BackgroundTo determine if infectious disease events in HIV-infected patients treated with highly active antiretroviral therapy (HAART) are a consequence of the restoration of pathogen-speci®c immune responses, a single-centre retrospective study of all HIV-infected patients commencing HAART prior to 1 July 1997 was undertaken to determine the incidence, characteristics and time of onset of disease episodes in HAART responders (decrease in plasma HIV RNA of > 1 log 10 copies/mL). MethodsBaseline and post-therapy changes in CD4 T-cell counts and HIV RNA were compared in patients with and without disease and delayed-type hypersensitivity responses to mycobacterial antigens were measured in selected patients. ResultsThirty-three of 132 HAART responders (25%) exhibited one or more disease episodes after HAART, related to a pre-existent or subclinical infection by an opportunistic pathogen. Disease episodes were most often related to infections by mycobacteria or herpesviruses but hepatitis C virus (HCV), molluscum contagiosum virus and human papilloma virus were also implicated. They were most common in patients with a baseline CD4 T-cell count of < 50/uL and occurred most often during the ®rst 2 months of therapy and when CD4 T-cell counts were increasing. Mycobacteria-and HCV-related diseases were associated with restoration of pathogen-speci®c immune responses. ConclusionsWe conclude that improved immune function in immunode®cient patients treated with HAART may restore pathogen-speci®c immune responses and cause in¯ammation in tissues infected by those pathogens. Key words: HAART, HIV, immune restorationReceived: 4 June 1999, accepted 13 September 1999 IntroductionWhile the immediate aim of using antiretroviral therapy is suppression of HIV replication, the ultimate aim is restoration or maintenance of protective HIV-speci®c and pathogen-speci®c immune responses. Treatment of immunode®cient patients with highly active antiretroviral therapy (HAART) appears to restore pathogen-speci®c immune responses resulting in prevention or regression of diseases caused by opportunistic pathogens [1]. However, in some patients suppression of HIV replication by antiretroviral therapy and the resultant increase in blood CD4 T-cells is associated with in¯ammation in tissues infected by those pathogens. Thus, disease related to subclinical or pre-existent infections by Mycobacterium avium complex (MAC) [2±4], M. tuberculosis (MTB) [5,6], Bacille Calmette±Guerin (BCG) [7], cytomegalovirus (CMV) [8±10], hepatitis B virus (HBV) [11,12], hepatitis C virus (HCV) [13] immunological response to HAART. Many of these disease episodes were associated with the presence of a pathogenspeci®c immune response and/or more exaggerated inammatory response than is usually present in patients with opportunistic infections. It has therefore been argued that the disease results from the effects of a restored immune response against the pathogen [2±7,10,11,13,14]. However, Michelet et al. have argued that`opportunistic infections' in patients treated...

NRTIs do have an independent contribution to fat wasting, but PI are the predominant influence and may act synergistically with NRTIs. NRTIs appear to predispose individuals to slowly progressive fat loss, which is markedly accelerated when a PI and NRTIs are combined. Of the NRTIs, stavudine leads to an earlier onset of clinically apparent fat wasting compared with zidovudine. Fat wasting associated with NRTI use may be a manifestation of mitochondrial toxicity, which may be exacerbated by PI use.

NRTI therapy is associated with mtDNA depletion and mitochondrial proliferation in adipocytes, consistent with the hypothesis that NRTI-induced mtDNA depletion contributes to the pathogenesis of subcutaneous fat wasting. Morphologic assessment also supports a role for NRTI therapy in inducing adipocyte metabolic dysfunction and cell death.