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Immune restoration following combination antiretroviral therapy (cART) questions the maintenance of prophylaxis among HIV-infected patients with cryptococcosis.To describe the long-term outcome after the diagnosis of cryptococcosis at the cART era.Multicentre cohort of patients with a diagnosis of cryptococcosis between 1996 and 2000, follow-up until December 2002. Comparison with a historical cohort (1990–1994) for survival.Eighty-four French AIDS clinical centres.Two-hundred and forty HIV-infected adult patients at the cART era and 149 at the pre-cART era experiencing a first episode of culture-confirmed cryptococcosis.In the cART era, 82/189 patients surviving more than 3 months after initiation of antifungal therapy had their maintenance therapy interrupted with a subsequent median follow-up of 19 months. Their relapse rate per 100 person-years was 0.9 [95%confidence interval (CI),0.0–2.0]. When considering the whole cART cohort, probability of reaching negative serum cryptococcal antigen was 71% after 48 months of follow-up. A CD4 cell count < 100/μl [relative risk (RR), 5.5; 95% CI, 1.3–22.2], antifungal therapy < 3 months over the past 6 months [RR, 5.0; 95% CI, 1.1–22.3] and serum cryptococcal antigen titre ≥ 1/512 [RR, 3.5; 95% CI, 1.1–10.8] were associated with a higher rate of cryptococcosis relapse. The mortality rate per 100 person-years was 15.3 [95% CI,12.2–18.4] in the cART era versus 63.8 [95% CI,53.0–74.9] in the pre-cART era although early mortality did not differ between the two periods.Overall survival after cryptococcosis has dramatically improved at the cART era. Immune restoration and low serum cryptococcal antigen titres are associated with lower cryptococcosis relapse rates.