The rapid CD4 + T-lymphocyte decline and human immunodeficiency virus progression in females compared to males.

CD4 + T-lymphocyte counts are used to assess CD4 + decline and the stage of human immunodeficiency virus (HIV) progression in HIV-infected patients. Clinical observation suggests that HIV progress more rapid in females than males. Of the original 5000 HIV-infected population of Western New York HIV/AIDS, Referral Center at Erie County Medical Center (ECMC), 1422 participated in the cohort study. We identified 333 HIV-infected patients with CD4 + T-cell-counts ≥ 500/µÆ–, among them 178 met the inclusion criteria for the 10-year study. Females had higher mode (600 vs. 540) and mean (741.9 vs. 712.2) CD4 + counts than males at baseline. However, CD4 + declined faster among females in a shorter time than males (234.5 vs. 158.6, P < 0.004), with rapid HIV progression. Univariate analyses determined that females had a 40% higher risk for CD4 + decline than males. The bivariate analyses specified CD4 + decline remained greater in females than males. Multivariate analyses which employed Cox's proportional Hazard-Model to adjust for numerous variables simultaneously identified women had almost twice the risk for CD4 + decline and rapid HIV progression than males (RR = 1.93; 95%CI 1.24, 2.99). Although the biological mechanism remains unknown, findings suggest gender differences in CD4 + decline, with a higher risk of rapid HIV progression and shorter longevity in females.

Impact of Size and Shape of Equine Femoral Subchondral Bone Cysts With a Transcondylar Screw on Predicted Bone Formation Area in a Finite Element Model.

Equine subchondral bone cysts (SBCs) develop most often in the medial femoral condyle (MFC) of yearlings intended for performance. SBCs often cause lameness and can cause secondary injuries to the meniscus and tibial cartilage. A novel surgical technique using a transcondylar lag screw (TLS) across an MFC SBC has shown success in lameness resolution and radiographic healing of MFC SBC. In a previous study using finite element analysis, our lab showed that a TLS stimulated bone formation on the inner surface of the SBC and altered third principal stress vectors to change the direction of surface compression to align with the screw axis. This work extended the previous study, which was limited by the use of only one idealized SBC. Our objective was to test SBCs of several sizes and shapes in a newly developed equine stifle FEM with a TLS to determine how cyst size affects bone formation stimulation. This study found that a transcondylar screw is most effective in stimulating bone formation in cysts of greater height (proximal-distal). The TLS increases stress stimulus in the bone around the cyst to promote bone apposition and directs compression across the cyst. If full penetration of the screw through the cyst is possible, it is recommended that the transcondylar screw be used to treat subchondral bone cysts. For the treatment of smaller cysts that are not accessible by the current screw surgical approach, future work could study the efficacy of a dual-pitch headless screw that may reach smaller cysts.

Enhanced care coordination improves HIV viral load suppression rates.

OBJECTIVES: Optimizing HIV treatment benefits the health of the individual and the community at large. Health department HIV surveillance data matched with Medicaid managed care rosters can be used to target people with HIV infection who have an unsuppressed viral load or are unengaged in care. MetroPlus Health Plan, a Medicaid managed care organization, implemented a 2-pronged approach: street outreach and peer care connection interventions. STUDY DESIGN: A cohort study that included demographics, program contact type and frequency, antiretroviral therapy refill pattern, and CD4 count and HIV viral load values/ranges and dates. METHODS: Members without a viral load test result during the prior 9 months (not engaged) received outreach, and those with unsuppressed viral loads received intensified care coordination and peer support. A retrospective statistical analysis was conducted on cohort members with sufficient viral load data. A subanalysis excluded members who had suppressed viral loads at baseline. RESULTS: A total of 1429 (82%) members in the state cross-referenced list were still enrolled in the plan at study initiation. Successful contact with targeted members by outreach was 60% compared with 40% by care coordination and peer support combined. Members who were successfully contacted by the program had a 44% suppression rate (<200 copies/mL) and a greater likelihood of achieving viral load suppression (odds ratio, 1.55; 95% CI, 1.23-1.95; P <.01) than those who were not. CONCLUSIONS: Surveillance data were successfully used to target HIV-positive Medicaid members who had an unsuppressed viral load or were unengaged in care. Individuals with an unsuppressed viral load can achieve suppression through intensified outreach, care coordination, and peer support by a Medicaid managed care plan.

Life stress and adherence to antiretroviral therapy among HIV-positive individuals: a preliminary investigation.

The present study sought to investigate the impact of life stress on treatment adherence and viral load of HIV-positive individuals. Three different aspects of life stress were examined in this investigation (perceived stress, acute life events unrelated to the HIV illness, and HIV-related acute life events). Furthermore, we examined whether these relationships were moderated by depressive severity, self-esteem, and neuroticism. Participants (n = 24) were treatment- seeking HIV-positive individuals who completed a series of questionnaires for this investigation. The majority of the participants in this sample were middle-aged, Caucasian males who identified themselves as either homosexual or bisexual, had contracted HIV via sexual contact, and met criteria for AIDS (mean CD4 count = 324). This sample was highly self-selected and varied from the county HIV-positive population in terms of gender, ethnicity, and HIV risk factor. Information on their adherence and viral load was collected from their medical records 6 to 9 months after completion of the psychological measurements. Results indicated that perceived stress, but not acute events, prospectively predicted adherence. Moreover, marginal trends suggested that depressive symptoms and neuroticism moderated the effect of perceived stress on adherence. Neither perceived stress nor acute life events were associated with viral load.

Preclinical and clinical performance of the Efoora test, a rapid test for detection of human immunodeficiency virus-specific antibodies.

Barriers to effective diagnostic testing for human immunodeficiency virus type 1 (HIV-1) infection can be reduced with simple, reliable, and rapid detection methods. Our objective was to determine the accuracy, sensitivity, and specificity of a new rapid, lateral-flow immunochromatographic HIV-1 antibody detection device. Preclinical studies were performed using seroconversion, cross-reaction, and interference panels, archived clinical specimens, and fresh whole blood. In a multicenter, prospective clinical trial, a four-sample matrix of capillary (fingerstick) whole-blood specimens and venous whole blood, plasma, and serum was tested for HIV-1 antibodies with the Efoora HIV rapid test (Efoora Inc., Buffalo Grove, IL) and compared with an enzyme immunoassay (EIA) (Abbott Laboratories) licensed by the Food and Drug Administration. Western blot and nucleic acid test supplemental assays were employed to adjudicate discordant samples. Preclinical testing of seroconversion panels showed that antibodies were often detected earlier by the rapid test than by a reference EIA. No significant interference or cross-reactions were observed. Testing of 4,984 archived specimens yielded a sensitivity of 99.2% and a specificity of 99.7%. A prospective multicenter clinical study with 2,954 adult volunteers demonstrated sensitivity and specificity for the Efoora HIV rapid test of 99.8% (95% confidence interval [CI], 99.3 and 99.98%) and 99.0% (95% CI, 98.5 and 99.4%), respectively. Reactive rapid HIV-1 antibody detection was confirmed in 99.6% of those with a known HIV infection (n = 939), 5.2% of those in the high-risk group (n = 1,003), and 0.1% of those in the low-risk group (n = 1,012). For 21 (0.71%) patients, there was discordance between the results of the rapid test and the confirmatory EIA/Western blot tests. We conclude that the Efoora HIV rapid test is a simple, rapid assay for detection of HIV-1 antibodies, with high sensitivity and specificity compared to a standardized HIV-1 EIA.

Cocaine modulates dendritic cell-specific C type intercellular adhesion molecule-3-grabbing nonintegrin expression by dendritic cells in HIV-1 patients.

We report that cocaine may act as cofactor in HIV pathogenesis by increasing dendritic cell-specific C type ICAM-3-grabbing nonintegrin (DC-SIGN) expression on dendritic cells (DC). Our results show that cocaine-using, long-term nonprogressors and normal progressors of HIV infection manifest significantly higher levels of DC-SIGN compared with cocaine-nonusing long-term nonprogressors and normal progressors, respectively. Furthermore, in vitro HIV infection of MDC from normal subjects cultured with cocaine and/or HIV peptides up-regulated DC-SIGN, confirming our in vivo finding. Cocaine, in synergy with HIV peptides, also up-regulates DC-SIGN gene expression by MDC. Furthermore, the cocaine-induced effects were reversed by a D1 receptor antagonist demonstrating the specificity of the reaction. Our results indicate that cocaine exacerbates HIV infection by up-regulating DC-SIGN on DC and these effects are mediated via dysregulation of MAPKs. These data are the first evidence that cocaine up-regulates the expression of DC-SIGN on DC. A better understanding of the role of DC-SIGN in HIV infection may help to design novel therapeutic strategies against the progression of HIV disease in the drug-using population.

Drug abuse and neuropathogenesis of HIV infection: role of DC-SIGN and IDO.

Dendritic cells are the critical mediators of various immune responses and are the first line of defense against any infection including HIV. They play a major role in harboring HIV and the subsequent infection of T cells and passage of virus through the blood-brain barrier (BBB). The recently discovered DC-specific, CD4-independent HIV attachment receptor, DC-SIGN, and T-cell suppressing factor, indolamine 2,3-dioxygenase (IDO), are known to play a critical role in the immuno-neuropathogenesis of HIV infection. Since brain microvascular cells (BMVEC) express dendritic cell (DC)-specific C type ICAM-3 grabbing nonintegrin (DC-SIGN), it is possible that DC-SIGN may play a critical role in human immunodeficiency virus-type 1 (HIV-1) infection and migration of infected DC across BBB. Matrix metalloproteinases (MMPs) are proteolytic enzymes known to be responsible for maintenance, turnover and integrity of extracellular matrix. Our results show that cocaine upregulates IDO and DC-SIGN expression by DC. Further, cocaine upregulates DC-SIGN and MMPs in BMVEC supporting the hypothesis that cocaine causes membrane permeability facilitating endothelial transmigration of infected DC in to the CNS. Targeting DC-SIGN and IDO with specific monoclonal antibodies, inexpensive synthetic antagonists, antisense oligonucleotides and siRNA may lead to develop novel treatment strategies particularly in high-risk populations such as cocaine users.

The effects of once-daily saquinavir/minidose ritonavir on the pharmacokinetics of methadone.

Twelve methadone-maintained HIV-negative subjects were given saquinavir/ritonavir (SQV/rtv) 1600 mg/100 mg once daily for 14 days. Pharmacokinetic evaluations of total and unbound methadone enantiomers (R and S) were conducted before and after SQV/rtv. SQV/rtv was well tolerated, with no ACTG Grade 3-4 adverse events, no evidence of sedation, and no changes in methadone dose. For R-methadone (active isomer), C(max), AUC(0-24 h), and C(min) were unchanged, but percent unbound 4 hours after dosing was reduced by 12%. For S-methadone, no differences in pharmacokinetic parameters of total drug were seen, but unbound concentrations were reduced by 15% and 21% at 4 and 24 hours after dosing, respectively. SQV trough concentrations exceeded the anticipated EC(50) (50 ng/mL) in 10/12 subjects, persisting for at least 6 hours after the final dose in 4/6 subjects. Once-daily SQV/rtv in methadone-maintained subjects is safe and not associated with any clinically significant interaction with methadone during 14 days of concomitant administration.

Human immunodeficiency virus-associated nephropathy: a primary care perspective.

The advent of highly active antiretroviral therapy represents a significant advance in medical care for human immunodeficiency virus (HIV)-infected persons. However, not everyone has derived the expected benefits of antiretroviral therapy and HIV-associated diseases such as nephropathy still occur in at-risk populations. Currently, there are no recommendations for screening HIV-positive patients for HIV-associated nephropathy. We propose semiannual screening for proteinuria in HIV-positive African Americans and patients with a family history of renal disease, and provide an algorithm for evaluation.

Serum interferon inhibitor declines in patients with HIV-1 infection after a change in antiretroviral therapy.

An inhibitor of interferon antiviral activity, which is absent in healthy HIV-seronegative persons, was detected in the sera of all 29 HIV-seropositive study participants. The relationship of the level of interferon inhibitor to CD4 count and HIV-RNA copy number was statistically significant in distinct models. Levels of interferon inhibitor declined by an average of 41-60% in patients who underwent a change in anti-retroviral therapy. Interferon inhibitor levels appear to decline as CD4 cell count rises and HIV-RNA levels fall. This suggests that interferon inhibitor may have a significant role in the host immune response to HIV infection.

Effects of didanosine formulations on the pharmacokinetics of amprenavir.

STUDY OBJECTIVES: To determine the effects of concurrent, single doses of didanosine (both buffered and encapsulated enteric-coated bead formulations) on amprenavir steady-state pharmacokinetics, and to determine the effect of staggered dosing of the buffered formulation. DESIGN: Two-period, single-sequence, prospective, open-label drug interaction study with a 10-day washout interval. SETTING: Clinical research unit. SUBJECTS: Sixteen healthy volunteers without human immunodeficiency virus infection. INTERVENTION: Amprenavir 600 mg twice/day was given for the first 4 days of each treatment period, with 12-hour pharmacokinetic evaluations conducted on the last 2 days of each period. Amprenavir was administered according to the following sequential treatments (all fasting): amprenavir alone, concurrent with buffered didanosine, 1 hour before buffered didanosine, and concurrent with the encapsulated enteric-coated bead formulation of didanosine. MEASUREMENTS AND MAIN RESULTS: Plasma was collected 0, 1, 2, 3, 4, 6, 8, and 12 hours after dosing and assayed for amprenavir by using high-performance liquid chromatography. Noncompartmental pharmacokinetic parameters were determined. Geometric mean ratios for each treatment relative to amprenavir alone were determined and reported with 90% confidence intervals (CIs). No significant trends were noted in predose concentrations measured during either period. Area under the concentration-time curve during one 12-hour dosing interval (AUC12) was found to be bioequivalent for all treatments. Peak drug concentration (Cmax) was reduced by 15% on average with concurrent administration of buffered didanosine, and bioequivalence was not demonstrated for this parameter. For concurrent enteric-coated didanosine, geometric mean ratios for Cmax and AUC12 were 0.93 and 0.94, respectively. For buffered didanosine given 1 hour after amprenavir, geometric mean ratios were 1.06 and 1.10 for the same parameters, respectively. No differences were observed in 12-hour concentration (C12) with concurrent administration of buffered or enteric-coated didanosine. CONCLUSION: Amprenavir AUC12 and C12 are not significantly affected by concurrent administration of the buffered or enteric-coated formulations of didanosine. Therefore, amprenavir may be administered concurrently with either the buffered or the encapsulated enteric-coated bead formulation of didanosine in the fasting state.

Pharmacokinetics of ritonavir and delavirdine in human immunodeficiency virus-infected patients.

To evaluate the pharmacokinetic effect of adding delavirdine mesylate to the antiretroviral regimens of human immunodeficiency virus (HIV)-infected patients stabilized on a full dosage of ritonavir (600 mg every 12 h), 12 HIV-1-infected subjects had delavirdine mesylate (400 mg every 8 h) added to their current antiretroviral regimens for 21 days. Ritonavir pharmacokinetics were evaluated before (day 7) and after (day 28) the addition of delavirdine, and delavirdine pharmacokinetics were evaluated on day 28. The mean values (+/- standard deviations) for the maximum concentration in serum (C(max)) of ritonavir, the area under the concentration-time curve from 0 to 12 h (AUC(0-12)), and the minimum concentration in serum (C(min)) of ritonavir before the addition of delavirdine were 14.8 +/- 6.7 micro M, 94 +/- 36 micro M. h, and 3.6 +/- 2.1 micro M, respectively. These same parameters were increased to 24.6 +/- 13.9 micro M, 154 +/- 83 micro M. h, and 6.52 +/- 4.85 micro M, respectively, after the addition of delavirdine (P is <0.05 for all comparisons). Delavirdine pharmacokinetic parameters in the presence of ritonavir included a C(max) of 23 +/- 16 micro M, an AUC(0-8) of 114 +/- 75 micro M. h, and a C(min) of 9.1 +/- 7.5 micro M. Therefore, delavirdine increases systemic exposure to ritonavir by 50 to 80% when the drugs are coadministered.

Delavirdine malabsorption in HIV-infected subjects with spontaneous gastric hypoacidity.

To determine the impact of gastric hypoacidity and acidic beverages on delavirdine mesylate pharmacokinetics in HIV-infected subjects, matched subjects with (n = 11) and without (n = 10) gastric hypoacidity received delavirdine 400 mg tid with either water or an acidic beverage (usually orange juice). The pharmacokinetics of delavirdine and its N-desalkyl metabolite were determined over 8 hours after 14 days of each treatment. Gastric pH was measured at baseline and during each pharmacokinetic evaluation. Delavirdine exposure (Cmax, AUC0-->8 h, and Cmin) was approximately 50% lower and the extent of delavirdine metabolism was higher in subjects with gastric hypoacidity. Orange juice produced a lower mean gastric pH compared to water and increased delavirdine absorption by 50% to 70% in subjects with gastric hypoacidity. However, orange juice had a marginal impact on delavirdine exposure in subjects without gastric hypoacidity. HIV-infected subjects with gastric hypoacidity significantly malabsorb delavirdine. Delavirdine administration with acidic beverages improves, but dose not normalize, absorption in these subjects.

New-onset seizures as an initial presentation of end-stage renal failure in patients with HIV/AIDS.

We present 2 patients with HIV/AIDS and suspected HIV-associated nephropathy who presented with end-stage renal disease and new-onset seizures. These cases highlight the relationship between metabolic disorders and new-onset seizures in HIV-infected persons. Causes of new-onset seizures in this setting include opportunistic infections, HIV-associated dementia (AIDS dementia complex), and various metabolic disorders. A sizable proportion of patients had no identifiable cause of seizures despite extensive workup. In these instances, seizures can be attributed to subclinical effects--direct and indirect--of HIV on the brain. Seizures tended to be recurrent, sometimes despite anticonvulsant therapy. In a subset of patients, seizures were the initial presenting sign of HIV infection.

Abacavir hypersensitivity reaction.

A hypersensitivity reaction occurs in association with initiation of abacavir therapy as part of combination antiretroviral therapy in approximately 3.7% of patients. The reaction is possibly the result of a combination of altered drug metabolism and immune dysfunction, which is poorly understood. White patients appear to be at higher risk and patients of African descent at lower risk of abacavir hypersensitivity. Clinical management involves supportive measures and discontinuation of abacavir therapy. Rechallenge with abacavir in a hypersensitive patient should be avoided because it might precipitate a life-threatening reaction.

Indinavir Pharmacokinetics during Different Phases of the Menstrual Cycle in HIV-Infected Women.

OBJECTIVE: To characterise the pharmacokinetics of indinavir during different phases of the menstrual cycle in HIV-infected women. DESIGN: Open-label study. SETTING: The immunodeficiency clinic at Erie County Medical Center, Buffalo, New York. PATIENTS: Ten HIV-infected women were enrolled in the study. Eligibility criteria included an acceptable medical history, chemistry profile, complete blood count with differential, lymphocyte profile, urinalysis and history of a regular menstrual cycle. PATIENTS had to be on a stable antiretroviral regimen that included indinavir 800mg taken every 8 hours. INTERVENTIONS: Blood sampling over an 8-hour period following an 800mg dose of indinavir during the menstrual, follicular and luteal phases of the menstrual cycle. MAIN OUTCOME MEASURES: Pharmacokinetic parameters in ten HIV-infected women adherent with indinavir 800mg every 8 hours during the menstrual, follicular and luteal phases of the menstrual cycle. Serum estradiol and progesterone levels were also obtained during each menstrual cycle phase. RESULTS: The peak plasma concentration, plasma concentration 8 hours after administration of a given dose of indinavir, elimination half-life and oral clearance of indinavir were not significantly different across the menstrual cycle phases. Indinavir exposure varied among the female patients with some individuals having similar areas under the concentration-time curve (AUCs) during the three phases while others had notable differences in AUC. Maximum plasma indinavir concentrations were highest during the follicular phase in four subjects, highest during the luteal phase in two individuals, and highest during the menstrual phase in three patients. CONCLUSIONS: No differences were found in indinavir pharmacokinetics during the menstrual cycle phases. Significant intra- and interpatient variability in indinavir pharmacokinetics were observed; however, indinavir exposure in women did not appear to be excessive compared with pharmacokinetic data obtained from prior studies conducted in men.