A Phase 1/2 Randomized, Placebo-Controlled Trial of Romidespin in Persons With HIV-1 on Suppressive Antiretroviral Therapy.

BACKGROUND: Romidepsin (RMD) is a histone deacetylase inhibitor reported to reverse HIV-1 latency. We sought to identify doses of RMD that were safe and induced HIV-1 expression. METHODS: Enrollees had HIV-1 RNA <40 copies/mL on antiretroviral therapy. Measurements included RMD levels, plasma viremia by single-copy HIV-1 RNA assay, HIV-1 DNA, cell-associated unspliced HIV-1 RNA (CA-RNA), acetylation of histone H3-lysine-9 (H3K9ac+), and phosphorylation of transcription factor P-TEFb. Wilcoxon tests were used for comparison. RESULTS: In the single-dose cohorts 1-3, 43 participants enrolled (36 participants 0.5, 2, 5 mg/m 2 RMD; 7 placebo) and 16 enrolled in the multidose cohort 4 (13 participants 5 mg/m 2 RMD; 3 placebo). One grade 3 event (neutropenia) was possibly treatment related. No significant changes in viremia were observed in cohorts 1-4 compared to placebo. In cohort 4, pharmacodynamic effects of RMD were reduced proportions of CD4+ T cells 24 hours after infusions 2-4 (median, -3.5% to -4.5%) vs placebo (median, 0.5% to 1%; P ≤ .022), and increased H3K9ac+ and phosphorylated P-TEFb in CD4 + T cells vs placebo (P ≤ .02). CONCLUSIONS: RMD infusions were safe but did not increase plasma viremia or unspliced CA-RNA despite pharmacodynamic effects on CD4 + T cells. CLINICAL TRIALS REGISTRATION: NCT01933594.

Vesatolimod, a Toll-like Receptor 7 Agonist, Induces Immune Activation in Virally Suppressed Adults Living With Human Immunodeficiency Virus-1.

BACKGROUND: Treatment with vesatolimod, an investigational, oral, toll-like receptor 7 (TLR7) agonist, leads to sustained viral remission in some non-human primates when combined with anti-envelope antibodies or therapeutic vaccines. We report results of a Phase Ib study evaluating safety, pharmacokinetics, and pharmacodynamics of vesatolimod in adults living with human immunodeficiency virus (HIV)-1. METHODS: In this double-blind, multicenter, placebo-controlled trial, participants on antiretroviral therapy with screening plasma HIV-1 RNA levels <50 copies/mL were randomized (6:2) to receive 6-10 doses of vesatolimod (1-12 mg) or matching placebo orally every other week in sequential dose-escalation cohorts. The primary study objectives included establishing the safety and virologic effects of vesatolimod (change from baseline in plasma HIV-1 RNA). Pharmacokinetics and pharmacodynamic/immunologic activity were assessed as secondary objectives. RESULTS: A total of 48 individuals were randomly assigned to vesatolimod (n = 36) or placebo (n = 12). Vesatolimod was generally well tolerated, with no study drug-related serious adverse events or adverse events leading to study drug discontinuation. There were no statistically significant changes from baseline in plasma HIV-1 RNA in the vesatolimod groups, compared to placebo.Vesatolimod plasma exposures increased dose proportionally; consistent responses in cytokines, interferon-stimulated gene expression, and lymphocyte activation were observed with increasing dose levels above 4 mg. Peak elevations 24 hours after receipt of a 6 mg dose were >3.9-fold higher for interferon gamma-induced protein 10 (IP-10), interleukin-1 receptor antagonist (IL-1RA), interferon-inducible T-cell alpha chemoattractant (ITAC) when compared to baseline values. CONCLUSIONS: Vesatolimod was well tolerated at doses ranging from 1 to 12 mg. Immune stimulation was observed at doses above 4 mg, providing rationale for future combination trials in people living with HIV. CLINICAL TRIALS REGISTRATION: NCT02858401.

Taking Control: The Efficacy and Durability of a Peer-Led Uncertainty Management Intervention for People Recently Diagnosed With HIV.

HIV creates substantial uncertainty for people infected with the virus, which subsequently affects a host of psychosocial outcomes critical to successful management of the disease. This study assessed the efficacy and durability of a theoretically driven, one-on-one peer support intervention designed to facilitate uncertainty management and enhance psychosocial functioning for patients newly diagnosed with HIV. Using a pretest-posttest control group design, 98 participants received information and training in specific communication strategies (e.g., disclosing to friends and family, eliciting social support, talking to health care providers, using the Internet to gather information, and building social networks through AIDS service organizations). Participants in the experimental group attended six 1-hour sessions, whereas control participants received standard of care for 12 months (after which they received the intervention). Over time, participants in the intervention fared significantly better regarding (a) illness uncertainty, (b) depression, and (c) satisfaction with social support than did those in the control group. Given the utility and cost-effectiveness of this intervention and the uncertainty of a multitude of medical diagnoses and disease experiences, further work is indicated to determine how this program could be expanded to other illnesses and to address related factors, such as treatment adherence and clinical outcomes.

Comparison of the metabolic effects of ritonavir-boosted darunavir or atazanavir versus raltegravir, and the impact of ritonavir plasma exposure: ACTG 5257.

BACKGROUND: Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24). METHODS: Treatment-naive adult subjects were randomized to ritonavir-boosted atazanavir or darunavir, or raltegravir-based cART. Changes in lipids and other metabolic outcomes over time were estimated. Differences between arms were estimated with 97.5% confidence intervals and compared using pairwise Student t tests. Associations between ritonavir C24 and lipid changes at week 48 were evaluated via linear regression. RESULTS: Analyses included 1797 subjects with baseline fasting data. Baseline lipid profiles and metabolic syndrome rates (approximately 21%) were similar across arms. Comparable increases occurred in total cholesterol, triglycerides, and low-density lipoprotein cholesterol with the boosted protease inhibitors (PIs); each PI had greater increases relative to raltegravir (all P ≤ .001 at week 96). Metabolic syndrome incident rates by week 96 (approximately 22%) were not different across arms. Ritonavir C24 was not different by arm (P = .89) (median, 69 ng/mL and 74 ng/mL in the atazanavir and darunavir arms, respectively) and were not associated with changes in lipid measures (all P > .1). CONCLUSIONS: Raltegravir produced the most favorable lipid profile. Metabolic syndrome rates were high at baseline and increased to the same degree in all arms. Ritonavir C24 was not different in the PI arms and had no relationship with the modest but comparable increases in lipids observed with either atazanavir or darunavir. The long-term clinical significance of the lipid changes noted with the PIs relative to raltegravir deserves further evaluation. CLINICAL TRIALS REGISTRATION: NCT 00811954.

Human N-acetyltransferase 1 *10 and *11 alleles increase protein expression through distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity.

OBJECTIVES: N-acetyltransferase 1 (NAT1) metabolizes drugs and environmental carcinogens. NAT1 alleles *10 and *11 have been proposed to alter protein level or enzyme activity compared with wild-type NAT1 *4 and to confer cancer risk, through uncertain pathways. This study characterizes regulatory polymorphisms and underlying mechanisms of NAT1 expression. METHODS: We measured allelic NAT1 mRNA expression and translation, as a function of multiple transcription start sites, alternative splicing, and three 3'-polyadenylation sites in human livers (one of which was discovered in this study), B lymphocytes, and transfected cells. In a clinical study of 469 patients with HIV/AIDS treated with the NAT1/NAT2 substrate sulfamethoxazole (SMX), associations were tested between SMX-induced hypersensitivity and NAT1 *10 and *11 genotypes, together with known NAT2 polymorphisms. RESULTS: NAT1 *10 and *11 were determined to act as common regulatory alleles accounting for most NAT1 expression variability, both leading to increased translation into active protein. NAT1 *11 (2.4% minor allele frequency) affected 3'-polyadenylation site usage, thereby increasing formation of NAT1 mRNA with intermediate length 3'-untranslated region (major isoform) at the expense of the short isoform, resulting in more efficient protein translation. NAT1 *10 (19% minor allele frequency) increased translation efficiency without affecting 3'-untranslated region polyadenylation site usage. Livers and B-lymphocytes with *11/*4 and *10/*10 genotypes displayed higher NAT1 immunoreactivity and NAT1 enzyme activity than the reference genotype *4/*4. Patients who carry *10/*10 and *11/*4 (fast NAT1 acetylators) were less likely to develop hypersensitivity to SMX, but this was observed only in individuals who are also carrying a slow NAT2 acetylator genotype. CONCLUSION: NAT1 *10 and *11 significantly increase NAT1 protein level/enzyme activity, enabling the classification of carriers into reference and rapid acetylators. Rapid NAT1 acetylator status seems to protect against SMX toxicity by compensating for slow NAT2 acetylator status.

No evidence for decay of the latent reservoir in HIV-1-infected patients receiving intensive enfuvirtide-containing antiretroviral therapy.

Human immunodeficiency virus type 1 (HIV-1) persists in a latent reservoir of infected resting memory CD4 cells in patients receiving antiretroviral therapy. We assessed whether multitarget therapy with enfuvirtide, 2 reverse-transcriptase inhibitors, and a ritonavir-boosted protease inhibitor leads to decay of this reservoir. Nineteen treatment-naive patients initiated this regimen; 9 experienced virologic suppression and continued enfuvirtide-containing therapy for at least 48 weeks. In enfuvirtide-treated patients with virological suppression, there was no decay of the latent reservoir (95% confidence interval for half-life, 11 months to infinity). The stability of the latent reservoir despite intensive therapy suggests that new strategies are needed to eradicate HIV-1 from this reservoir. (ClinicalTrials.gov identifier: NCT00051831 .).

Impact of HLA Class I Alleles on Timing of HIV Rebound After Antiretroviral Treatment Interruption.

BACKGROUND: Identifying host determinants associated with HIV reservoir size and timing of viral rebound after an analytic treatment interruption (ATI) is an important step in the search for an HIV functional cure. We performed a pooled analysis of 103 participants from 4 AIDS Clinical Trials Group ATI studies to identify the association between HLA class I alleles with HIV reservoir size and viral rebound timing. METHODS: Total HIV DNA and cell-associated HIV RNA (CA-RNA) were quantified in pre-ATI peripheral blood mononuclear cell samples, and residual plasma viremia was measured using the single-copy assay. HLA class I typing was performed, and we generated an odds ratio (OR) of predicted HLA effect on HIV viremia control for each individual and compared this with time to viral rebound, and levels of HIV DNA and CA-RNA. RESULTS: There was no significant association between the HLA ORs and levels of HIV DNA or CA-RNA, but carriage of protective HLA-B alleles (lower OR scores) was associated with delayed viral rebound (P = 0.02). Higher OR scores at the HLA-C locus were associated with longer duration of ART treatment (P = 0.02) and this trend was also seen with the combined OR score (P < 0.01). Individuals with protective HLA-B alleles had delayed viral rebound after treatment interruption that was not explained by differences in baseline reservoir size. CONCLUSIONS: The results indicate the vital role of cellular host immunity in preventing HIV rebound and the importance of taking into account the HLA status of study participants being evaluated in trials for an HIV cure.

StudySearch: a web-based application for posting and searching clinical research studies.

Participant accrual into research studies is critical to advancing clinical and translational research to clinical care. Without sufficient recruitment, the purpose of any research study cannot be realized; yet, low recruitment and enrollment of participants persist. StudySearch is a web-based application designed to provide an easily readable, publicly accessible, and searchable listing of IRB-approved protocols that are accruing study participants. The Regulatory, Recruitment and Biomedical Informatics Cores of the Center for Clinical and Translational Science (CCTS) at The Ohio State University developed this research study posting platform. Postings include basic descriptive information: study title, purpose of the study, eligibility criteria and study personnel contact information. Language concerning benefits and/or inducements is not included; therefore, while IRB approval for a study to be listed on StudySearch is required, IRB approval of the posted language is not. Studies are listed by one of two methods; one automated and one manual: (1). Studies registered on ClinicalTrials.gov are automatically downloaded once a month; or (2). Studies are submitted directly by researchers to the CCTS Regulatory Core staff. In either case, final language is a result of an iterative process between researchers and CCTS staff. Deployed in January 2011 at OSU, this application has grown to approximately 200 studies currently posted and 1500 unique visitors per month. Locally, StudySearch is part of the CCTS recruitment toolkit. Features continue to be modified to better accommodate user behaviors. Nationally, this open source application is available for use.

The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption.

OBJECTIVES: Therapies to achieve sustained antiretroviral therapy-free HIV remission will require validation in analytic treatment interruption (ATI) trials. Identifying biomarkers that predict time to viral rebound could accelerate the development of such therapeutics. DESIGN: A pooled analysis of participants from six AIDS Clinical Trials Group ATI studies to identify predictors of viral rebound. METHODS: Cell-associated DNA (CA-DNA) and CA-RNA were quantified in pre-ATI peripheral blood mononuclear cell samples, and residual plasma viremia was measured using the single-copy assay. RESULTS: Participants who initiated antiretroviral therapy (ART) during acute/early HIV infection and those on a non-nucleoside reverse transcriptase inhibitor-containing regimen had significantly delayed viral rebound. Participants who initiated ART during acute/early infection had lower levels of pre-ATI CA-RNA (acute/early vs. chronic-treated: median <92 vs. 156 HIV-1 RNA copies/10 CD4 cells, P < 0.01). Higher pre-ATI CA-RNA levels were significantly associated with shorter time to viral rebound (≤4 vs. 5-8 vs. >8 weeks: median 182 vs. 107 vs. <92 HIV-1 RNA copies/10 CD4 cells, Kruskal-Wallis P < 0.01). The proportion of participants with detectable plasma residual viremia prior to ATI was significantly higher among those with shorter time to viral rebound. CONCLUSION: Higher levels of HIV expression while on ART are associated with shorter time to HIV rebound after treatment interruption. Quantification of the active HIV reservoir may provide a biomarker of efficacy for therapies that aim to achieve ART-free HIV remission.

Brief Report: Relationship Among Viral Load Outcomes in HIV Treatment Interruption Trials.

Viral load (VL) rebound timing and set point were analyzed in 235 participants undergoing analytic treatment interruption (ATI) in 6 AIDS Clinical Trials Group studies. There was no significant association between rebound timing and ATI VL set point for those who rebounded ≤12 weeks. VL set points were lower in participants with rebound >12 weeks (P < 0.001) and participants treated during early infection (P < 0.001). Pre-antiretroviral therapy VL correlated with set point, though 68% of participants had a set point lower than pre-antiretroviral therapy VL. These results illustrate complex relationships between post-ATI virologic outcomes and the potential presence of biological factors mediating rebound timing and set point.

Population pharmacokinetics of delavirdine and N-delavirdine in HIV-infected individuals.

OBJECTIVE: Delavirdine is a non-nucleoside reverse transcriptase inhibitor used in combination regimens for the treatment of HIV-1 infection. Our objective was to characterise the population pharmacokinetics of delavirdine in HIV-infected patients who participated in the adult AIDS Clinical Trials Group (ACTG) 260 and 261 studies. METHODS: ACTG 261 was a randomised, double-blind study of delavirdine 400mg three times daily, in various combination regimens; ACTG 260 was a concentration-targeted monotherapy study. Two hundred and thirty-four patients, and 1254 and 1251 plasma concentrations for delavirdine and N-delavirdine, respectively, were available for population pharmacokinetic analysis. The pharmacokinetic model (and initial parameters), based on previous studies, included two compartments for delavirdine (peripheral and central) and parallel clearance pathways (nonlinear conversion to N-delavirdine and first order clearance from the body). The model was one compartment for N-delavirdine with first order clearance. Diurnal variation of delavirdine and N-delavirdine oral clearance was modelled as a cosine function, with amplitude variation a fitted parameter. Pharmacokinetic parameter estimates were derived from iterative two-stage analysis; observed delavirdine and N-delavirdine concentrations fit with weighting by the inverse observation variance. Covariates were analysed by multiple general linear modelling. RESULTS: The mean (percent coefficient of variation [%CV]) CD4 count was 315 (109) cells/mm(3), weight 76.9 (14.7) kg, age 37 (8.5) years, and 15% of the population were women. Mean (%CV) population pharmacokinetic parameter estimates for delavirdine were: volume of distribution at steady state 67.6 (100) L, intrinsic oral clearance 19.8 (64) L/h, concentration at half the maximum velocity of metabolism (V(max)) 6.3 (69) micromol/L and first order oral clearance 0.57 (86) L/h. For N-delavirdine, the mean (%CV) apparent volume of distribution was 24.7 (75) L and apparent clearance 29.7 (42) L/h. The mean V(max) was 1376 (68) mg/day. The final model for average intrinsic clearance of delavirdine included race, sex, weight and age as significant covariates (p < 0.05); however, these covariates do not explain a significant proportion of the overall variability in the population. CONCLUSIONS: Delavirdine disposition exhibits nonlinear pharmacokinetics and large interpatient variability, and is significantly altered by time of day (impacting potential therapeutic drug monitoring and future pharmacokinetic study designs). Although race and sex appear to influence delavirdine pharmacokinetics, men and women and patients of different races should receive similar mg/kg dosage regimens. The presence of large interpatient variability supports the further investigation of the utility of therapeutic drug monitoring for delavirdine, if target drug concentrations can be better defined.

Third-trimester maternal toxicity with nevirapine use in pregnancy.

OBJECTIVE: Nevirapine-based therapy is associated with increased frequency of adverse events among women with CD4+ cell count of 250 cells/microL or greater. We evaluated the safety of nevirapine-based antiretroviral therapy in human immunodeficiency virus (HIV)-1-infected pregnant women. METHODS: We retrospectively evaluated 23 pregnancies managed with nevirapine-based regimens from July 2001 to April 2005. The incidence of adverse events was determined and analyzed by CD4+ cell count of either less than or greater than or equal to 250 cells/microL, and gestational age when nevirapine was initiated. Liver function abnormality was graded according to the National Institute of Allergy and Infectious Diseases Division of AIDS toxicity guidelines. RESULTS: Five of 23 patients (21.7%) started nevirapine-based therapy after 27 weeks of gestation. All 3 cases of adverse events occurred in this group within 6 weeks of initiating therapy and with CD4+ cell count greater than 250 cells/microL. A significant difference was noted in the proportion of patients who developed toxicity while starting nevirapine in the third trimester (3/5, 60%; 95% confidence interval 14.66-94.73) compared with those starting nevirapine earlier in pregnancy (0/18, 0%; 95% confidence interval 0.0-18.53; P < .006). Two patients developed rash, eosinophilia, and liver function abnormality, with one developing clinical hepatitis and renal failure. A third patient had abnormal elevation of liver enzymes but was asymptomatic. CONCLUSION: The incidence of adverse events with nevirapine may be lower than previously reported (13% versus 29%) and may be primarily noted with initiating the drug late in pregnancy. Further study of nevirapine in larger cohorts of HIV-infected pregnant women is warranted to determine the relationship between nevirapine hepatotoxicity and trimester use. LEVEL OF EVIDENCE: II-3.

Drug rash with eosinophilia and systemic symptoms syndrome and renal toxicity with a nevirapine-containing regimen in a pregnant patient with human immunodeficiency virus.

BACKGROUND: Antiretroviral therapy is associated with serious adverse events. We report the case of a pregnant human immunodeficiency virus type 1-infected woman who developed drug rash with eosinophilia and systemic symptoms syndrome and renal failure shortly after initiation of a nevirapine-containing antiretroviral regimen at 27 weeks' gestation. CASE: A 26-year-old primigravida presented with a fever of 40.2C, urticarial rash, and icteric sclera 6 weeks after starting a nevirapine-containing antiretroviral regimen. Eosinophils, serum creatinine, bilirubin, and liver enzymes were markedly elevated, and abnormal coagulation studies were noted on admission. Serology testing was negative for viral hepatitis and microbiologic cultures were negative for growth. Abnormal laboratory findings at discharge resolved within 4 months after discontinuation of antiretroviral agents and systemic corticosteroid therapy. CONCLUSION: Our case suggests the need for close monitoring of liver and renal function after initiation of nevirapine-containing antiretroviral regimens.

Impact of chemotherapy for HIV-1 related lymphoma on residual viremia and cellular HIV-1 DNA in patients on suppressive antiretroviral therapy.

The first cure of HIV-1 infection was achieved through complex, multimodal therapy including myeloablative chemotherapy, total body irradiation, anti-thymocyte globulin, and allogeneic stem cell transplantation with a CCR5 delta32 homozygous donor. The contributions of each component of this therapy to HIV-1 eradication are unclear. To assess the impact of cytotoxic chemotherapy alone on HIV-1 persistence, we longitudinally evaluated low-level plasma viremia and HIV-1 DNA in PBMC from patients in the ACTG A5001/ALLRT cohort on suppressive antiretroviral therapy (ART) who underwent chemotherapy for HIV-1 related lymphoma without interrupting ART. Plasma HIV-1 RNA, total HIV-1 DNA and 2-LTR circles (2-LTRs) in PBMC were measured using sensitive qPCR assays. In the 9 patients who received moderately intensive chemotherapy for HIV-1 related lymphoma with uninterrupted ART, low-level plasma HIV-1 RNA did not change significantly with chemotherapy: median HIV-1 RNA was 1 copy/mL (interquartile range: 1.0 to 20) pre-chemotherapy versus 4 copies/mL (interquartile range: 1.0 to 7.0) post-chemotherapy. HIV-1 DNA levels also did not change significantly, with median pre-chemotherapy HIV-1 DNA of 355 copies/106 CD4+ cells versus 228 copies/106 CD4+ cells post-chemotherapy. 2-LTRs were detectable in 2 of 9 patients pre-chemotherapy and in 3 of 9 patients post-chemotherapy. In summary, moderately intensive chemotherapy for HIV-1 related lymphoma in the context of continuous ART did not have a prolonged impact on HIV-1 persistence. Clinical trials registration unique identifier: NCT00001137.

The design of single-arm clinical trials of combination antiretroviral regimens for treatment-naive HIV-infected patients.

Single-arm clinical trials are useful to evaluate antiretroviral regimens in certain populations of HIV-infected treatment-naive patients for whom a randomized controlled trial is not feasible or desirable. They can also be useful to establish initial estimates of efficacy and safety/tolerability of novel regimens to inform the design of large phase III trials. In this article, we discuss key design considerations for such single-arm studies.

Polymorphism in glutamate cysteine ligase catalytic subunit (GCLC) is associated with sulfamethoxazole-induced hypersensitivity in HIV/AIDS patients.

BACKGROUND: Sulfamethoxazole (SMX) is a commonly used antibiotic for prevention of infectious diseases associated with HIV/AIDS and immune-compromised states. SMX-induced hypersensitivity is an idiosyncratic cutaneous drug reaction with genetic components. Here, we tested association of candidate genes involved in SMX bioactivation and antioxidant defense with SMX-induced hypersensitivity. RESULTS: Seventy seven single nucleotide polymorphisms (SNPs) from 14 candidate genes were genotyped and assessed for association with SMX-induced hypersensitivity, in a cohort of 171 HIV/AIDS patients. SNP rs761142 T > G, in glutamate cysteine ligase catalytic subunit (GCLC), was significantly associated with SMX-induced hypersensitivity, with an adjusted p value of 0.045. This result was replicated in a second cohort of 249 patients (p = 0.025). In the combined cohort, heterozygous and homozygous carriers of the minor G allele were at increased risk of developing hypersensitivity (GT vs TT, odds ratio = 2.2, 95% CL 1.4-3.7, p = 0.0014; GG vs TT, odds ratio = 3.3, 95% CL 1.6 - 6.8, p = 0.0010). Each minor allele copy increased risk of developing hypersensitivity 1.9 fold (95% CL 1.4 - 2.6, p = 0.00012). Moreover, in 91 human livers and 84 B-lymphocytes samples, SNP rs761142 homozygous G allele carriers expressed significantly less GCLC mRNA than homozygous TT carriers (p < 0.05). CONCLUSIONS: rs761142 in GCLC was found to be associated with reduced GCLC mRNA expression and with SMX-induced hypersensitivity in HIV/AIDS patients. Catalyzing a critical step in glutathione biosynthesis, GCLC may play a broad role in idiosyncratic drug reactions.

HIV and asthma, is there an association?

OBJECTIVE: To evaluate whether asthma and airway hyper-responsiveness are associated with HIV infection. METHODS: We reviewed the literature on HIV-associated pulmonary diseases, pulmonary symptoms, and immune changes which may play a role in asthma. The information was analyzed comparing the pre-HAART era to the post-HAART era data. RESULTS: HIV-seropositive individuals commonly experience respiratory complaints yet it is unclear if the frequency of these complaints have changed with the initiation of HAART. Changes in pulmonary function testing and serum IgE are seen with HIV infection even in the post-HAART era. An increased prevalence of asthma among HIV-seropositive children treated with HAART has been reported. CONCLUSION: The spectrum of HIV-associated pulmonary disease has changed with the introduction of HAART. Current data is limited to determine if asthma and airway hyper-responsiveness are more common among HIV-seropositive individuals treated with HAART.

Phase I/II trial of the anti-HIV activity of mifepristone in HIV-infected subjects ACTG 5200.

BACKGROUND: Mifepristone is a glucocorticoid receptor inhibitor shown in vitro to have anti-HIV activity and anti-simian immunodeficiency virus activity in a macaque model. A phase I/II trial was performed to assess the drug's safety and anti-HIV activity. METHODS: A 28-day double-blind, placebo-controlled trial of mifepristone at doses of 75 mg, 150 mg, and 225 mg given daily was conducted in HIV+ persons with CD4+ lymphocyte counts >or=350 cells per cubic millimeter who had no recent antiretroviral therapy. RESULTS: Fifty-six male and 1 female subjects with a median entry CD4+ lymphocyte count of 555 cells per cubic millimeter and plasma HIV-1 RNA of 15,623 copies per milliliter were accrued. Forty-five subjects (78.9%) were available for endpoint analysis. In each arm, changes from baseline to day 28 in plasma HIV-1 RNA and CD4+ lymphocyte count were not significantly different from zero (no change). There was no relationship between mifepristone trough concentrations and plasma HIV-1 RNA. Day 28 morning plasma cortisol levels were significantly higher in the 150 mg and 225 mg arms compared with placebo, confirming biologic activity, and returned to baseline by day 56. Serum lipids did not change during the trial. Fasting blood sugar was 2.5 mg/dL higher on day 28 in the mifepristone arms, but the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) did not change. Three subjects (7.3%) receiving mifepristone developed a grade 2 rash. CONCLUSIONS: Mifepristone at doses of 75-225 mg daily was safe and well-tolerated, but did not show significant anti-HIV activity.

HIV testing outside of the study among men who have sex with men participating in an HIV vaccine efficacy trial.

OBJECTIVES: Participants who obtain an HIV test outside of an HIV vaccine efficacy trial could potentially unblind themselves which could result in differential behavior change and loss to follow-up based on assignment status. In a reanalysis of the VaxGen VAX004 data, the objectives were to determine: 1) the proportion of participants who were tested for HIV outside of the study (despite instructions not to do this) and reasons why; 2) demographic and risk factors associated with reported testing outside of the study; and 3) if outside testing was related to participant loss to follow-up. METHODS: Analyses were restricted to men who have sex with men (MSM) who completed a survey at one or more annual visits in a randomized, double-blind, placebo-controlled efficacy trial of a bivalent rgp 120 vaccine conducted from 1998-2002. A generalized linear mixture model assessed associations with outside testing. RESULTS: Despite instructions to the contrary, 16.9% (791/4670) of MSM reported being tested for HIV outside of the study, with the top two reasons being a) medical provider request (28.1%) and b) insurance requirement (17.1%). Increased odds of self-reported outside testing was associated with site location, reporting one or more sexually transmitted infections (STIs), joining the trial because of the belief that participation might confer some protection against HIV infection, engaging in unprotected anal sex, and being lost to follow-up. Decreased odds of self-reported outside testing was associated with perceived study arm assignment to vaccine or uncertainty about study arm assignment compared to placebo. CONCLUSIONS: To avoid biases such as differential risk behavior and loss to follow-up based on perceived assignment status, initiating additional procedures to reduce the likelihood of outside testing will be important to assure the validity of future study results.

Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers.

The combination of efavirenz with HIV-1 protease inhibitors (PI) results in complex interactions secondary to mixed induction and inhibition of oxidative metabolism. ACTG A5043 was a prospective, open-label, controlled, two-period, multiple-dose study with 55 healthy volunteers. The objective of the present study was to evaluate the potential pharmacokinetic interaction between efavirenz and dual PIs. The subjects received a daily dose of 600 mg efavirenz for 10 days with amprenavir 600 mg twice daily added at day 11 and were randomized to receive nelfinavir, indinavir, ritonavir, saquinavir, or no second PI on days 15-21. Intensive pharmacokinetic studies were conducted on day 14 and 21. Efavirenz plasma concentrations were fit to candidate models using weighted non-linear regression. The disposition of efavirenz was described by a linear two-compartment model with first order absorption following a fitted lag time. Apparent clearance (CLt/F), volume of distribution at steady state (Vss/F), inter-compartmental clearance, and the central and peripheral volume of distribution were estimated. The mean CLt/F and Vss/F of efavirenz were 0.126 l/h/kg and 4.412 l/kg, respectively. Both AUC and CLt/F of efavirenz remained unchanged after 7 days of dual PI dosing. The mean Vss/F of efavirenz increased an average of 89% across arms, ranging from 52% (nelfinavir) to 115% (indinavir) relative to efavirenz with amprenavir alone. Increases were also observed in Vp/F after the addition of nelfinavir, indinavir, ritonavir and saquinavir by 85%, 170%, 162% and 111%, respectively. In conclusion, concomitant administration of dual PIs is unlikely to have any clinically significant effect on the pharmacokinetics of CYP2B6 substrates in general or oral efavirenz specifically.