Tuberculosis and risk of acute myocardial infarction: a propensity score-matched analysis.

Several pathogens have been associated with increased cardiovascular disease (CVD) risk. Whether this occurs with Mycobacterium tuberculosis infection is unclear. We assessed if tuberculosis disease increased the risk of acute myocardial infarction (AMI). We identified patients with tuberculosis index claims from a large de-identified database of ~15 million adults enrolled in a U.S. commercial insurance policy between 2008 and 2010. Tuberculosis patients were 1:1 matched to patients without tuberculosis claims using propensity scores. We compared the occurrence of index AMI claims between the tuberculosis and non-tuberculosis cohorts using Kaplan-Meier curves and Cox Proportional Hazard models. Data on 2026 patients with tuberculosis and 2026 propensity-matched patients without tuberculosis were included. AMI was more frequent in the tuberculosis cohort compared with the non-tuberculosis cohort, 67 (3·3%) vs. 32 (1·6%) AMI cases, respectively, P < 0·01. Tuberculosis was associated with an increased risk of AMI (adjusted hazard ratio (HR) 1·98, 95% confidence intervals (CI) 1·3-3·0). The results were similar when the analysis was restricted to pulmonary tuberculosis (adjusted HR 2·43, 95% CI 1·5-4·1). Tuberculosis was associated with an increased risk of AMI. CVD risk assessment should be considered in tuberculosis patients. Mechanistic studies of tuberculosis and CVD are warranted.

Effect of low-dose IL-2 immunotherapy on frequency and phenotype of regulatory T cells and NK cells in HIV/HCV-coinfected patients.

We evaluated the effect of low-dose IL-2 therapy (daily 1.2 MIU/m(2), subcutaneously) on the number and phenotype of regulatory T cells (T(regs)) and natural killer (NK) cells in HIV/HCV-coinfected patients taking antiretroviral therapy. The frequency and phenotype of circulating T(regs) (defined as CD3(+) CD4(+) CD25(high) or CD3(+) CD4(+) FOXP3(+)) and NK cells (CD3(-) CD16(+)/CD56(+)) were evaluated at baseline and after 12 weeks of treatment. The expression of CD25, CTLA-4, and granzymes A and B by CD4(+) FOXP3(+) cells, as well as the expression of KIR receptors (NKB1, CD158a, and NKAT2) on NK cells, was evaluated. Low doses of IL-2 resulted in the augmented frequency and absolute number of T(regs) in coinfected individuals. FOXP3 levels per cell as well as augmented CD25 and CTLA-4 expression by T(regs) suggested that IL-2 may lead to both expansion and activation of T(regs), although changes in the proportion of CD4(+) FOXP3(+) cells were not associated with changes in HCV viral load and CD4(+) cells between baseline and week 12. NK cell frequency also increased after IL-2 therapy. Interestingly, the pattern of expression of KIR receptors was changed by IL-2 treatment, since the frequency of NK cells expressing NKB1 augmented whereas the frequency of NK expressing CD158a and NKAT2 decreased.

Osteomyelitis of the skull in early-acquired syphilis: evaluation by MR imaging and CT.

We present an unusual case of acquired secondary syphilis manifesting as osteomyelitis of the skull in a patient with a history of human immunodeficiency virus infection, evaluated by CT, volumetric CT reconstructions, and MR imaging.

Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy.

Changes in fat distribution, dyslipidemia, disordered glucose metabolism, and lactic acidosis have emerged as significant challenges to the treatment of human immunodeficiency virus (HIV) infection. Over the past decade, numerous investigations have been conducted to better define these conditions, identify risk factors associated with their development, and test potential therapeutic interventions. The lack of standardized diagnostic criteria, as well as disparate study populations and research methods, have led to conflicting data regarding the diagnosis and treatment of metabolic and body shape disorders associated with HIV infection. On the basis of a review of the medical literature published and/or data presented before April 2006, we have prepared a guide to assist the clinician in the detection and management of these complications.

HIV protease inhibitor induces fatty acid and sterol biosynthesis in liver and adipose tissues due to the accumulation of activated sterol regulatory element-binding proteins in the nucleus.

The mechanism by which human immunodeficiency virus (HIV) protease inhibitor therapy adversely induces lipodystrophy and hyperlipidemia has not been defined. This study explored the mechanism associated with the adverse effects of the prototype protease inhibitor ritonavir in mice. Ritonavir treatment increased plasma triglyceride and cholesterol levels through increased fatty acid and cholesterol biosynthesis in adipose and liver. Ritonavir treatment also resulted in hepatic steatosis and hepatomegaly. These abnormalities, which were especially pronounced after feeding a Western type high fat diet, were due to ritonavir-induced accumulation of the activated forms of sterol regulatory binding protein (SREBP)-1 and -2 in the nucleus of liver and adipose, resulting in elevated expression of lipid metabolism genes. Interestingly, protease inhibitor treatment did not alter SREBP mRNA levels in these tissues. Thus, the adverse lipid abnormalities associated with protease inhibitor therapy are caused by the constitutive induction of lipid biosynthesis in liver and adipose tissues due to the accumulation of activated SREBP in the nucleus.

Impact of prophylaxis for Mycobacterium avium complex on bacterial infections in patients with advanced human immunodeficiency virus disease.

The epidemiology and natural history of bacterial infections among ambulatory patients with advanced human immunodeficiency virus (HIV) disease has not been well described. In this prospective study, 394 subjects were enrolled and followed at 8-week intervals for a median of 21 months. During follow-up, 164 (42%) of 394 patients developed at least 1 bacterial infection. The most common infections were sinusitis, bacterial pneumonia, skin and soft tissue infection, and bronchitis. Serious bacterial infections (defined as bacterial pneumonia, bacteremia, or deep visceral abscess) were reported by 56 subjects (14%). Female sex, age of <40 years, and Karnofsky score of < or =80 were independent risk factors for bacterial infections. Prophylaxis with clarithromycin, trimethoprim and sulfamethoxazole, or both had significant protective effect. The occurrence of any confirmed bacterial infection was associated with a significantly increased risk of mortality. This study documents that bacterial infections are common among patients with advanced HIV disease, especially among women.

Elevated lactate levels in hospitalized persons with HIV infection.

Lactic acidosis has been described in persons with HIV infection particularly in association with the use of nucleoside reverse transcriptase inhibitors (NRTIs). Little is known about the epidemiology of this problem. We reviewed the records of all HIV-infected adults with elevated lactate levels admitted to Barnes-Jewish hospital from 1996 to 1998. There were 37 patients identified with elevated lactate levels. The annual rate of elevated lactate levels was 22.6, 33.9, and 30.8 per 1,000 admissions in 1996, 1997, and 1998, respectively. The median age of the patients was 40.4 years; median CD4(+) count was 148 cells/mm(3); and the median HIV-1 RNA level was 4,401 copies/ml. The median lactate level was 4.5 mmol/liter (range, 2.2-19 mmol/liter). Twenty-nine patients (78%) had elevated lactate levels at admission. Elevated lactate levels were associated with sepsis (48.7%), pancreatitis (13.5%), liver failure (8.1%), multiorgan failure (8.1%), and other conditions. Five patients had lactic acidosis associated with the use of antiretroviral medications; one patient with unexplained lactic acidosis and four patients with pancreatitis. The mortality rate was 45.9% (17/37). Higher lactate levels were associated with increased mortality. In conclusion, elevated lactate levels were uncommon but not rare in hospitalized patients with HIV infection. Sepsis was the most commonly associated condition and antiretroviral medications were the second most frequently associated factor. There was no significant increase in the annual rate of lactic acidosis during this 3-year period.

In vivo virulence of Candida albicans isolates causing mucosal infections in people infected with the human immunodeficiency virus.

Mucosal candidiasis is common in human immunodeficiency virus (HIV) infection. Susceptibility to such infections may be attributed to reduced host defense mechanisms and/or virulence of the organism. In the present study, we compared the virulence of mucosal Candida albicans isolates from HIV-infected people, with and without fluconazole-refractory infection, in established murine models of systemic and vaginal candidiasis. Compared with the mortality rate ( approximately 70%) after intravenous challenge with 2 virulent reference isolates, challenge with most clinical isolates (66%-77%) resulted in prolonged survival. In contrast, fungal burden induced by intravaginal challenge of nearly all (97%) isolates was similar to that of the virulent controls. There were no differences in in vitro growth rates for any of the isolates, and there was no association between reduced mortality and clinical failure to fluconazole, in vitro antifungal susceptibility, site of infection, or other host factors. These results suggest that virulence of C. albicans is tissue specific and is not a factor in the development of fluconazole-refractory infections in advanced HIV disease.

Amphotericin B oral suspension for fluconazole-refractory oral candidiasis in persons with HIV infection. Adult AIDS Clinical Trials Group Study Team 295.

OBJECTIVE: To determine the efficacy and safety of amphotericin B oral suspension (ABOS) for the treatment of fluconazole refractory oral candidiasis in persons with HIV infection. DESIGN AND SETTING: A prospective, multicenter, open label trial at 25 study centers within the AIDS Clinical Trials Group. PATIENTS AND METHODS: Individuals with diffuse oral candidiasis after 14 days of treatment with 200 mg of fluconazole daily (more than five plaques or a single plaque > 3 cm largest length) were treated with ABOS, 100 mg/ml, 5 ml swish and swallow, four times daily for 14 days. Thereafter incomplete or non-responders received an additional 14 days of therapy and responders received maintenance ABOS twice daily for up to 6 months. Relapses during maintenance ABOS were treated by increasing the dose to four times daily. MAIN OUTCOME MEASURES: To demonstrate an ABOS clinical response rate > 33% and a treatment-limiting toxicity rate < 50%. Clinical response was defined as the absence of mouth pain and the presence of less than five oral plaques, the largest being < 3 cm largest dimension. RESULTS: Fifty-eight subjects with a median age of 39 years and a median CD4 count of 10 x 10(6) cells/l were enrolled. Four subjects were excluded from the analysis because of inadequate follow-up after randomization (n = 3) or the presence of active esophageal disease (n = 1). Of the remaining 54 subjects, 23 (42.6%; 95% lower confidence interval, 31.1%) were classified as responders after 28 days. Five subjects (9%) stopped treatment due to toxicity. Relapse occurred in 16 responders (70%). CONCLUSIONS: Amphotericin B oral suspension is well tolerated but has limited efficacy for the treatment of fluconazole refractory oral candidiasis.

Refractory mucosal candidiasis in advanced human immunodeficiency virus infection.

We conducted a multicenter, prospective study of the risk factors, natural history, and outcome of fluconazole-refractory mucosal candidiasis (FRMC) in 832 persons with advanced human immunodeficiency virus (HIV) infection (median CD4 cell count, 14/mm3) during 1994-1996. FRMC was defined as mucosal candidiasis that failed to resolve despite 14 days of therapy with daily doses (> or =200 mg) of fluconazole. Thirty-six persons (4.3%) had FRMC (35, oral; 1, esophageal), for an incidence of 4.2 per 100 person-years (859.7 total years of follow-up). In a multivariate model, the use of trimethoprim-sulfamethoxazole within 6 months of enrollment (relative risk [RR], 2.39; P=.04) and the use of fluconazole daily or every other day (RR, 5.64; P=.004) were significantly associated with the development of FRMC. The median survival after the development of FRMC was 32.6 weeks. In conclusion, the annual incidence of FRMC was <5%. Refractory candidiasis was a poor prognostic indicator. Daily or every-other-day use of fluconazole was associated with the development of refractory infection.

Rifabutin but not clarithromycin prevents cryptosporidiosis in persons with advanced HIV infection.

BACKGROUND: Macrolides have been reported to be effective for the prevention of cryptosporidiosis in persons with HIV infection. OBJECTIVE: To evaluate the efficacy of clarithromycin and rifabutin for the prevention of cryptosporidiosis in persons with advanced HIV infection. DESIGN: Cross-protocol analysis involving 2288 individuals with a history of a CD4 cell counts of < or = 100 x 10(6) cell/l who were enrolled in two prospective clinical trials to prevent Mycobacterium avium complex (MAC) infection and cytomegalovirus (CMV) end-organ disease. INTERVENTIONS: Clarithromycin 500 mg twice daily, rifabutin 300-450 mg daily, the combination of the two or no MAC prophylaxis. MAIN OUTCOME MEASUREMENT: Laboratory-confirmed cryptosporidiosis. Subjects were analyzed in an intent-to-treat and as-treated manner using time-to-event analyses (Cox proportional hazards models). RESULTS: The median length of follow up was 463 days. The median CD4 count at entry was 29 x 10(6) cell/l (range 0-182). There were 60 cases of cryptosporidiosis during the prospective observational period, with an event rate of 2.2 per 100 person-years. In the intent-to-treat [relative risk (RR) 0.50; 95% confidence interval (CI) 0.26-0.96; P = 0.041 and as-treated (RR 0.42; 95% CI 0.20-0.91; P = 0.03) analyses, rifabutin alone was significantly associated with a lower rate of cryptosporidiosis. Clarithromycin alone was not protective in similar analyses (P = 0.98 and 0.90, respectively). CONCLUSIONS: In doses used to prevent MAC infection, rifabutin but not clarithromycin decreases the risk of developing cryptosporidiosis in persons with advanced HIV infection who are not receiving potent combination antiretroviral therapy.

A pilot study of the management of uncomplicated candidemia with a standardized protocol of amphotericin B.

We evaluated an amphotericin treatment strategy on the basis of duration of candidemia and clinical findings. Patients without neutropenia who had uncomplicated candidemia received 200 mg of amphotericin B over 5-7 days if they had had 1 day of positive cultures (PC group). The clinical cure rate was 93% (95% confidence interval [CI], 77%-99%; n=29 episodes) in the SC group, with no relapses (median follow-up, 272 days). The clinical cure rate was 83% (95% CI, 64%-94%; n=29 episodes) in the PC group, with 1 relapse (4.2%). The results of this pilot study suggest that patients with candidemia may be stratified into risk groups on the basis of the duration of positive blood cultures and other clinical findings. Decisions about the duration of therapy can be made 4-7 days after initiation of treatment. Carefully selected patients with transient uncomplicated candidemia may be safely treated with a short course of amphotericin B. Further prospective validation of this concept should be undertaken particularly to evaluate the impact on low-frequency late complications (e.g., endophthalmitis).

Progressive multifocal leukoencephalopathy in patients with AIDS receiving highly active antiretroviral therapy.

Recent reports suggest that human immunodeficiency virus (HIV)-associated progressive multifocal leukoencephalopathy (PML) may improve with highly active antiretroviral therapy (HAART). We observed three patients who developed PML while receiving HAART. All patients received HAART for 4-11 months and had low plasma levels of HIV-1 RNA before the onset of symptoms of PML. Antiretroviral therapy was changed in two patients, and their plasma HIV-1 RNA levels declined significantly. Despite this virologic response, PML did not improve in these patients. The third patient's HIV-1 RNA level became undetectable while he was receiving HAART, and his symptoms of PML improved after the addition of interferon alpha. Our observations suggest that PML can develop in patients who have shown clinical response to HAART. Furthermore, PML may not improve despite an adequate virologic response to HAART. Definitive therapy is still needed for PML.

Peer-delivered interventions reduce HIV risk behaviors among out-of-treatment drug abusers.

OBJECTIVE: The purpose of this chapter is to describe the results of a randomized study (funded by the National Institute on Drug Abuse [NIDA]) comparing a peer-delivered enhanced intervention to the NIDA standard intervention for reducing human immunodeficiency virus (HIV) risk behaviors. METHODS: Data come from the ongoing St. Louis Each One Teach One (EOTO) study on HIV risk behaviors among out-of-treatment crack cocaine users and injecting drug users (IDUs). The study has a randomized prospective design, and for this chapter, three risk behaviors were analyzed--the frequency of crack cocaine use and the number of sex partners and condom use over the past 30-day period. We report the level of risk at baseline and at the three-month follow-up period to determine the proportion of individuals improving or worsening based on a dichotomous outcome in which remaining at low risk or decreasing moderate or high risk behaviors is considered "improving" and increasing risk behavior or remaining at moderate or high risk is considered "worsening". RESULTS: Overall, 80% of the sample "improved" their crack cocaine use, meaning they maintained at low level or reduced their use. Although both the standard and enhanced intervention groups made substantial improvement in their crack cocaine use, individuals in the enhanced intervention group were statistically more likely to reduce their risk than those assigned to the standard intervention (83% vs. 75%, P < 0.05). As for the number of sex partners, 75% of the overall sample improved; that is, they reduced the number of sex partners or remained abstinent or in a one-partner relationship at baseline and follow-up. There was no statistically significant difference between the enhanced and standard groups (76% vs 73%). Stratified by gender, the results showed a trend toward improvement among women assigned to the enhanced intervention compared with those assigned to the standard. In terms of condom use, the overall sample worsened more than it improved (65% vs. 44%), and no differences were found between the enhanced and standard groups. CONCLUSIONS: These findings show that the use of peers as role models in promoting HIV risk reduction is feasible and effective among out-of-treatment drug abusers, particularly for drug use itself. Condom use was found to be more difficult to change than other behaviors. Possible reasons for this lack of improvement and suggestions for future interventions are given.

Genotypic and phenotypic characterization of Cryptosporidium parvum isolates from people with AIDS.

Genotypic analysis of Cryptosporidium parvum has demonstrated the presence of two subgroups within the species, whereas biochemical and antigenic characterization have shown more heterogeneity. The clinical relevance of these observations is unknown. C. parvum isolates from people with AIDS were studied with respect to parasite genotypes and virulence in cell monolayers and laboratory animals. Ten of 13 oocyst samples had a characteristic human-associated (H) genotype; 3 had a genotype typical of calf-excreted oocysts (C). Virulence in cell culture was mildly or markedly lower in the 5 isolates tested (4 H and 1 C) compared with the GCH1 reference isolate. H isolates did not infect newborn ICR mice, whereas 1 of the 2 C isolates tested did. These findings reinforce the concept of C. parvum genetic subgroupings that correlate to some extent with infectivity and suggest that additional heterogeneity is present within the subgroups.

Cryptosporidium parvum infection of human intestinal xenografts in SCID mice induces production of human tumor necrosis factor alpha and interleukin-8.

The protozoan parasite Cryptosporidium parvum invades intestinal epithelial cells and can cause life-threatening diarrhea in immunocompromised individuals. Despite the clinical importance of this organism, much remains to be learned about the pathogenesis of C. parvum-induced diarrhea. To explore the role of the intestinal inflammatory response in C. parvum disease, using C. parvum oocysts we infected human intestinal xenografts in severe combined immunodeficient (SCID) mice. Seven days after infection, we found levels of human tumor necrosis factor alpha and interleukin-8 in C. parvum-infected human intestinal xenografts that were significantly higher than those seen in uninfected control xenografts. These results demonstrate that human intestinal cells produce proinflammatory cytokines in response to C. parvum infection and establish SCID-HU-INT mice as a model system to study the interactions of C. parvum with the human intestine.