Benjamin T. Davis

Metabolic Abnormalities and Cardiovascular Disease Risk Factors in Adults with Human Immunodeficiency Virus Infection and Lipodystrophy

We evaluated metabolic and clinical features of 71 HIV-infected patients with lipodystrophy by comparing them with 213 healthy control subjects, matched for age and body mass index, from the Framingham Offspring Study. Thirty HIV-infected patients without fat redistribution were compared separately with 90 matched control subjects from the Framingham Offspring Study. Fasting glucose, insulin, and lipid levels; glucose and insulin response to standard oral glucose challenge; and anthropometric measurements were determined. HIV-infected patients with lipodystrophy demonstrated significantly increased waist-to-hip ratios, fasting insulin levels, and diastolic blood pressure compared with controls. Patients with lipodystrophy were more likely to have impaired glucose tolerance, diabetes, hypertriglyceridemia, and reduced levels of high-density lipoprotein (HDL) cholesterol than were controls. With the exception of HDL cholesterol level, these risk factors for cardiovascular disease (CVD) were markedly attenuated in patients without lipodystrophy and were not significantly different in comparison with controls. These data demonstrate a metabolic syndrome characterized by profound insulin resistance and hyperlipidemia. CVD risk factors are markedly elevated in HIV-infected patients with fat redistribution.

Prediction of Coronary Heart Disease Risk in HIV-Infected Patients with Fat Redistribution

A metabolic syndrome has been described among human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy; the syndrome is characterized by fat redistribution, insulin resistance, and dyslipidemia. We compared the 10-year coronary heart disease (CHD) risk estimates for 91 HIV-infected men and women with fat redistribution with the risk estimates for 273 age-, sex-, and body mass index (BMI)-matched subjects enrolled in the Framingham Offspring Study. Thirty HIV-infected patients without fat redistribution were also compared with 90 age- and BMI-matched control subjects. The 10-year CHD risk estimate was significantly elevated among HIV-infected patients with fat redistribution, particularly among men; however, when they were matched with control subjects by waist-to-hip ratio, the 10-year CHD risk estimate did not significantly differ between groups. HIV-infected patients without fat redistribution did not have a greater CHD risk estimate than did control subjects. In addition, the CHD risk estimate was greatest in HIV-infected patients who had primary lipoatrophy, compared with those who had either lipohypertrophy or mixed fat redistribution. Therefore, although CHD risk is increased in HIV-infected patients with fat redistribution, the pattern of fat distribution and sex are potential important components in determining the risk in this population.

Fully Differentiated HIV-1 Specific CD8+ T Effector Cells Are More Frequently Detectable in Controlled than in Progressive HIV-1 Infection

Background CD8+ T cells impact control of viral infections by direct elimination of infected cells and secretion of a number of soluble factors. In HIV-1 infection, persistent HIV-1 specific IFN-γ+ CD8+ T cell responses are detected in the setting of disease progression, consistent with functional impairment in vivo. Recent data suggest that impaired maturation, as defined by the lineage markers CD45RA and CCR7, may contribute to a lack of immune control by these responses. Methodology/Principal Findings We investigated the maturation phenotype of epitope-specific CD8+ T cell responses directed against HIV-1 in 42 chronically infected, untreated individuals, 22 of whom were “Controllers” (median 1140 RNA copies/ml plasma, range<50 to 2520), and 20 “progressors” of whom had advanced disease and high viral loads (median 135,500 RNA copies/ml plasma, range 12100 to >750000). Evaluation of a mean of 5 epitopes per person revealed that terminally differentiated CD8+ T cells directed against HIV-1 are more often seen in HIV-1 Controllers (16/22; 73%) compared to HIV-1 progressors (7/20; 35%)(p = 0.015), but the maturation state of epitope-specific responses within a given individual was quite variable. Maturation phenotype was independent of the HLA restriction or the specificity of a given CD8+ T cell response and individual epitopes associated with slow disease progression were not more likely to be terminally differentiated. Conclusions/Significance These data indicate that although full maturation of epitope-specific CD8+ T cell responses is associated with viral control, the maturation status of HIV-1 specific CD8+ T cell responses within a given individual are quite heterogeneous, suggesting epitope-specific influences on CD8+ T cell function.

Impaired Hepatitis C Virus-Specific T Cell Responses and Recurrent Hepatitis C Virus in HIV Coinfection

Background Hepatitis C virus (HCV)-specific T cell responses are critical for spontaneous resolution of HCV viremia. Here we examined the effect of a lymphotropic virus, HIV-1, on the ability of coinfected patients to maintain spontaneous control of HCV infection. Methods and Findings We measured T cell responsiveness by lymphoproliferation and interferon-γ ELISPOT in a large cohort of HCV-infected individuals with and without HIV infection. Among 47 HCV/HIV-1-coinfected individuals, spontaneous control of HCV was associated with more frequent HCV-specific lymphoproliferative (LP) responses (35%) compared to coinfected persons who exhibited chronic HCV viremia (7%, p = 0.016), but less frequent compared to HCV controllers who were not HIV infected (86%, p = 0.003). Preservation of HCV-specific LP responses in coinfected individuals was associated with a higher nadir CD4 count (r 2 = 0.45, p < 0.001) and the presence and magnitude of the HCV-specific CD8+ T cell interferon-γ response (p = 0.0014). During long-term follow-up, recurrence of HCV viremia occurred in six of 25 coinfected individuals with prior control of HCV, but in 0 of 16 HIV-1-negative HCV controllers (p = 0.03, log rank test). In these six individuals with recurrent HCV viremia, the magnitude of HCV viremia following recurrence inversely correlated with the CD4 count at time of breakthrough (r = −0.94, p = 0.017). Conclusions These results indicate that HIV infection impairs the immune response to HCV—including in persons who have cleared HCV infection—and that HIV-1-infected individuals with spontaneous control of HCV remain at significant risk for a second episode of HCV viremia. These findings highlight the need for repeat viral RNA testing of apparent controllers of HCV infection in the setting of HIV-1 coinfection and provide a possible explanation for the higher rate of HCV persistence observed in this population.

Ocular syphilis among HIV-infected patients: a systematic analysis of the literature

Background Ocular syphilis among HIV-infected patients continues to be a problem in the highly active antiretroviral therapy (HAART) era. However, outside of case reports or small case series, little is known about the clinical, laboratory, and treatment outcomes of these patients. Objective To examine the literature on HIV-infected patients and determine the results of treatment. Methods Systematic review of cases series and case reports among HIV-infected individuals with ocular syphilis. Reviews, languages other than English and pre-1980 reports were excluded. The effect of CD4 count and virological suppression on clinical manifestations and diagnostic laboratory values was evaluated. Results A total of 101 HIV-infected individuals in case series and case reports were identified. Ocular syphilis led to the HIV diagnosis in 52% of cases, including patients with CD4 count >200 cells/mm3. Posterior uveitis was significantly more common in individuals with CD4 count <200 cells/mm3 (p=0.002). Three patients with confirmed ocular syphilis had negative non-treponemal tests. Ninety-seven per cent of patients with visual impairment improved following intravenous penicillin or ceftriaxone. Conclusions Non-treponemal tests may be negative in HIV-infected patients with ocular syphilis. Ocular syphilis remains an important clinical manifestation that can lead to initial HIV diagnosis.

BK Virus–Associated Hemorrhagic Cystitis in a Human Immunodeficiency Virus–Infected Patient

BK virus-associated hemorrhagic cystitis is a common clinical problem in bone marrow transplant recipients but is considered rare in other immunosuppressed patient populations. We describe a human immunodeficiency virus-infected patient with non-Hodgkins lymphoma in whom BK virus-associated hemorrhagic cystitis developed; viruria was quantitated in urine by immunocytochemistry, and the patient showed no response to cidofovir.

Ocular syphilis among HIV-infected individuals

We describe a human immunodeficiency virus (HIV)-infected individual with ocular manifestations of secondary syphilis. Twelve other cases of HIV-associated ocular syphilis are also presented. Six of 12 individuals had normal cerebrospinal fluid study results, and 3 patients required retreatment within 1.5 years. In patients with HIV infection, clinicians should be vigilant for ocular syphilis despite normal cerebrospinal fluid measures and for syphilis reinfection.

Reversible dementia in a patient with central nervous system escape of human immunodeficiency virus

HIV-associated neurocognitive disorders (HAND) are a group of conditions ranging from asymptomatic neurocognitive impairment to disabling dementia. The clinical spectrum and pathogenesis of these disorders is changing in the era of highly active antiretroviral therapy (HAART). High levels of HIV may exist in the cerebrospinal fluid (CSF) of some patients despite suppression of serum viral loads by HAART. We report a case of a 51-year-old male with profound levels of HIV in the CSF despite low serum levels. Adjusting his HAART regimen based on HIV genotype susceptibility data and a CNS Penetrating Effectiveness (CPE) score resulted in a dramatic improvement in cognitive function. Progressive dementia in this context is a rare but emerging trend and may be reversible.

High-dose daptomycin for the treatment of endocarditis caused by Staphylococcus aureus with intermediate susceptibility to glycopeptides

Endovascular infections caused by meticillin-resistant Staphyococcus aureus (MRSA) with reduced susceptibility to vancomycin epresent a serious clinical challenge, especially when associated ith resistance to alternative antibiotic agents. Here we describe n 84-year-old man who was referred to Massachusetts General ospital (Boston, MA) after developing high-grade bacteraemia and itral valve endocarditis caused by MRSA. Despite early treatment ith vancomycin (trough levels >12 g/mL) at an outside hospital, e remained febrile and daily blood cultures grew MRSA for 8 days. n admission to our hospital, daptomycin (6 mg/kg) was substiuted for vancomycin but his blood cultures remained positive. A ransthoracic echocardiogram showed a 3.5 cm × 1.5 cm vegetation n his mitral valve with indirect signs suggestive of a paravalvular bscess. Because of worsening clinical status, ongoing bacteraemia or 12 days and no surgical treatment options, the patient’s daptoycin dose was increased to 12 mg/kg (administered once daily), nd rifampicin was added at a dose of 300 mg twice daily. With this egimen, the patient’s blood cultures became sterile within 72 h nd no significant biochemical or clinical toxicities were observed. is blood cultures remained sterile for the next 14 days of therapy, efore active medical management was discontinued and comfort easures were initiated. Retrospective investigation of the MRSA isolated at the outside ospital prior to daptomycin treatment revealed two morphologcally distinct colonies. One was fully susceptible to vancomycin nd daptomycin, with minimum inhibitory concentrations (MICs) f <0.5 g/mL for both agents as determined by microdilution assay. owever, similar testing of the second colony revealed MICs of g/mL for both vancomycin and daptomycin. Further testing by test using brain–heart infusion (BHI) agar and a 2.0 McFarland noculum after 24 h/48 h showed MICs of 4/4 for vancomycin and /8 for teicoplanin, suspicious of but not meeting definitive criteria or a heterogeneous glycopeptide-intermediate S. aureus (hGISA) opulation [1,2]. Interestingly, the organisms isolated from the atient’s last positive blood culture at our hospital had become ore resistant to daptomycin (daptomycin microdilution MICs of g/mL and 4 g/mL for the first and second colony, respectively), nd both colony types had vancomycin MICs of 2 g/mL. Etest on HI agar with a 2.0 McFarland inoculum at 24 h/48 h revealed MICs f 4/4 for vancomycin and 14/>32 for teicoplanin, consistent with GISA [1]. This case illustrates the rapid evolution of a highly resistant GISA organism in the setting of endocarditis and a paravalvuar abscess for which no surgical drainage could be performed. nterestingly, reduced susceptibility to daptomycin had already merged in one of the patient’s bacterial colonies before expoAntimicrobial Agents 35 (2010) 93–99

Managing Symptomatic Drug-Induced Liver Injury in HIV—Hepatitis C Virus—Coinfected Patients: A Role for Interferon

BACKGROUND Human immunodeficiency virus (HIV)-infected patients with hepatitis C virus (HCV) coinfection are at increased risk for drug-induced liver injury (DILI) compared with patients with HIV infection alone. The mechanism underlying this observation is unknown. We hypothesized that interferon (IFN) would induce biochemical improvement through its anti-inflammatory properties and thereby facilitate the reintroduction of antiretroviral therapy (ART) in patients with DILI. METHODS Patients with symptomatic DILI were referred for evaluation; biopsy of a liver sample was performed for all patients, except 1 with clinical cirrhosis. RESULTS Twelve patients with acquired immunodeficiency syndrome and symptomatic grade 3/4 hepatotoxicity received treatment with IFN and ribavirin (RBV). Seven of these patients had a history of recurrent DILI. The mean baseline CD4(+) T cell counts and HIV RNA levels were 124 cells/mm(3) and 115,369 copies/mL, respectively. Biopsies of liver samples demonstrated significant necroinflammation (mean grade, 10.3) and fibrosis (mean stage, 2.9). Three patients continued to receive ART when they began treatment with IFN-RBV; 9 reinitiated ART within an average of 12 weeks (range, 4-20 weeks) of HCV treatment initiation. All patients attained marked improvement in aminotransferases and continued to receive ART treatment during a mean follow-up regimen of 26.5 months, with subsequent virologic suppression and immunologic reconstitution (mean CD4(+) cell count increase, 251/mm(3)). However, only 1 patient maintained HCV suppression after completion of treatment with IFN-RBV. CONCLUSIONS In patients with symptomatic DILI, treatment with IFN-ribavirin (RBV) led to decreases in aminotransferase levels, which enabled the reinitiation of ART. The beneficial effects of IFN-based therapy may be modulated through the suppression of proinflammatory cytokines, even in virologic nonresponders. Herein, we propose a novel mechanism for DILI, whereby HCV- and HIV-associated inflammatory mediators induce liver injury synergistically.