Oluwatoyin Adeyemi

The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial.

The CCR5 inhibitor maraviroc has been hypothesized to decrease T-cell activation in HIV-infected individuals, but its independent immunologic effects have not been established in a placebo-controlled trial. We randomized 45 HIV-infected subjects with CD4 counts <350 cells per mm(3) and plasma HIV RNA levels <48 copies per mL on antiretroviral therapy (ART) to add maraviroc vs placebo to their regimen for 24 weeks followed by 12 weeks on ART alone. Compared with placebo-treated subjects, maraviroc-treated subjects unexpectedly experienced a greater median increase in % CD38+HLA-DR+ peripheral blood CD8+ T cells at week 24 (+2.2% vs -0.7%, P = .014), and less of a decline in activated CD4+ T cells (P < .001). The % CD38+HLA-DR+ CD4+ and CD8+ T cells increased nearly twofold in rectal tissue (both P < .001), and plasma CC chemokine receptor type 5 (CCR5) ligand (macrophage-inflammatory protein 1β) levels increased 2.4-fold during maraviroc intensification (P < .001). During maraviroc intensification, plasma lipopolysaccharide declined, whereas sCD14 levels and neutrophils tended to increase in blood and rectal tissue. Although the mechanisms explaining these findings remain unclear, CCR5 ligand-mediated activation of T cells, macrophages, and neutrophils via alternative chemokine receptors should be explored. These results may have relevance for trials of maraviroc for HIV preexposure prophylaxis and graft-versus-host disease. This trial was registered at www.clinicaltrials.gov as #NCT00735072.

Vitamin D deficiency in HIV-infected and HIV-uninfected women in the United States

Background:Vitamin D deficiency is of increasing concern in HIV-infected persons because of its reported association with a number of negative health outcomes that are common in HIV. We undertook this study to determine the prevalence and predictors of vitamin D deficiency among a nationally representative cohort of middle-aged, ethnically diverse, HIV-infected and HIV-uninfected women enrolled in the Womens Interagency HIV Study (WIHS). Methods:Vitamin D testing was performed by Quest Diagnostics on frozen sera using the liquid chromatography/mass spectroscopy method. Vitamin D deficiency was defined as 25(OH)D ≤20 ng/mL. Comparisons of continuous and categorical characteristics among HIV-infected and HIV-uninfected women were made by Wilcoxon tests and Pearson χ2 tests, respectively. Results:One thousand seven hundred seventy-eight women (1268 HIV positive) were studied. Sixty-three percent had vitamin D deficiency (60% HIV positive vs. 72% HIV negative; P < 0.001). Multivariable predictors of vitamin D deficiency were being African American (adjusted odds ratio 3.02), Hispanic (adjusted odds ratio 1.40), body mass index (adjusted odds ratio 1.43), age (adjusted odds ratio 0.84), HIV positive (adjusted odds ratio 0.76), glomerular filtration rate <90·mL−1·min−1 (adjusted odds ratio 0.94), and WIHS sites Los Angeles (adjusted odds ratio 0.66) and Chicago (adjusted odds ratio 0.63). In the HIV-positive women, multivariate predictors were undetectable HIV RNA (adjusted odds ratio 0.69), CD4 50-200 cells per cubic millimeter (adjusted odds ratio 1.60), CD4 <50 cells per cubic millimeter (adjusted odds ratio 1.94), and recent protease inhibitor use (adjusted odds ratio 0.67). Conclusions:In this study of more than 1700 women in the United States, most women with or without HIV infection had low vitamin D levels and African American women had the highest rates of vitamin D deficiency. An understanding of the role that vitamin D deficiency plays in non-AIDS-related morbidities is planned for investigation in WIHS.

Circulating vitamin D correlates with serum antimüllerian hormone levels in late-reproductive-aged women: Women's Interagency HIV Study

OBJECTIVE To study the correlation between circulating 25-hydroxyvitamin D (25OH-D) levels and serum antimüllerian hormone (AMH) in women enrolled in the Womens Interagency HIV Study. DESIGN Cross-sectional study. SETTING None. PATIENT(S) All premenopausal women (n = 388) with regular menstrual cycles were included and subdivided into three groups: group 1 with age <35 years (n = 128), group 2 with age 35-39 years (n = 119), and group 3 with age ≥40 years (n = 141). INTERVENTION(S) Serum for 25OH-D, AMH, fasting glucose and insulin, and creatinine levels. MAIN OUTCOME MEASURE(S) Correlation between 25OH-D and AMH before and after adjusting for HIV status, body mass index, race, smoking, illicit drug use, glucose and insulin levels, estimated glomerular filtration rate, and geographic site of participation. RESULT(S) After adjusting for all covariates, the regression slope in all participants for total 25OH-D predicting log(10)AMH for 25-year-olds (youngest participant) was -0.001 (SE = 0.008); and for 45-year-olds (oldest participant) the corresponding slope was +0.011 (SE = 0.005). Fasting insulin level was negatively correlated with serum AMH. The regression slope for the correlation between 25OH-D and AMH in group 1 was +0.002 (SE = 0.006); in group 2 was +0.006 (SE = 0.005); and in group 3 was +0.011 (SE = 0.005). There was no association between HIV and AMH. CONCLUSION(S) A novel relationship is reported between circulating 25OH-D and AMH in women aged ≥40 years, suggesting that 25OH-D deficiency might be associated with lower ovarian reserve in late-reproductive-aged women.

Metabolic Syndrome in Older HIV-Infected Patients: Data from the CORE50 Cohort

Metabolic abnormalities and cardiovascular disease are increasingly recognized in HIV-infected patients. While HIV-infected patients older than 50 years of age account for up to 25% of HIV cases in the United States, there are limited data on these individuals. To determine the prevalence and predictors of the metabolic syndrome among a cohort of older, HIV-infected patients and to calculate their 10-year Framingham cardiac risk (FCR) score a cross-sectional study of HIV patients older than 50 years of age was conducted at the CORE Center, Chicago, Illinois, between May 2005 and February 2006. There were 121 HIV-infected patients with a median age of 54 years, of whom 79% were male, 83% African American, 9% Hispanic, and 6% Caucasian. Thirty-four percent of patients had the metabolic syndrome, 49% had a moderate-high (>10%) 10-year FCR, and 13% had a high (>20%) 10-year FCR. Patients with the metabolic syndrome were significantly more likely to have a greater than 20% 10-year FCR. Sixty-five percent of all patients were current smokers and 55% of patients with the metabolic syndrome were current smokers. There were significant differences in the components of the metabolic syndrome by gender with women having significantly more components related to insulin resistance such as elevated waist circumference and diabetes, while men were more likely to have low high-density lipoprotein (HDL) levels. This study shows a high prevalence of the metabolic syndrome in older HIV-infected patients and an association between the metabolic syndrome and FCR in our study population. As the HIV population ages, attention to modifiable cardiac risk factors will become increasingly important.

Hepatitis C Treatment Eligibility in an Urban Population with and without HIV Coinfection

In an urban referral clinic, 182 hepatitis C-infected adults including 110 (60%) with HIV coinfection were evaluated for pegylated interferon and ribavirin therapy. Overall, only 33% were eligible for treatment. Considering all patients together, the major barriers to treatment were nonadherence with the evaluation process (23%), refusal of treatment (10%), active substance abuse (9%), and medical contraindication (8%). There was a trend toward a higher rate of treatment eligibility in HIV coinfected patients (39% vs. 25%; p = 0.07), who were significantly more likely to be adherent with the evaluation process compared to those with hepatitis C alone (86% vs. 63%; p = <0.001). Acceptance of antiviral therapy for hepatitis C was similar between eligible persons with and without HIV. These findings highlight the need to develop interventions to improve adherence and to manage substance abuse and other comorbidities in order to maximize the impact of interferon and ribavirin therapy on urban patients with hepatitis C.

Vitamin D insufficiency may impair CD4 recovery among Women's Interagency HIV Study participants with advanced disease on HAART

Background:Recent studies in HIV-infected men report an association between low vitamin D (25OH-D) and CD4 recovery on HAART. We sought to test this relationship in the Womens Interagency HIV Study (WIHS). Methods:We examined 204 HIV-infected women with advanced disease, who started HAART after enrollment in the WIHS. We measured vitamin D (25OH-D) levels about 6 months prior to HAART initiation. The relationship between CD4 recovery (defined as increases of ≥50, 100, and 200 cells at 6, 12, and 24 months) and exposure variables was examined using logistic regression models at 6, 12 and 24 months post-HAART initiation in unadjusted and adjusted analyses, and using multivariable longitudinal Generalized Estimating Equations (GEE). Vitamin D insufficiency was defined as 25OH-D levels at least 30 ng/ml. Results:The majority were non-Hispanic black (60%) and had insufficient vitamin D levels (89%). In adjusted analyses, at 24 months after HAART, insufficient vitamin D level (OR 0.20, 95% CI 0.05–0.83) was associated with decreased odds of CD4 recovery. The undetectable viral load (OR 11.38, 95% CI 4.31–30.05) was associated with CD4 recovery. The multivariable GEE model found that average immune reconstitution attenuated significantly (P < 0.01) over time among those with insufficient vitamin D levels compared with those with sufficient vitamin D levels. Conclusion:Vitamin D insufficiency is associated with diminished late CD4 recovery after HAART initiation among US women living with advanced HIV. The mechanism of this association on late CD4 recovery may be late vitamin D-associated production of naive CD4 cells during immune reconstitution.

Sofosbuvir and Velpatasvir for the Treatment of Hepatitis C Virus in Patients Coinfected with Human Immunodeficiency Virus Type 1: An Open-Label, Phase 3 Study

Background A safe, simple, effective, and pan-genotypic regimen to treat hepatitis C virus (HCV) infection in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains a medical need. We assessed the efficacy and safety of the NS5B polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir for HCV in patients coinfected with HIV-1. Methods This phase 3, open-label, single-arm study at 17 sites in the United States enrolled patients with HCV of any genotype and HIV-1 coinfection, including those with compensated cirrhosis. All patients received sofosbuvir-velpatasvir once daily for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). Efficacy and safety were assessed in all patients receiving at least 1 dose of treatment. Results Of 106 patients, 91 (86%) were men, 48 (45%) were black, and 19 (18%) had cirrhosis. SVR12 was achieved by 101 of 106 (95% [95% confidence interval {CI}, 89%-99%]) patients: 74 of 78 (95% [95% CI, 87%-99%]) with genotype 1; all 11 (100% [95% CI, 72%-100%]) with genotype 2; 11 of 12 (92% [95% CI, 62%-100%]) with genotype 3; and all 5 (100% [95% CI, 48%-100%]) with genotype 4. All 19 patients with cirrhosis had SVR12. Two patients relapsed, 2 were lost to follow-up, and 1 withdrew consent. Two discontinued treatment due to adverse events and 2 had serious adverse events. The most common adverse events were fatigue (25%), headache (13%), upper respiratory tract infection (8%), and arthralgia (8%). Conclusions Sofosbuvir-velpatasvir for 12 weeks was safe and provided high rates of SVR12 in patients coinfected with HCV and HIV-1. Clinical Trials Registration NCT02480712.

Are we meeting the american diabetes association goals for HIV-infected patients with diabetes mellitus?

We determined rates of achieving the American Diabetes Association goals among human immunodeficiency virus (HIV)-infected diabetic patients. American Diabetes Association goals (for hemoglobin A1c, blood pressure, and lipid levels) were defined by 2008 American Diabetes Association guidelines. HIV-infected diabetic patients achieved American Diabetes Association goals at rates similar to those in general medicine clinic patients. A multidisciplinary approach is needed to improve diabetes management in HIV clinics.

Virologic Response, Early HIV-1 Decay, and Maraviroc Pharmacokinetics With the Nucleos(t)ide-Free Regimen of MaravIroc Plus Darunavir/Ritonavir in a Pilot Study

Objective:To address the need for nucleos(t)ide reverse transcriptase inhibitor (NRTI)–sparing regimens, we explored the virologic and pharmacokinetic characteristics of maraviroc plus ritonavir-boosted darunavir in a single-arm, open-label, 96-week study. Methods:Twenty-four antiretroviral-naive R5 HIV-1–infected participants received maraviroc 150 mg and darunavir/ritonavir (DRV/r) 800/100 mg (MVC/DRV/r) once daily. The primary outcome was virologic failure (VF) = confirmed viral load (VL) >50 copies per milliliter at week 24 in the modified intent-to-treat population. To determine viral dynamics, participant-specific first- and second-phase empirical Bayes estimates were compared with decay rates from efavirenz (EFV) plus lopinavir/ritonavir, lopinavir/ritonavir plus 2NRTIs, and EFV plus 2NRTIs. Maraviroc plasma concentrations were determined at weeks 2, 4, 12, 24, and 48. Results:Baseline median (Q1, Q3) CD4 count and VL were 455 (299, 607) cells per cubic millimeter and 4.62 (4.18, 4.80) log10 copies per milliliter, respectively. VF occurred in 3 of 24 participants {12.5% [95% confidence interval (CI): 2.7 to 32.4]} at week 24. One of these resuppressed, yielding a week 48 VF rate of 2/24 [8.3% (95% CI: 1.0 to 27.0)]. The week 48 failures were 2 of the 4 participants (50%) with baseline VL >100,000 copies per milliliter. Week 96 VF rate was 2/20 [10% (95% CI: 1.2 to 31.7)]. Phase 1 decay was faster with MVC/DRV/r than reported for ritonavir-boosted lopinavir plus 2NRTIs (P = 0.0063) and similar to EFV-based regimens. Individual maraviroc trough concentrations collected between 20 and 28 hours post dose (n = 59) was 13.7 to 130 ng/mL (Q1, 23.4 ng/mL; Q3, 46.5 ng/mL), and modeled steady-state concentration was 128 ng/mL. Conclusions:MVC/DRV/r 150/800/100 mg once daily has potential for treatment-naive patients with R5 HIV-1.

Early development of non-hodgkin lymphoma following initiation of newer class antiretroviral therapy among HIV-infected patients - implications for immune reconstitution

BackgroundIn the HAART era, the incidence of HIV-associated non-Hodgkin lymphoma (NHL) is decreasing. We describe cases of NHL among patients with multi-class antiretroviral resistance diagnosed rapidly after initiating newer-class antiretrovirals, and examine the immunologic and virologic factors associated with potential IRIS-mediated NHL.MethodsDuring December 2006 to January 2008, eligible HIV-infected patients from two affiliated clinics accessed Expanded Access Program antiretrovirals of raltegravir, etravirine, and/or maraviroc with optimized background. A NHL case was defined as a pathologically-confirmed tissue diagnosis in a patient without prior NHL developing symptoms after starting newer-class antiretrovirals. Mean change in CD4 and log10 VL in NHL cases compared to controls was analyzed at week 12, a time point at which values were collected among all cases.ResultsFive cases occurred among 78 patients (mean incidence = 64.1/1000 patient-years). All cases received raltegravir and one received etravirine. Median symptom onset from newer-class antiretroviral initiation was 5 weeks. At baseline, the median CD4 and VL for NHL cases (n = 5) versus controls (n = 73) were 44 vs.117 cells/mm3 (p = 0.09) and 5.2 vs. 4.2 log10 (p = 0.06), respectively. The mean increase in CD4 at week 12 in NHL cases compared to controls was 13 (n = 5) vs. 74 (n = 50)(p = 0.284). Mean VL log10 reduction in NHL cases versus controls at week 12 was 2.79 (n = 5) vs. 1.94 (n = 50)(p = 0.045).ConclusionsAn unexpectedly high rate of NHL was detected among treatment-experienced patients achieving a high level of virologic response with newer-class antiretrovirals. We observed trends toward lower baseline CD4 and higher baseline VL in NHL cases, with a significantly greater decline in VL among cases by 12 weeks. HIV-related NHL can occur in the setting of immune reconstitution. Potential immunologic, virologic, and newer-class antiretroviral-specific factors associated with rapid development of NHL warrants further investigation.