, and genital warts and ulcers) declined significantly during 1990-96, with the most consistent decreases recorded among HIV-positive women. In a follow-up study of 1173 HIV-seronegative, postpartum women evaluated for 2302 person-years (average duration, 30.9 months), 97 seroconverted (4.21/100 person-years). The seroconversion rate declined steadily from 21.26/100 person-years in 1990 to 1.11/100 person-years in 1994-95. These findings are consistent with those from other sub-Saharan African countries, indicating a rapid increase in HIV prevalence followed by stabilization within about 10 years of the onset of the epidemic. The large decline in STD prevalence in the antenatal population suggests that Malawi's national AIDS prevention program is having an impact, either through improved STD diagnosis and treatment or reduced risk behaviors.

Evidence that anoreceptive intercourse with ejaculate exposure is associated with rapid CD4 cell loss.

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.

Association of HIV-1 load and CD4 lymphocyte count with mortality among untreated African children over one year of age.

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.

Kaposi's sarcoma-associated herpesvirus infection prior to onset of Kaposi's sarcoma.

OBJECTIVES: Kaposi's sarcoma-associated herpesvirus (KSHV), a newly discovered human gammaherpesvirus, is found in the majority of KS lesions from patients with and without AIDS. Peripheral blood mononuclear cells (PBMC) were examined for KSHV DNA to determine whether viral infection precedes onset of this neoplasm. DESIGN: Randomized and blinded case-control study of prospectively collected PBMC samples from ongoing cohort studies. METHODS: Paired PBMC drawn before and after KS onset from 21 AIDS-KS patients were compared to paired PBMC from 23 high-risk HIV-infected homo-/bisexual patients who did not develop KS and to a single PBMC sample from 19 low-risk, HIV-infected hemophiliac patients. Extracted DNA samples were amplified by polymerase chain reaction (PCR) using two non-overlapping nested primer sets to control for potential PCR contamination. RESULTS: In all comparisons, patients who went on to develop KS were significantly more likely to show evidence of KSHV infection prior to onset of KS than either control group. Of PBMC samples from AIDS-KS patients drawn prior to KS, 52% were positive for KSHV DNA whereas both high- and low-risk control groups had lower rates of PBMC infection (9-13%). KSHV infection can precede KS onset by up to 21 months among AIDS-KS patients. CONCLUSIONS: AIDS-KS patients are significantly more likely to show evidence of KSHV infection in PBMC prior to KS onset than control HIV-infected patients. Because identical PBMC samples from cases and controls were examined blindly, these results are not caused by a bias in tissue sampling. Homo-/bisexual and hemophiliac AIDS patients who do not develop KS appear to have a low prevalence of infection. These findings indicate that KSHV infection is specifically associated with the subsequent development of KS in AIDS patients.

Association of HLA profiles with early plasma viral load, CD4+ cell count and rate of progression to AIDS following acute HIV-1 infection. Multicenter AIDS Cohort Study.

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.

Bacterial vaginosis and disturbances of vaginal flora: association with increased acquisition of HIV.

BACKGROUND: Cross-sectional studies suggest an association between bacterial vaginosis (BV) and HIV-1 infection. However, an assessment of a temporal effect was not possible. OBJECTIVES: To determine the association of BV and other disturbances of vaginal flora with HIV seroconversion among pregnant and postnatal women in Malawi, Africa. DESIGN: Longitudinal follow-up of pregnant and postpartum women. METHODS: Women attending their first antenatal care visit were screened for HIV after counselling and obtaining informed consent. HIV-seronegative women were enrolled and followed during pregnancy and after delivery. These women were again tested for HIV at delivery and at 6-monthly visits postnatally. Clinical examinations and collection of laboratory specimens (for BV and sexually transmitted diseases) were conducted at screening and at the postnatal 6-monthly visits. The diagnosis of BV was based on clinical criteria. Associations of BV and other risk factors with HIV seroconversion, were examined using contingency tables and multiple logistic regression analyses on antenatal data, and Kaplan-Meier proportional hazards analyses on postnatal data. RESULTS: Among 1196 HIV-seronegative women who were followed antenatally for a median of 3.4 months, 27 women seroconverted by time of delivery. Postnatally, 97 seroconversions occurred among 1169 seronegative women who were followed for a median of 2.5 years. Bacterial vaginosis was significantly associated with antenatal HIV seroconversion (adjusted odds ratio = 3.7) and postnatal HIV seroconversion (adjusted rate ratio = 2.3). There was a significant trend of increased risk of HIV seroconversion with increasing severity of vaginal disturbance among both antenatal and postnatal women. The approximate attributable risk of BV alone was 23% for antenatal HIV seroconversions and 14% for postnatal seroconversions. CONCLUSIONS: This prospective study suggests that progressively greater disturbances of vaginal flora, increase HIV acquisition during pregnancy and postnatally. The screening and treating of women with BV could restore normal flora and reduce their susceptibility to HIV.

Pharmacokinetic characteristics, efficacy, and safety of buccal testosterone in hypogonadal males: a pilot study.

Transbuccal administration of drugs provides an easy route of administration. To test the safety and efficacy of a novel testosterone (T) product, we performed a randomized, double blind, placebo-controlled study in a parallel design. Men with serum T levels below 250 ng/dL were administered either an active buccal tablet containing 10 mg T (n = 7) or a buccal placebo tablet (n = 6) containing 3 mg pseudoephedrine HCl for taste matching. Men were studied while taking a standard T enanthate dose, after 6 weeks of a wash-out period, and after 8 weeks of therapy. The men were matched for age (mean +/- SD, 41 +/- 16 vs. 47 +/- 16) and type of hypogonadism (three primary testicular failures in each group, with the remainder having a central etiology). Acute pharmacokinetic testing showed peak serum hormone levels at 30 min, with a mean serum T concentration of 2688 +/- 147 ng/dL (range, 1820-3770 ng/dL). Levels returned to baseline in 4-6 h, resulting in a total T area under the curve level of 3865 ng/hn.dL, less than that using other available forms of T administration. Similar pharmacokinetics were observed for the hormone's metabolites, bioavailable T, free T, and estradiol. After 8 weeks of treatment, the results of nocturnal penile tumescence studies evaluating rigidity and circumference were significantly different from those in the placebo group (P < 0.05) and comparable to those during T enanthate therapy. In conclusion, transbuccal T therapy was sufficient to maintain normal sexual function while minimizing the total time of exposure to elevated circulating serum T levels.

Serum hormones in men with human immunodeficiency virus-associated wasting.

Weight loss is commonly associated with increased morbidity and mortality in individuals with human immunodeficiency virus (HIV) infection. We performed a nested case-control study of 26 HIV-infected subjects recruited from a cohort of gay men enrolled in the Multicenter Acquired Immunodeficiency Syndrome Cohort Study. To test the hypothesis that hormonal changes precede and may induce the wasting syndrome, we performed a nested case-control study and analyzed serum gonadal steroids and GH in samples of HIV-infected men with or without weight loss, uncomplicated by diarrhea or ever having an opportunistic infection. We studied 13 cases (mean age +/- SD, 45 +/- 7.2 yr) with a mean weight loss of 13 +/- 3.6%, considered to have the wasting syndrome by Centers for Disease Control criteria (weight loss of > 10%) and 13 controls matched for age and duration of follow-up. Serum bioavailable testosterone (T) levels decreased in the case group (P < 0.05) before the definition of wasting was attained, although weight loss had already begun. More impressive declines occurred in serum T (P = 0.012), free T (P = 0.0025), and bioavailable T (P < 0.0001) during the 6 months immediately before documentation of wasting. These changes were concurrent with an increase in serum FSH (P = 0.0135) without a change in serum LH. We conclude that a decline in bioavailable T occurs early in the course of events leading to wasting, suggesting that changes in gonadal hormones may contribute to the multifactorial etiology of the wasting syndrome.

Changes in depressive symptoms as AIDS develops. The Multicenter AIDS Cohort Study.

OBJECTIVE: The authors sought to determine whether rates of depressive symptoms change from early- to late-stage HIV-1 infection and to determine the predictors of depressive symptoms as AIDS develops. METHOD: The data for this study were from 911 HIV-seropositive men-community volunteers from four U.S. cities-who entered the 10-year Multicenter AIDS Cohort Study without a diagnosis of AIDS and subsequently developed AIDS. The subjects underwent semiannual follow-ups during the study period. The outcome measures-overall depressive symptoms, nonsomatic depressive symptoms, syndromal depression, and severe depression-were assessed over the 5 years before and the 2 years after AIDS diagnosis from responses on the Center for Epidemiologic Studies Depression Scale (CES-D Scale). RESULTS: Depressive symptoms were stable over time from month 60 to month 18 before AIDS developed. However, beginning 12-18 months before AIDS diagnosis, there was a significant rise in all measures of depression, which reached a plateau within 6 months before AIDS developed. At this plateau, there was a 45% increase in mean CES-D Scale scores above baseline. An elevated CES-D Scale score in the earlier stages of infection, a self-report of AIDS-related symptoms (such as rash and lymphadenopathy), concurrent unemployment, cigarette smoking, and limited social supports were consistent predictors of higher rates of depression as AIDS developed. CONCLUSIONS: There is a dramatic, sustained rise in depressive symptoms as AIDS develops, beginning as early as 18 months before clinical AIDS is diagnosed. Prior depression, HIV-disease-related factors, and psychological stressors contribute to this rise. This robust phenomenon invites further characterization.