Although antiretroviral therapy (HAART) has decreased the morbidity and mortality associated with HIV infection, it has not eliminated HIV-related complications, such as opportunistic infections and malignancies. Moreover, new, previously unrecognized complications have been identified in HIV-infected patients receiving HAART, that are a consequence of such therapy or the underlying infection itself. Thus, better understanding of the pathogenesis of these complications, and improvements in their diagnosis and treatment, should lead to improvements in the quality of life of HIV-infected patients. ? Epstein Barr Virus (EBV)-associated primary central nervous system lymphoma (PCNSL) remains a major problem among AIDS patients. The clinical presentation is often clinically indistinguishable from toxoplasmic encephalitis. The method of choice for establishing the definitive diagnosis is brain biopsy. This procedure can be associated with a significant morbidity and mortality, and therefore less invasive means of diagnosing cerebral mass lesions have been studied. ? We have undertaken a study to evaluate an algorithm for the workup of HIV infected patients with focal brain lesions so as to expedite the diagnosis and subsequent treatment of PCNSL, using the combination of EBV detection in the CSF and FDG-PET scanning. Up to one hundred twenty HIV-infected patients with a history of at least one focal brain lesion will be screened for enrollment. All patients will be treated empirically for toxoplasmic encephalitis until an alternative diagnosis is confirmed. Those patients with a positive EBV-PCR in the CSF or a positive FDG-PET scan will undergo immediate brain biopsy. All enrolled patients will be treated concurrently with antiretroviral therapy. Patients identified to have PCNSL will be referred to an NCI Treatment of PCNSL Protocol for further treatment. ? Both HIV infection and antiretroviral nucleoside analogues (nucleoside reverse transcriptase inhibitors or NRTIs) are known to affect mitochondrial DNA content and mitochondrial function. A number of important clinical syndromes observed in HIV-infected persons relate to mitochondrial dysfunction including lactic acidosis, myopathy, cardiomyopathy, pancreatitis, peripheral neuropathy, and possibly lipodystrophy [1, 2]. Fatigue, one of the most prevalent complaints among persons with HIV infection, may also be the result of mitochondrial toxicity, though this has not been clearly established. ? Availability of minimally invasive tests to assess mitochondrial toxicity would greatly facilitate understanding of the contribution of mitochondrial dysfunction to clinical syndromes. Muscle and liver biopsies are currently considered to be the reference standards for the evaluation and diagnosis of mitochondrial toxicity in muscle and liver, but these invasive tests are impractical for routine and repeated evaluations. The recent development of a real-time polymerase chain reaction (PCR) assay to accurately quantify the mtDNA copy numbers per cell in peripheral blood mononuclear cells (PBMCs) may allow non-invasive assessment of mitochondrial toxicity. We have undertaken a pilot study seeks to examine the relationship between fatigue and other clinical parameters and markers of mitochondrial dysfunction. The goals of this study are threefold: 1) to investigate the relationship between subjective fatigue ratings and mitochondrial dysfunction through measurements of mtDNA depletion in skeletal muscle 2) to determine whether there is a relationship between evidence of mitochondrial dysfunction in muscle and evidence of mitochondrial dysfunction in lymphocytes or adipose tissue suggesting that examination of lymphocytes or adipose tissue may be adequate for the accurate diagnosis of mitochondrial dysfunction and 3) to identify genes and proteins as potential biomarkers for fatigue and mitochondrial toxicity. Three groups of participants will be enrolled: HIV positive patients on NRTI-containing and protease-inhibitor sparing regimens (n=30), HIV patients currently taking no antiretroviral medications (n=30) and healthy controls (n=15). HIV patients on NRTIs will be stratified according to their fatigue level (0-3, 4-7 or 8-10). Participants will complete a battery of questionnaires regarding fatigue and undergo muscle and adipose tissue biopsy. ? At present, there are no clear guidelines as to when antiretroviral (ARV) therapy for human immunodeficiency virus (HIV) should be stopped in the setting of elevated liver enzymes. In large part, this is due to a limited understanding of the natural history of ARV-related hepatotoxicity. We have undertaken a pilot study to estimate the prevalence of hepatic fibrosis in a cohort of sixty HIV-infected patients who have chronically elevated transaminases while on ARV therapy in the absence of Hepatitis B (HBV) or C (HCV) coinfection. Liver biopsy specimens will be evaluated for fibrosis by microscopic examination, the current gold standard for assessing the nature and severity of liver disease. Fibrosis, as well as other histopathology, will be measured using a validated scoring system. This study should provide clinically relevant information on the significance of elevated transaminases in HIV-infected patients without co-infection with HCV or HBV.
