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Excerpt
Current guidelines recommend that treatment for disseminated MAC disease should continue at full therapeutic doses for life [3]. Treatment of MAC generally requires the use of at least two drugs, most commonly clarithromycin in combination with ethambutol, although rifabutin continues to be widely used as a third agent. Clarithromycin and rifabutin are primarily metabolized via cytochrome P450 isozyme 3A4 (CYP3A4), which is also responsible for metabolism of the approved protease inhibitors. Significant drug interactions have been reported with both clarithromycin and rifabutin with protease inhibitors.
Clarithromycin, a competitive inhibitor of CYP3A4, increases levels of saquinavir (1.5-fold). Ritonavir and indinavir are not affected but increase clarithromycin levels by around 77 and 50%, respectively [4]. It is not currently known whether dosage adjustments are required with this interaction. No data on nelfinavir with clarithromycin have been reported.
Rifabutin levels are significantly increased by ritonavir, increasing the risk of rifabutin-associated uveitis. Rifabutin, an inducer of CYP3A4, lowers exposure to saquinavir hard gel, and therefore coadministration is not recommended. This agent has a two–way interaction with both indinavir and nelfinavir: when indinavir exposure is reduced by 34%, rifabutin exposure increases two–threefold, and when nelfinavir exposure is reduced by 32%, rifabutin exposure increases 207%. The rifabutin dose should, therefore, be reduced to 150 mg every day when given with these protease inhibitors [4,5] (Viracept, prescription information, Agouron, La Jolla, California, USA). Importantly, no three-way interaction studies have been performed. Therefore, guidelines for coadministering protease inhibitors with persons requiring anti-MAC treatment do not exist. Coadministration risks both suboptimal protease inhibitor exposure and hence a reduced antiviral effect, and either lower or higher exposure to anti-MAC drugs with the risk of subtherapeutic effect or toxicity. Additionally, anti-MAC therapy adds substantially to the pill load and complexity of treatment regimens.
There are limited data available on the rates of recurrence of disseminated MAC infection once treatment has been discontinued. However, reports have suggested that patients with disseminated MAC have a significantly shortened survival [6,7].
The use of highly active antiretroviral therapy (HAART) may substantially reduce the risk of developing MAC bacteraemia in those patients with low CD4 cell counts [8] and is associated with a reduced risk of clinical disease progression and death [9,10]. Until the role of HAART in the prevention of MAC is known, clinicians treating patients with disseminated MAC are left with the choice of either stopping anti-MAC treatment and risking recurrence, or continuing full treatment and risking drug interactions.
Azithromycin is a macrolide antibiotic with a long plasma and leukocyte half-life and potent activity against most clinical MAC isolates. It is neither an inducer nor an inhibitor of cytochrome P450 isozymes [11] and no significant interactions with antiretroviral agents have been reported [4]. Weekly azithromycin has been shown to be an effective and convenient agent for primary prophylaxis against disseminated MAC in HIV-positive patients [12], although its use as a secondary prophylaxis has not been investigated.
This retrospective analysis included all patients at the Chelsea and Westminster Hospital with disseminated MAC infection, treated for a minimum 6 months and with clinically quiescent disease, who were offered secondary prophylaxis with azithromycin (1250 mg weekly).
