The effective life of ivermectin on Western Australian sheep farms--a survival analysis.

A mail survey of 235 Western Australian sheep farmers who had performed faecal egg count reduction tests for anthelmintic resistance in 1999 or 2000 was conducted, with some telephone follow-up. A response of 56% was achieved. Resistance to ivermectin, a member of the macrocyclic lactone class of anthelmintics, had developed on 44% of the farms surveyed. We used time to occurrence of resistance to ascertain factors that contributed to extending the time ivermectin remained an effective drench on these farms (median time=10.5 years). This time was significantly longer when farmers implemented more worm control practices on their farms (P=0.003). We developed a multivariable survival model that contained the following main effects: reduced winter drenching frequency, 0-2 flock treatments in 5 years (hazard ratio (HR) 0.52); availability of alternative effective anthelmintic classes on the farm (HR 0.30); always using safe pastures (HR 0.23); and veterinarians as the primary source of worm control advice (HR 0.58). The relationship of these findings to the understanding of anthelmintic resistance is discussed.

Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy.

OBJECTIVE: To determine the prevalence, course and risk factors for hyperlactatemia in HIV-infected patients. DESIGN: A prospective, longitudinal study of venous lactate concentrations over an 18-month period in 349 participants of the Western Australian HIV Cohort Study. RESULTS: In 516 patient-years of observation, two patients experienced severe fulminant lactic acidosis (lactate > 5 mmol/l) and hepatic steatosis attributable to nucleoside analogue reverse transcriptase inhibitors (NRTI). A further five patients with lesser elevations of lactate (2.8-4.1 mmol/l) but with symptoms of nausea or abdominal discomfort and evidence of hepatic steatosis had NRTI therapy revised, with relief of symptoms and a fall in lactate levels. Most remaining patients on highly active antiretroviral therapy (HAART) had mild, chronic, asymptomatic hyperlactatemia, with mean lactate level between 1.5 mmol/l and 3.5 mmol/l most commonly. Longitudinal data was analysed in a non-linear mixed effects growth model which indicated that average lactate levels rose after the start of HAART but tended to stabilise at low-grade elevation, with an average 0.23 mmol/l greater long term level in stavudine users compared with zidovudine users (p < 0.01). A multiple linear regression model showed that the association between stavudine and higher lactate level was not confounded by longer duration of total NRTI exposure. Risk of hyperlactatemia was not significantly associated with use of other NRTIs, protease inhibitors, non-nucleoside analogue reverse transcriptase inhibitors or multiple immunological and virological factors in multivariate analyses. CONCLUSIONS: Chronic, compensated, asymptomatic hyperlactatemia is common in patients taking HAART. Decompensated, life-threatening lactic acidosis/hepatic steatosis is rare. Treatment with stavudine appears to be the predominant risk factor for development of chronic hyperlactatemia.

Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection.

BACKGROUND: Progressive subcutaneous fat wasting, fat accumulation, dyslipidaemia and insulin resistance in HIV-infected patients on antiretroviral therapy has been attributed to the long-term toxicity of HIV protease inhibitors (PI). More recently, fat wasting has been observed in patients who have never taken a PI, implicating an independent effect of nucleoside analogue reverse transcriptase inhibitor (NRTI) therapy. OBJECTIVES: To determine the relative contribution of NRTI and PI, as well as any other factors, to fat wasting in HIV-infected patients. DESIGN: Longitudinal cohort study involving 277 participants of the Western Australian HIV Cohort Study. METHODS: The time to onset of clinically apparent fat wasting in patients receiving different antiretroviral regimens was compared using standardized clinical criteria. Regional fat measured by dual energy X-ray absorptiometry (DEXA) in 161 patients was also compared. The average rate of percentage fat reduction was estimated in 70 patients who had consecutive DEXA scans at approximately 6-monthly intervals. Multiple confounding factors were considered in the analyses. RESULTS: Progressive subcutaneous fat wasting, indistinguishable from that described in PI-treated patients, does occur in PI-naive, NRTI-treated patients. In patients taking triple combination antiretroviral therapy, age (relative risk = 1.052 per year; P < 0.0001), white race (relative risk = 3.9; P = 0.023), longer duration of dual NRTI therapy prior to addition of PI (relative risk = 1.021 per month; P = 0.0046) and increased cumulative time on stavudine-containing regimens compared with time on zidovudine-containing regimens (relative risk = 1.085 per month; P < 0.0001) are associated with increased risk of fat wasting. Stavudine increases the risk of fat wasting by 265% per year compared with zidovudine. However PI therapy is associated with faster progression to clinically apparent wasting compared with dual NRTI therapy without PI. The results of DEXA scanning supports these clinical data and suggest a non-linear decline in fat over time. CONCLUSIONS: 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.

Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy.

BACKGROUND: To determine if infectious disease events in HIV-infected patients treated with highly active antiretroviral therapy (HAART) are a consequence of the restoration of pathogen-specific 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 log10 copies/mL). METHODS: Baseline 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. RESULTS: Thirty-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 first 2 months of therapy and when CD4 T-cell counts were increasing. Mycobacteria- and HCV-related diseases were associated with restoration of pathogen-specific immune responses. CONCLUSIONS: We conclude that improved immune function in immunodeficient patients treated with HAART may restore pathogen-specific immune responses and cause inflammation in tissues infected by those pathogens.