Pyomyositis and human immunodeficiency virus infection

Pyomyositis is a bacterial infection of skeletal muscle usually caused by Staphylococcus aureus and characterized by localized muscle pain, swelling, and tenderness. The disease is endemic in the tropics. Though only approximately 50 cases have been reported from the continental United States, pyomyositis has been increasingly recognized here in the last decade. We report two patients with human immunodeficiency virus (HIV) infection and pyomyositis, and review five previously reported cases. Given the predisposition of patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) for infections caused by S aureus, pyomyositis may become increasingly more common in temperate areas.     

Meningioma in four patients with human immunodeficiency virus infection

We describe four patients infected with the human immunodeficiency virus (HIV) who had development of meningiomas. In contrast to those in the general population who have meningiomas, all our patients were young men; the mean age was 40 years (range, 32 to 50). Their risk behavior for HIV was homosexuality (three patients) and intravenous drug use (one patient). The CD4+ cell count in each of the three homosexual men was less than 50/microL and was 280/microL in the drug user. Imaging studies showed enhancing lesions in three of the patients. Although each of these meningiomas could have occurred in otherwise normal young to middle-aged men, we speculate that the meningiomas may have grown in these HIV-infected hosts because of either loss of immune function or dysregulation of cytokines.     

Proteinuria in paediatric patients with human immunodeficiency virus infection

In human immunodeficiency virus (HIV)-infected people kidney disease is as an important cause of morbidity and mortality. Clinical features of kidney damage in HIV-infected patients range from asymptomatic microalbuminuria to nephrotic syndrome. The lack of specific clinical features despite the presence of heavy proteinuria may mask the renal involvement. Indeed, it is important in HIV patients to monitor renal function to early discover a possible kidney injury. After the introduction of antiretroviral therapy, mortality and morbidity associated to HIV-infection have shown a substantial reduction, although a variety of side effects for long-term use of highly active antiretroviral therapy, including renal toxicity, has emerged. Among more than 20 currently available antiretroviral agents, many of them can occasionally cause reversible or irreversible nephrotoxicity. At now, three antiretroviral agents, i.e., indinavir, atazanavir and tenofovir disoproxil fumarate have a well established association with direct nephrotoxicity. This review focuses on major causes of proteinuria and other pathological findings related to kidney disease in HIV-infected children and adolescents.     

Severe tuberculosis in patients with human immunodeficiency virus infection

Tuberculosis has now been well documented as a complication of infection with human immunodeficiency virus (HIV), but no studies concern patients requiring admission to the ICU. We report 12 cases of severe disseminated tuberculosis in patients who were seropositive for HIV. Eight patients had diffuse pulmonary involvement responsible for acute respiratory failure, 7 of whom required mechanical ventilation. Four developed septic shock, and in 3 blood cultures were positive forM. tuberculosis. Four patients had central nervous system involvement, with coma requiring mechanical ventilation 3 times. Rapid diagnosis was permitted in 10 patients by acid-fast smears of pulmonary specimens (8 patients) and/or tissue biopsies (4 patients). Seven patients died despite intensive therapy; autopsy was performed in 4 patients, showing disseminated tuberculosis. On the basis of this report, tuberculosis in HIV infection may present as an overwhelming systemic disease and thus requires an aggressive diagnostic and therapeutic approach.     

Ocular melanoma and human immunodeficiency virus infection

The number of reports of malignant complications of human immunodeficiency virus infections is increasing. Cutaneous melanoma has been previously reported in five patients with human immunodeficiency virus infection, but no cases of ocular melanoma have been documented. We describe the first case of ocular melanoma reported in a patient with human immunodeficiency virus infection.     

Approaches to gene therapy for human immunodeficiency virus infection

Much progress has been made in developing new and more efficient treatments for human immunodeficiency virus (HIV) infection, the cause of acquired immunodeficiency syndrome (AIDS). However, the scope of the HIV epidemic and the limitations of existing treatments necessitate the continued development of novel treatment strategies. Gene therapy is one such forward-looking strategy. Gene therapy approaches for HIV infection include efforts to interfere with viral replication directly by engineering HIV-resistant cells or indirectly by eliminating infected cells from the body, primarily by eliciting a therapeutic immune response to destroy HIV-infected cells. Although the prospect of gene therapy as a routine treatment for HIV infection remains distant, continuous progress is being made, which should also have implications for gene therapy strategies for a variety of other diseases. This article reviews some of the strategies for investigating the feasibility of gene transfer for the treatment of HIV infection.     

Population pharmacokinetics of atazanavir in patients with human immunodeficiency virus infection

Atazanavir (ATV) is a new azapeptide protease inhibitor recently approved and currently used at a fixed dose of either 300 mg once per day (q.d.) in combination with 100 mg ritonavir (RTV) or 400 mg q.d. without boosting. ATV is highly bound to plasma proteins and extensively metabolized by CYP3A4. Since ATV plasma levels are highly variable and seem to be correlated with both viral response and toxicity, dosage individualization based on plasma concentration monitoring might be indicated. This study aimed to assess the ATV pharmacokinetic profile in a target population of HIV patients, to characterize interpatient and intrapatient variability, and to identify covariates that might influence ATV disposition. A population analysis was performed with NONMEM with 574 plasma samples from a cohort of 214 randomly selected patients receiving ATV. A total of 346 randomly collected ATV plasma levels and 19 full concentration-time profiles at steady state were available. The pharmacokinetic parameter estimates were an oral clearance (CL) of 12.9 liters/h (coefficient of variation [CV], 26%), a volume of distribution of 88.3 liters (CV, 29%), an absorption rate constant of 0.405 h(-1) (CV, 122%), and a lag time of 0.88 h. A relative bioavailability value was introduced to account for undercompliance due to infrequent follow-ups (0.81; CV, 45%). Among the covariates tested, only RTV significantly reduced CL by 46%, thereby increasing the ATV elimination half-life from 4.6 h to 8.8 h. The pharmacokinetic parameters of ATV were adequately described by a one-compartment population model. The concomitant use of RTV improved the pharmacokinetic profile. However, the remaining high interpatient variability suggests the possibility of an impact of unmeasured covariates, such as genetic traits or environmental influences. This population pharmacokinetic model, together with therapeutic drug monitoring and Bayesian dosage adaptation, can be helpful in the selection and adaptation of ATV doses.     

Neuromuscular complications of human immunodeficiency virus infection

Neurologic complications of HIV infection are common, and are a significant source of morbidity. The chronic nature of HIV today, the complexity of highly active antiretroviral therapy regimens, and the multiple and diffuse effects of HIV on the nervous system present an exciting diagnostic challenge, in which a systematic, comprehensive approach to diagnosis and treatment is necessary.     

Serologic testing of human immunodeficiency virus infection

This article describes laboratory methods available for testing serum to determine whether a patient is infected with human immunodeficiency virus (HIV). Included is discussion of uses and limitations of the assays, patient counseling, laboratory safety, and interpretation of the test results.     

The neurology of human immunodeficiency virus infection

HIV-infected patients are at markedly increased risk for neurological dysfunction, which may occur at any level of the neuraxis (see Table 1). The most common syndromes--AIDS dementia complex, vacuolar myelopathy, and possibly distal symmetric peripheral neuropathy--appear to be related to HIV infection within the nervous system, rather than due to the immunoincompetence caused by HIV. However, the mechanism(s) by which HIV causes these syndromes, e.g., infecting neurons or oligodendroglia directly, interfering with neurotrophic factors, effecting toxic monokine production, etc., is unknown. Early, albeit incomplete, success with azidothymidine is encouraging. Less commonly, neurological syndromes may be secondary to the immunoincompetence produced by HIV. Many different etiologies--most of which are treatable--have been encountered, but a few of these (cerebral toxoplasmosis, cryptococcal meningitis, primary CNS lymphoma, and progressive multifocal leukoencephalopathy) are responsible for most of the opportunistic complications. Marked differences in symptoms and signs between AIDS patients and immunologically normal patients may complicate recognition of some of these diseases (e.g., herpes simplex encephalitis). Finally, some HIV-associated syndromes, e.g., inflammatory demyelinating polyradiculoneuropathy and retinal microvasculopathy, are of unknown etiology.     

Laboratory diagnosis of human immunodeficiency virus infection

The technical issues relevant to the laboratory diagnosis of human immunodeficiency virus (HIV) infection are dealt with. Performance characteristics of the various HIV diagnostic assays are presented.     

Gene-based immunotherapy for human immunodeficiency virus infection and acquired immunodeficiency syndrome

More than 40 million people are infected with human immunodeficiency virus (HIV), and a successful vaccine is at least a decade away. Although highly active antiretroviral therapy prolongs life, the maintenance of viral latency requires life-long treatment and results in cumulative toxicities and viral escape mutants. Gene therapy offers the promise to cure or prevent progressive HIV infection by interfering with HIV replication and CD4+ cell decline long term in the absence of chronic chemotherapy, and approximately 2 million HIV-infected individuals live in settings where there is sufficient infrastructure to support its application with current technology. Although the development of HIV/AIDS gene therapy has been slow, progress in a number of areas is evident, so that studies to date have significantly advanced the field of gene-based immunotherapy. Advances have helped to define a series of ongoing and planned trials that may shed light on potential mechanisms for the successful clinical gene therapy of HIV.     

Neurologic abnormalities in human immunodeficiency virus infection

Neurologic abnormalities involving the central and peripheral nervous system are common in patients infected with the human immunodeficiency virus (HIV). Evidence of central nervous system infection (cerebrospinal fluid abnormalities) occurs early; however, evidence of central and peripheral nervous system dysfunction usually occurs at later stages. Neurologic manifestations may be due to chronic immunosuppression, direct neurotropic effect of HIV, or medication effects. It is important to recognize that brain and spine imaging studies are highly sensitive in detecting abnormal pathologic processes, but these studies have low specificity for establishing a specific pathologic diagnosis.     

Serum prolactin in human immunodeficiency virus infection

Patients infected with human immunodeficiency virus (HIV) have higher serum prolactin compared to healthy controls but this is controversial. As part of a laboratory audit investigating the interference of macroprolactin in our prolactin assay, we investigated whether low biological activity macroprolactin could account for the increased serum prolactin concentrations observed in HIV infection. We, therefore, compared serum total prolactin and free prolactin in 32 subjects infected with HIV (HIV+ve) with 52 subjects not infected with HIV (HIV-ve). Serum total prolactin concentrations were similar in HIV+ve and HIV-ve patients [median (95% confidence limits); 167.0 (122.4 - 313.8) vs 206.5 (187.8 - 248.4) mU/L respectively]. Serum free prolactin concentrations were lower (p <0.005) in HIV+ve subjects than in HIV-ve subjects [112.0 (91.1-141.8) vs 171.0 (154.5 - 200.9) mU/L respectively; p<0.0005]. These results are consistent with the notion that low biological activity macroprolactin contributes to circulating prolactin concentrations in HIV+ve subjects.     

Pharmacokinetics and safety of levofloxacin in patients with human immunodeficiency virus infection.

Levofloxacin, the bacteriologically active isomer of ofloxacin, has microbiologic activity against many pathogens common in human immunodeficiency virus (HIV)-infected patients, including Mycoplasma species which may be cofactors in the progression of HIV disease. The purpose of this phase I, double-blind, randomized (1:1), placebo-controlled trial was to evaluate the pharmacokinetics and safety of levofloxacin hemihydrate in 10 asymptomatic HIV-infected males. Plasma concentrations by chiral high-performance liquid chromatography (HPLC) were evaluated for 48 h after a single 350-mg oral dose, at morning predose during the multiple-dosing phase, and for 72 h at steady state after a week of 350 mg every 8 h orally. Mean +/- standard deviation levofloxacin pharmacokinetic parameters (by noncompartmental moment method) after multiple dosing were as follows: area under the concentration-time curve, 31.24 +/- 5.60 mg.h/liter; apparent total body clearance, 11.18 +/- 1.76 liters/h; renal clearance, 8.63 +/- 2.82 liters/h; steady-state volume of distribution, 104.10 +/- 12.48 liters; and effective half-life, 6.50 +/- 0.51 h. Single-dose parameters were not significantly different from the multiple-dose parameters, with the exception of peak concentrations in plasma, which were 4.79 +/- 1.00 and 6.92 +/- 1.56 mg/liter for single- and multiple-dose data, respectively. Essentially identical parameter values were obtained from curve-fitting analysis when the entire 13-day plasma concentration profiles of the subjects were analyzed simultaneously by a two-compartmental distribution model. Levofloxacin pharmacokinetics in HIV-infected patients remained linear upon multiple dosing. The dosing regimen studied provides levels in plasma and urine well above those found to be effective in vitro against pathogens common in HIV-infected patients. Levofloxacin was well- tolerated in this group of asymptomatic HIV-infected males: there were no statistically significant differences in adverse effects in the two groups (P = 0.22). Use of placebo control helped to differentiate disease-related adverse effects from those related to the study drug.     

Pharmacokinetics and pharmacodynamics of saquinavir in pediatric patients with human immunodeficiency virus infection

OBJECTIVE: Our objective was to investigate the clinical pharmacologic characteristics of saquinavir given as a soft gelatin capsule, either alone or in combination with nelfinavir, to children and adolescents with human immunodeficiency virus infection. METHODS: The pharmacokinetics of 50 mg/kg saquinavir 3 times a day (tid) alone versus 33 mg/kg saquinavir tid plus 30 mg/kg nelfinavir tid was assessed after single-dose administration and after short- and long-term administration. The single-dose pharmacokinetics of fixed (1200 mg) versus unrestricted weight-adjusted dosing (50 mg/kg) was also investigated. RESULTS: Saquinavir as the sole protease inhibitor resulted in lower saquinavir exposure in children (steady-state geometric mean area under the concentration-time curve from time zero to 24 hours [AUC (0-24 h)], 5790 ng x h/ml; steady-state concentration 8 hours after drug administration [C(8h,SS)], 65 ng/ml) and adolescents [steady-state geometric mean AUC(0-24 h), 5914 ng x h/ml] than that reported in adults treated with 1200 mg tid [steady-state geometric mean AUC(0-24 h), 21,700 ng x h/ml; C(8h,SS), 223 ng/ml]. This finding appeared to be attributable to markedly higher apparent oral clearance, potentially as a result of increased systemic clearance and reduced oral bioavailability. Nelfinavir combined with saquinavir reduced apparent oral clearance, increasing saquinavir exposure in children [steady-state geometric mean AUC(0-24 h), 11,070 ng x h/ml; C(8h,SS), 380 ng/ml] to levels that approach those observed in adults. A significant correlation between average trough concentration and sustained viral load suppression was observed in children. The apparent threshold for maintaining viral load suppression was a mean trough saquinavir concentration above 200 ng/ml. CONCLUSIONS: The pharmacokinetics of saquinavir in children is different from that of adults, and administration of saquinavir alone will not give consistently efficacious plasma levels. The best way of improving saquinavir exposure in children is through combination therapy with other protease inhibitors that inhibit saquinavir metabolism.