Nevirapine pharmacokinetics in HIV-infected persons receiving rifapentine and isoniazid for TB prevention.

BACKGROUND: The use of rifamycin antibiotics for TB prevention carries a risk of detrimental drug-drug interactions with concomitantly used ART. OBJECTIVES: To evaluate the interaction of the antiretroviral drug nevirapine in combination with 4 weeks of daily rifapentine and isoniazid for TB prevention in people living with HIV. METHODS: Participants were individuals enrolled in the BRIEF-TB study receiving nevirapine and randomized to the rifapentine/isoniazid arm of the study. Participants provided sparse pharmacokinetic (PK) sampling at baseline and weeks 2 and 4 for trough nevirapine determination. Nevirapine apparent oral clearance (CL/F) was estimated and the geometric mean ratio (GMR) of CL/F prior to and during rifapentine/isoniazid was calculated. RESULTS: Seventy-eight participants had evaluable PK data: 61 (78%) female, 51 (65%) black non-Hispanic and median (range) age of 40 (13-66) years. Median (IQR) nevirapine trough concentrations were: week 0, 7322 (5266-9302) ng/mL; week 2, 5537 (3552-8462) ng/mL; and week 4, 5388 (3516-8243) ng/mL. Sixty out of 78 participants (77%) had nevirapine concentrations ≥3000 ng/mL at both week 2 and 4. Median (IQR) nevirapine CL/F values were: week 0 pre-rifapentine/isoniazid, 2.03 (1.58-2.58) L/h; and during rifapentine/isoniazid, 2.62 (1.81-3.42) L/h. The GMR (90% CI) for nevirapine CL/F was 1.30 (1.26-1.33). CONCLUSIONS: The CL/F of nevirapine significantly increased with concomitant rifapentine/isoniazid. The decrease in nevirapine trough concentrations during rifapentine/isoniazid therapy suggests induction of nevirapine metabolism, consistent with known rifapentine effects. The magnitude of this drug-drug interaction suggests daily rifapentine/isoniazid for TB prevention should not be co-administered with nevirapine-containing ART.

Digitizing Medicines for Remote Capture of Oral Medication Adherence Using Co-encapsulation.

High-resolution measurement of medication adherence is essential to personalized drug therapy. A US Food and Drug Administration (FDA)-cleared device, using an edible ingestion sensor (IS), external wearable patch, and paired mobile device can detect and record ingestion events. Oral medications must be combined with an IS to generate precise "digitized-medication" ingestion records. We developed a Good Manufacturing Practice protocol to repackage oral medications with the IS within certified Capsugel capsules, termed co-encapsulation (CoE). A randomized bioequivalence study of CoE-IS-Rifamate (Isoniazid/Rifampin 150/300 mg) vs. native-Rifamate was conducted in 12 patients with active Mycobacterium tuberculosis and demonstrated bioequivalence using the population method ratio test (95% confidence interval). Subsequently, CoE-IS-medications across all biopharmaceutical classes underwent in vitro dissolution testing utilizing USP and FDA guidelines. CoE-IS medications tested met USP dissolution specifications and were equivalent to their native formulations. CoE combines oral medications with the IS without altering the quality of the native formulation, generating "digitized" medications for remote capture of dosing histories.

Common developmental genome deprogramming in schizophrenia - Role of Integrative Nuclear FGFR1 Signaling (INFS).

The watershed-hypothesis of schizophrenia asserts that over 200 different mutations dysregulate distinct pathways that converge on an unspecified common mechanism(s) that controls disease ontogeny. Consistent with this hypothesis, our RNA-sequencing of neuron committed cells (NCCs) differentiated from established iPSCs of 4 schizophrenia patients and 4 control subjects uncovered a dysregulated transcriptome of 1349 mRNAs common to all patients. Data reveals a global dysregulation of developmental genome, deconstruction of coordinated mRNA networks, and the formation of aberrant, new coordinated mRNA networks indicating a concerted action of the responsible factor(s). Sequencing of miRNA transcriptomes demonstrated an overexpression of 16 miRNAs and deconstruction of interactive miRNA-mRNA networks in schizophrenia NCCs. ChiPseq revealed that the nuclear (n) form of FGFR1, a pan-ontogenic regulator, is overexpressed in schizophrenia NCCs and overtargets dysregulated mRNA and miRNA genes. The nFGFR1 targeted 54% of all human gene promoters and 84.4% of schizophrenia dysregulated genes. The upregulated genes reside within major developmental pathways that control neurogenesis and neuron formation, whereas downregulated genes are involved in oligodendrogenesis. Our results indicate (i) an early (preneuronal) genomic etiology of schizophrenia, (ii) dysregulated genes and new coordinated gene networks are common to unrelated cases of schizophrenia, (iii) gene dysregulations are accompanied by increased nFGFR1-genome interactions, and (iv) modeling of increased nFGFR1 by an overexpression of a nFGFR1 lead to up or downregulation of selected genes as observed in schizophrenia NCCs. Together our results designate nFGFR1 signaling as a potential common dysregulated mechanism in investigated patients and potential therapeutic target in schizophrenia.

Cerebral organoids reveal early cortical maldevelopment in schizophrenia-computational anatomy and genomics, role of FGFR1.

Studies of induced pluripotent stem cells (iPSCs) from schizophrenia patients and control individuals revealed that the disorder is programmed at the preneuronal stage, involves a common dysregulated mRNA transcriptome, and identified Integrative Nuclear FGFR1 Signaling a common dysregulated mechanism. We used human embryonic stem cell (hESC) and iPSC-derived cerebral organoids from four controls and three schizophrenia patients to model the first trimester of in utero brain development. The schizophrenia organoids revealed an abnormal scattering of proliferating Ki67+ neural progenitor cells (NPCs) from the ventricular zone (VZ), throughout the intermediate (IZ) and cortical (CZ) zones. TBR1 pioneer neurons and reelin, which guides cortico-petal migration, were restricted from the schizophrenia cortex. The maturing neurons were abundantly developed in the subcortical regions, but were depleted from the schizophrenia cortex. The decreased intracortical connectivity was denoted by changes in the orientation and morphology of calretinin interneurons. In schizophrenia organoids, nuclear (n)FGFR1 was abundantly expressed by developing subcortical cells, but was depleted from the neuronal committed cells (NCCs) of the CZ. Transfection of dominant negative and constitutively active nFGFR1 caused widespread disruption of the neuro-ontogenic gene networks in hESC-derived NPCs and NCCs. The fgfr1 gene was the most prominent FGFR gene expressed in NPCs and NCCs, and blocking with PD173074 reproduced both the loss of nFGFR1 and cortical neuronal maturation in hESC cerebral organoids. We report for the first time, progression of the cortical malformation in schizophrenia and link it to altered FGFR1 signaling. Targeting INFS may offer a preventive treatment of schizophrenia.

Improved tuberculosis outcomes with daily vs. intermittent rifabutin in HIV-TB coinfected patients in India.

SETTING: Y R Gaitonde Centre for AIDS Research and Education, Chennai, India. OBJECTIVE: To compare anti-tuberculosis treatment outcomes in individuals with human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection on atazanavir/ritonavir (ATV/r) antiretroviral therapy (ART) plus daily rifabutin (RBT) 150 mg with those on ATV/r plus thrice-weekly RBT 150 mg. DESIGN: A retrospective study was conducted of two HIV-TB co-infected cohorts between 2003 and 2014. Basic demographic and TB outcome data were obtained from an electronic database and patient records. The χ(2) and Fisher's exact test were used to compare daily and intermittent RBT treatment groups. RESULTS: Of 292 individuals on an ATV/r-based ART regimen plus RBT, 118 (40.4%) received thrice-weekly RBT and 174 (59.6%) daily RBT. Patients in the two RBT treatment groups were similar in sex, age, previous history of TB, site of TB and acid-fast bacilli smear status. More individuals in the daily vs. the intermittent RBT group achieved clinical cure (73.0% vs. 44.1%, P < 0.001), with no significant differences in relapse/recurrence or all-cause mortality between groups. CONCLUSION: There were higher rates of clinical TB cure in individuals on a boosted protease inhibitor-based ART regimen with daily RBT compared to intermittently dosed RBT. Optimal RBT dosing in this setting requires further investigation.

"Nuclear FGF receptor-1 and CREB binding protein: an integrative signaling module".

In this review we summarize the current understanding of a novel integrative function of Fibroblast Growth Factor Receptor-1 (FGFR1) and its partner CREB Binding Protein (CBP) acting as a nuclear regulatory complex. Nuclear FGFR1 and CBP interact with and regulate numerous genes on various chromosomes. FGFR1 dynamic oscillatory interactions with chromatin and with specific genes, underwrites gene regulation mediated by diverse developmental signals. Integrative Nuclear FGFR1 Signaling (INFS) effects the differentiation of stem cells and neural progenitor cells via the gene-controlling Feed-Forward-And-Gate mechanism. Nuclear accumulation of FGFR1 occurs in numerous cell types and disruption of INFS may play an important role in developmental disorders such as schizophrenia, and in metastatic diseases such as cancer. Enhancement of INFS may be used to coordinate the gene regulation needed to activate cell differentiation for regenerative purposes or to provide interruption of cancer stem cell proliferation.

Effect of statin therapy in reducing the risk of serious non-AIDS-defining events and nonaccidental death.

BACKGROUND: Excessive inflammation persists despite antiretroviral treatment. Statins decrease cardiovascular (CV) disease risk by reducing low-density lipoprotein cholesterol and inflammation. We performed an exploratory analysis to evaluate whether statin therapy decreased risk of non-AIDS-defining events and nonaccidental death. METHODS: A total of 3601 subjects not on a statin from the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort were included. Outcome was time to first clinical event (CV event, renal or hepatic disease, incident diabetes, thrombotic/embolic event, nontraumatic fracture, non-AIDS-defining malignancy, serious bacterial infection, or nonaccidental death); event categories were also analyzed separately. Inverse probability of treatment and censoring weighted Cox proportional hazard models were used to assess the causal statin effect. Differential statin effects by baseline covariates were evaluated. RESULTS: Over 15 135 person-years (PY) of follow-up, 484 subjects initiated statins; 616 experienced an event (crude event rate, 4.4/100 PY on a statin and 4.1/100 PY not on a statin); the unadjusted hazard ratio (HR) was 1.17 (95% confidence interval [CI], .91-1.50). In a final weighted model, the adjusted HR (AHR) was 0.81 (95% CI, .53- 1.24). Results for other clinical events were similar, except for malignancies (AHR, 0.43 [95% CI, .19-.94]) and bacterial infections (AHR, 1.30 [95% CI, .64-2.65]). No differential statin effects by baseline covariates were detected. CONCLUSIONS: Although statin therapy was not associated with a reduction in time to all non-AIDS-defining event or nonaccidental death, it was associated with a statistically significant 57% reduction in non-AIDS-defining malignancies. Confirmatory studies are needed to evaluate statin-associated reduction in risk of cancer and non-AIDS-associated morbidities.

Incidence rate of and factors associated with loss to follow-up in a longitudinal cohort of antiretroviral-treated HIV-infected persons: an AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) analysis.

PURPOSE: Examine incidence and factors associated with loss to follow-up (LTFU) in the AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) cohort. METHOD: ALLRT is a prospective cohort of HIV-infected persons randomized to antiretroviral (ARV) regimens/strategies in ACTG trials and followed long-term after the trial ends. Person-years were calculated from ALLRT entry until loss to follow-up (LTFU; defined using off-study reasons or ≥ 3 consecutive missed visits), death/ severe debilitation/site closures, or June 2009 (censored). Poisson regression was used to examine LTFU factors separately among participants who were ARV naïve or ARV experienced at trial entry. RESULTS: Among 4,630 participants (22,524 person-years), 1,140 were lost to follow-up, 237 died, 29 were severely debilitated, and 443 were at sites that closed. The LTFU incidence was 5.5 and 4.2 per 100 person-years among previously ARV-naïve and ARV-experienced participants, respectively. In both groups, age ≤ 50, site location, being off ARVs, and viral load ≥ 400 copies/mL were associated with a higher risk of LTFU. Among ARV-naïve participants, male sex, education <16 years, intravenous drug use, and cigarette smoking were also associated with LTFU. CONCLUSION: Knowledge of differential LTFU can help researchers identify participants at risk of LTFU in longitudinal HIV cohorts and design retention strategies, thereby limiting study bias. The identified factors should be included in inverse probability of weighting models to account for LTFU.

Toward a definition of HIV expertise: a survey of experienced HIV physicians.

Medical care for human immunodeficiency virus (HIV)-infected persons has grown increasingly complex, yet few studies have examined experienced HIV physicians' views about current HIV medical care. The objective of this study was to examine the relationship between physicians' HIV experience, self-perceived expertise, and confidence with providing 18 aspects of HIV medical care and between confidence in aspects of care and medical specialty. At geographically diverse, HIV continuing medical education programs conducted in the fall of 1999, 359 currently practicing HIV physicians completed a written survey measuring participants' demographic characteristics, experience, HIV expertise, and level of confidence providing essential aspects of HIV care. Participants currently managed a median of 50 HIV-infected patients with a career total of 300. Significant correlations were found between experience and expertise items and experience and 15 of 18 confidence items. Confidence levels varied from 11% to 85% highly confident across 18 aspects of HIV care. Physicians' confidence with providing aspects of HIV care varied by the three predominant specialty groups (infectious diseases, internal medicine, and family practice/general medicine). Physicians who have informally specialized in HIV care reported a range of self-perceived expertise and confidence, indicating the complexity of HIV medical care today. Our results suggest that even the most experienced HIV physicians in the United States continue to benefit from more experience and that each medical specialty examined in this study brings its own set of skills needed to provide optimal HIV care. This study constitutes a first step toward defining and formalizing HIV medical care.

Recurrences of cytomegalovirus retinitis in a human immunodeficiency virus-infected patient, despite potent antiretroviral therapy and apparent immune reconstitution.

We describe a 42-year-old man with human immunodeficiency virus infection who developed multiple recurrences of cytomegalovirus (CMV) retinitis despite receiving highly active antiretroviral therapy and having apparent immune reconstitution as evidenced by CD4(+) T lymphocyte counts of > 200 cells/mm(3). Laboratory investigation during one recurrence of retinitis confirmed that there was active CMV replication in the plasma and vitreous fluid. In addition, lymphoproliferative responses to CMV antigens were absent despite evidence of reactivity to Candida antigen and pokeweed mitogen. The clinical significance of this case and of other recently reported cases is discussed.

Structured treatment interruption in HIV infection.

Structured (and unstructured) treatment interruptions have been evaluated during well-controlled acute and chronic HIV infection and before multidrug salvage therapy. In the first 2 instances, the rationale for this strategy is to stimulate or preserve HIV-specific CD4 T cells and broadly directed cytotoxic T-lymphocyte responses. Before salvage therapy, treatment interruptions have led to the reemergence of drug-susceptible virus, at least in blood plasma. Although some evidence suggests beneficial immune stimulation with successive interruptions of therapy begun during acute infection, the long-term benefits of this strategy remain unproved in any clinical setting. The potential dangers of interrupting treatment--recrudescent acute retroviral syndrome, emergence of drug-resistant virus, substantial declines in CD4 T cells, and new or recurrent opportunistic infections--are not theoretic.

Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy-induced increases in CD4+ cell count. A randomized, double-blind, placebo-controlled trial. AIDS Clinical Trials Group 362 Study Team.

BACKGROUND: Patients infected with HIV who experience increases in CD4(+) cell counts are at reduced risk for opportunistic infections. However, the safety of discontinuing prophylaxis against Mycobacterium avium complex has been uncertain. OBJECTIVE: To compare the rate of M. avium complex infection in patients with increased CD4(+) cell counts who receive azithromycin and those receiving placebo. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: 29 university-based clinical centers in the United States. PARTICIPANTS: 643 HIV-1-infected patients with a previous CD4(+) cell count less than 0.05 x 10(9) cells/L and a sustained increase to greater than 0.10 x 10(9) cells/L during antiretroviral therapy. INTERVENTION: Azithromycin, 1200 mg once weekly (n = 321), or matching placebo (n = 322). MEASUREMENTS: Mycobacterium avium complex cultures, CD4(+) cell counts, and clinical evaluations for AIDS-defining illnesses and bacterial infections were done every 8 weeks. Plasma HIV-1 RNA levels were measured at 16-week intervals. RESULTS: During follow-up (median, 16 months), 2 cases of M. avium complex infection were reported among the 321 patients assigned to placebo (incidence rate, 0.5 event per 100 person-years [95% CI, 0.06 to 1.83 events per 100 person-years]) compared with no cases among the 322 patients assigned to azithromycin (CI, 0 to 0.92 events per 100 person-years), resulting in a treatment difference of 0.5 event per 100 person-years (CI, -0.20 to 1.21 events per 100 person-years) for placebo versus azithromycin. Both cases were atypical in that M. avium complex was localized to the vertebral spine. Patients receiving azithromycin were more likely than those receiving placebo to discontinue treatment with the study drug permanently because of adverse events (8% vs. 2%; hazard ratio, 0.24 [CI, 0.10 to 0.57]). CONCLUSIONS: Prophylaxis against Mycobacterium avium complex can safely be withdrawn or withheld in adults with HIV infection who experience increases in CD4(+) cell count while receiving antiretroviral therapy.

Clarithromycin or rifabutin alone or in combination for primary prophylaxis of Mycobacterium avium complex disease in patients with AIDS: A randomized, double-blind, placebo-controlled trial. The AIDS Clinical Trials Group 196/Terry Beirn Community Programs for Clinical Research on AIDS 009 Protocol Team.

The efficacy and safety of clarithromycin and rifabutin alone and in combination for prevention of Mycobacterium avium complex (MAC) disease were compared in 1178 patients with AIDS who had < or =100 CD4 T cells/microL in a randomized, double-blind, placebo-controlled trial. MAC disease occurred in 9%, 15%, and 7% of those randomized to clarithromycin or rifabutin alone or in combination, respectively; time-adjusted event rates per 100 patient-years (95% confidence interval [CI]) were 6.3 (4.2-8.3), 10.5 (7.8-13.2), and 4. 7 (2.9-6.5). Risk of MAC disease was reduced by 44% with clarithromycin (risk ratio [RR], 0.56; 95% CI, 0.37-0.84; P=.005) and by 57% with combination therapy (RR, 0.43; 95% CI, 0.27-0.69; P=. 0003), versus rifabutin. Combination therapy was not more effective than clarithromycin (RR, 0.79; 95% CI, 0.48-1.31; P=.36). Of those in whom clarithromycin or combination therapy failed, 29% and 27% of MAC isolates, respectively, were resistant to clarithromycin. There were no survival differences. Clarithromycin and combination therapy were more effective than rifabutin for prevention of MAC disease, but combination therapy was associated with more adverse effects (31%; P<.001).

Effects of Mycobacterium avium complex-infection treatment on cytokine expression in human immunodeficiency virus-infected persons: results of AIDS clinical trials group protocol 853.

Human immunodeficiency virus (HIV) type 1-infected persons with newly diagnosed Mycobacterium avium complex (MAC) bacteremia were enrolled in an 8-week study to determine whether treatment of MAC infection is associated with decreases in plasma tumor necrosis factor (TNF)-alpha levels. Blood specimens were obtained for quantitative MAC cultures and to determine plasma levels of HIV RNA, TNF-alpha, and other proinflammatory cytokines. MAC levels decreased by 1.75 log at week 4 (P=.008) and by 2.48 log at week 8 (P=.001). Plasma TNF-alpha decreased by 0.15 log at week 4 (P=.042) and by 0. 40 log at week 8 (P=.027). Plasma interleukin (IL)-6 decreased by 0. 56 log at week 8 (P=.039). There were nonsignificant trends (P<.10) for plasma levels of IL-1beta and HIV RNA to decrease at week 8. Nonsignificant decreases in plasma levels of TNF-alpha, IL-1beta, IL-6, and HIV RNA were also seen in those individuals who remained on stable antiretroviral therapy throughout the 8 weeks of the study.

Body composition in HIV-infected women.

Although loss of lean body mass is a common complication of human immunodeficiency virus (HIV) infection that can occur across the disease trajectory, few studies have characterized the body composition of HIV-infected women. We used bioelectrical impedance analysis to characterize the body composition of HIV-infected (n = 56) and uninfected (n = 12) women who were matched on percentage of ideal body weight. The HIV-infected women did not differ from the uninfected women by height-adjusted fat mass or body cell mass. Intergroup comparisons among the HIV-infected women showed that underweight women had significantly less fat mass than did normal-weight women but did not significantly differ with respect to body cell mass. Among all HIV-infected women, CD4(+) lymphocyte count was positively correlated with fat mass (r = 0.32, P = 0.01) but not with body cell mass. No significant correlations were found between any body-composition parameter and plasma viral load. Our findings suggest that, unlike men, HIV-infected underweight women show a preferential loss of fat mass and a relative preservation of body cell mass. This altered pattern of weight loss may relate to higher premorbid fat stores in women and/or hormonal differences.

Prevalence of and risk factors for tuberculin positivity and skin test anergy in HIV-1-infected and uninfected at-risk women. Women's Interagency HIV Study (WIHS).

OBJECTIVES: To determine differences in rates of reactivity to purified protein derivative (PPD) tuberculin and of skin test anergy in relationship to serostatus, immune status, demographic characteristics, and other risk factors in women infected with or at high risk for infection with HIV-1; and to compare the usefulness of three different antigens in assessing delayed type hypersensitivity. DESIGN/METHODS: Cross-sectional analysis of baseline data in a multicenter prospective cohort study of 1343 HIV-1-seropositive and 390 seronegative but at-risk women recruited from sites of HIV primary care and through community-based outreach for a longitudinal cohort study. RESULTS: 4.7% of the 1343 HIV-1-seropositive women and 15.4% of the 390 HIV-seronegative women were tuberculin-positive (p < .001). A lower threshold in millimeters of induration for tuberculin reactivity among HIV-seropositive women resulted in a smaller difference between the seropositive and the seronegative groups. Even when a 2-mm threshold was used in HIV-seropositive respondents, with a 10-mm threshold among seronegative participants, the difference between the seropositive (6.9% reactive) and the seronegative (15.4% reactive) groups remained statistically significant (p < .001). Limiting analysis to women who responded to the non-PPD antigens did not eliminate the differences in PPD reactivity between the HIV-seropositive and HIV-seronegative women. In multivariate analysis, tuberculin reactivity was associated with HIV-negative serostatus, a history of tuberculosis infection or disease, geographic site, and CD4 count >200 cells/mm3 in the HIV-seropositive women. In all, 41% of HIV-seropositive women and 12% of seronegative women were anergic (p < .001). Candida antigen had the lowest response rates. In multivariate analyses, only HIV-serostatus and CD4 cell counts in HIV-seropositive women were significantly associated with anergy. CONCLUSIONS: In this community-based cohort of HIV-seropositive and HIV-seronegative women, we found significant differences between the seronegative and seropositive women even with a lower threshold of induration defining PPD reactivity among seropositive women and among women not anergic to the non-PPD antigens. Prevalence of PPD reactivity was higher than in previously described in cohorts of homosexual men, but lower than in cohorts of predominantly male injection drug users. Rates of anergy were similar to those in most previously described cohorts.

Predictors for multidrug-resistant tuberculosis among HIV-infected patients and response to specific drug regimens. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and the AIDS Clinical Trials Group (ACTG), National Institutes for Health.

SETTING: Mortality associated with human immunodeficiency virus (HIV) related multidrug-resistant tuberculosis (MDR-TB) is reduced with effective early therapy. Identifying predictors of, and effective regimens for, MDR-TB is critical. OBJECTIVE: A multicenter prospective study was initiated to 1) determine the demographic, behavioral, clinical and geographic risk factors associated with the occurrence of MDR-TB among HIV-infected patients, and 2) to evaluate the overall survival and clinical response of MDR-TB patients treated with specific drug regimens. METHODS: Patients were prospectively evaluated for MDR-TB. Information included history of prior treatment for tuberculosis, close contact with a known case of MDR-TB, and residence in a facility with known or suspected MDR-TB transmission. Patients with known MDR-TB, or those suspected to be at high risk, were offered enrollment in a treatment pilot study. Study drugs included levofloxacin and at least two additional drugs to which the patient's isolate was known, or most likely, to be susceptible. Survival was the primary endpoint. RESULTS: Complete data are available for 156 HIV-infected patients with confirmed tuberculosis. Sixteen (10%) had MDR-TB. Only a history of prior tuberculosis treatment was associated with MDR-TB in multivariate analysis (OR = 4.4, P < 0.02). Twelve patients with MDR-TB enrolled in the treatment pilot had a median CD4 cell count of 51/mm3. The cumulative probability of survival at one year was 75% (95% CI 50.5-99.5) and at 18 months, 65.6% (95% CI 38.1-93.1). Toxicity requiring discontinuation of medications occurred in two patients. CONCLUSIONS: A history of treatment for tuberculosis was the only predictor for MDR-TB in a cohort of HIV-infected patients with tuberculosis. In addition, this prospective study supports the results of prior retrospective studies that effective treatment impacts on mortality. Current second-line treatment, including high dose levofloxacin, appears to be reasonably well tolerated.

Use of the ganciclovir implant for the treatment of cytomegalovirus retinitis in the era of potent antiretroviral therapy: recommendations of the International AIDS Society-USA panel.

PURPOSE: To describe the risks, benefits, and recommended use of the ganciclovir implant for the treatment of human immunodeficiency virus-related cytomegalovirus (CMV) retinitis in the era of potent antiretroviral therapy. METHODS: A panel of physicians with expertise in the use of the ganciclovir implant and in the management of CMV retinitis was convened by the International AIDS Society-USA. The panel reviewed and discussed available data, and developed recommendations for the use of the ganciclovir implant, the surgical technique, and related management issues. Recommendations were rated according to the strength and quality of the supporting evidence. RESULTS: The effect of potent antiretroviral therapy on the immunologic status of patients with human immunodeficiency virus disease has changed the manifestation and course of CMV retinitis in many patients. The clinical management of CMV retinitis and the role of the ganciclovir implant are thus changing. Factors in the decision to choose the ganciclovir implant include the patient's potential for immunologic improvement, location and severity of CMV retinitis, and the risks and costs associated with implantation and concomitant oral ganciclovir therapy. CONCLUSIONS: The ganciclovir implant is safe and effective for the treatment of CMV retinitis. The indications for its use should be modified to account for increased patient survival and the potential for CMV retinitis to be controlled by effective antiretroviral therapy. Optimal use of the ganciclovir implant and discontinuation of therapy in selected patients with improvement in immunity may result in better long-term visual outcomes.

Chemokines are present in the genital tract of HIV-seropositive and HIV-seronegative women: correlation with other immune mediators.

In this cross-sectional study, 53 cervicovaginal lavage samples (CVL) from 41 women were analyzed for the chemokines interleukin-8 (IL-8), regulated-on-activation normal T-expressed and secreted (RANTES) factor, and macrophage inflammatory protein-1alpha (MIP-1alpha) by enzyme-linked immunosorbent assay (ELISA). IL-8 was detected in 81% of CVL, whereas RANTES was detected in 32%, and MIP-1alpha in 15% of the CVL. The mean levels of IL-8, RANTES, and MIP-1alpha in positive samples were 396 pg/ml, 102 pg/ml, and 34 pg/ml, respectively. IL-8 levels correlated positively with IL-1beta and IgG in a subset of CVL samples. RANTES levels correlated positively with complement protein levels. Additionally, the levels of RANTES, but not MIP-1alpha, reached levels reported in previous studies of the effects of beta chemokines to inhibit HIV replication. These results suggest that measuring chemokines in CVL specimens can provide important information regarding immune responses in the genital tract.