Effects of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of AIDS-associated P. carinii pneumonia

TY - JOUR

T1 - Effects of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of AIDS-associated P. carinii pneumonia

AU - Helweg-Larsen, J

AU - Benfield, Thomas

AU - Eugen-Olsen, Jesper

AU - Lundgren, J D

AU - Lundgren, Bettina

PY - 1999

Y1 - 1999

N2 - BACKGROUND: Sulpha drugs are widely used for the treatment and long-term prophylaxis of Pneumocystis carinii pneumonia (PCP) in HIV-1-infected individuals. Sulpha resistance in many microorganisms is caused by point mutations in dihydropteroate synthase (DHPS), an enzyme that is essential for folate biosynthesis. We assessed whether mutations in the DHPS gene of P. carinii were associated with exposure to sulpha drugs and influenced outcome from PCP. METHODS: We studied bronchoalveolar samples collected in 1989-99 from a prospective cohort of HIV-1-infected patients who had PCP. In 144 patients with 152 episodes of PCP, we analysed portions of DHPS using PCR and direct sequencing. The relation between survival, P. carinii DHPS mutations, and other predictors of treatment failure was assessed by Kaplan-Meier and multivariate Cox regression analysis. FINDINGS: P. carinii DHPS mutations were found in 31 (20.4%) of 152 PCP episodes. 3-month survival was significantly lower in patients infected with mutant P. carinii DHPS strains than in those with wild-type strains (p=0.002). After adjustment for other prognostic variables, presence of DHPS mutations remained the most important predictor of mortality (hazard ratio 3.1 [95% CI 1.2-8.1]). DHPS mutations were significantly more common in patients who had previous exposure to sulpha drugs (18 of 29 [62%]) than in those who had no exposure (13 of 123 [10.5%]; p<0.0001). A significant increase with time in the rate of DHPS mutations (p=0.01 for trend) was closely correlated with the rate of previous or current use of sulpha drugs as chemoprophylaxis. INTERPRETATION: Mutations in DHPS are associated with impaired prognosis in PCP, and may develop as a result of exposure to sulpha drugs.

AB - BACKGROUND: Sulpha drugs are widely used for the treatment and long-term prophylaxis of Pneumocystis carinii pneumonia (PCP) in HIV-1-infected individuals. Sulpha resistance in many microorganisms is caused by point mutations in dihydropteroate synthase (DHPS), an enzyme that is essential for folate biosynthesis. We assessed whether mutations in the DHPS gene of P. carinii were associated with exposure to sulpha drugs and influenced outcome from PCP. METHODS: We studied bronchoalveolar samples collected in 1989-99 from a prospective cohort of HIV-1-infected patients who had PCP. In 144 patients with 152 episodes of PCP, we analysed portions of DHPS using PCR and direct sequencing. The relation between survival, P. carinii DHPS mutations, and other predictors of treatment failure was assessed by Kaplan-Meier and multivariate Cox regression analysis. FINDINGS: P. carinii DHPS mutations were found in 31 (20.4%) of 152 PCP episodes. 3-month survival was significantly lower in patients infected with mutant P. carinii DHPS strains than in those with wild-type strains (p=0.002). After adjustment for other prognostic variables, presence of DHPS mutations remained the most important predictor of mortality (hazard ratio 3.1 [95% CI 1.2-8.1]). DHPS mutations were significantly more common in patients who had previous exposure to sulpha drugs (18 of 29 [62%]) than in those who had no exposure (13 of 123 [10.5%]; p<0.0001). A significant increase with time in the rate of DHPS mutations (p=0.01 for trend) was closely correlated with the rate of previous or current use of sulpha drugs as chemoprophylaxis. INTERPRETATION: Mutations in DHPS are associated with impaired prognosis in PCP, and may develop as a result of exposure to sulpha drugs.

U2 - http://dx.doi.org/10.1016/S0140-6736(99)03320-6

DO - http://dx.doi.org/10.1016/S0140-6736(99)03320-6

M3 - Journal article

SN - 0140-6736

VL - 354

SP - 1347

EP - 1351

JO - Lancet

JF - Lancet

IS - 9187

ER -