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Effects of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of AIDS-associated P. carinii pneumonia.
Abstract
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.
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“Sulfa medications appear to exert selective pressure on Pneumocystis (18), as the DHPS gene is more likely to display mutations in highly conserved regions in patients with PCP who have previously been exposed to sulfa medications (19–25).”
From Dihydropteroate Synthase Gene Mutations in Pneumocystis and Sulfa Resistance (2004) · cites this paper as [20]
In the citing paper
“Nevertheless, seven of the nine studies found that most HIV-infected patients with a diagnosis of PCP who had been prescribed TMP-SMX or dapsone for PCP prophylaxis had Pneumocystis that contained DHPS mutations (range 19%–80%, Table 2) (19–24,30).”
From Dihydropteroate Synthase Gene Mutations in Pneumocystis and Sulfa Resistance (2004) · cites this paper as [20]
In the citing paper
“These DHPS gene mutations were rarely found in clinical isolates before the early 1990s (19,20,22).”
From Dihydropteroate Synthase Gene Mutations in Pneumocystis and Sulfa Resistance (2004) · cites this paper as [20]
In the citing paper
“Several studies have consistently demonstrated a significant association between the use of TMP-SMX or dapsone for PCP prophylaxis in HIV-infected persons and the presence of DHPS gene mutations (Table 2) (19–25,30).”
From Dihydropteroate Synthase Gene Mutations in Pneumocystis and Sulfa Resistance (2004) · cites this paper as [20]
In the citing paper
“In this study, DHPS mutation was the strongest predictor of death, and patients who had Pneumocystis that contained DHPS mutations had a greater than threefold increased risk for death within 3 months compared to patients with the wild-type DHPS, after important mortality cofactors such as age, CD4+/cell count, and arterial oxygen partial pressure (PaO2) were controlled for.”
From Dihydropteroate Synthase Gene Mutations in Pneumocystis and Sulfa Resistance (2004) · cites this paper as [20]
In the citing paper
“DHPS mutation was an independent predictor associated with increased deaths (OR = 3.1, p = 0.01).”
From Dihydropteroate Synthase Gene Mutations in Pneumocystis and Sulfa Resistance (2004) · cites this paper as [20]
In the citing paper
“In fact, 12 (63%) of 19 PCP patients with Pneumocystis that contained DHPS gene mutations responded to PCP treatment with TMP-SMX.”
From Dihydropteroate Synthase Gene Mutations in Pneumocystis and Sulfa Resistance (2004) · cites this paper as [20]
In the citing paper
“In a multivariate analysis, Helweg-Larsen and colleagues found that DHPS mutations were an independent predictor associated with increased death rates (20).”
From Dihydropteroate Synthase Gene Mutations in Pneumocystis and Sulfa Resistance (2004) · cites this paper as [20]
In the citing paper
“19 patients with DHPS mutations were treated with TMP-SMX: 7 died; 12 (63%) responded and survived.”
From Dihydropteroate Synthase Gene Mutations in Pneumocystis and Sulfa Resistance (2004) · cites this paper as [20]
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Metadata
- Authors
- Helweg-Larsen, J., Benfield, T. L., Eugen-Olsen, J., Lundgren, J. D., & Lundgren, B.
- Affiliations
- University of Copenhagen (DK)
- Statens Serum Institut (DK)
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 1999-10
- Volume
- 354
- Issue
- 9187
- Pages
- 1347-1351
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2076316807
- Cited by
- 274
- References
- 30
- Citations by year
- 2026: 3 · 2024: 3 · 2023: 1 · 2022: 5 · 2021: 6 · 2020: 2 · 2019: 2 · 2018: 8 · 2017: 8 · 2016: 9 · 2015: 4 · 2014: 8 · 2013: 5 · 2012: 10
- FWCI
- 18.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Sundhed og Sygdom, Det Frie Forskningsråd
- Topics
- Health Sciences › Medicine › Epidemiology › Pneumocystis jirovecii pneumonia detection and treatment
- Health Sciences › Medicine › Epidemiology › Pneumonia and Respiratory Infections
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Keywords
- Pneumocystis carinii pneumonia, dihydropteroate synthase, dhps mutations, HIV-1 infection, AIDS, survival, mortality, chemoprophylaxis, folate biosynthesis, treatment failure
- MeSH terms
- Adult, Aged, Bronchoalveolar Lavage Fluid, Dihydropteroate Synthase, Drug Resistance, Microbial, Genotype, Humans, Middle Aged, Pneumocystis, Pneumonia, Pneumocystis, Prognosis, Recurrence, Regression Analysis, Sulfamethoxazole, Cohort Studies, HIV-1, Survival Analysis, Polymerase Chain Reaction, AIDS-Related Opportunistic Infections, Point Mutation
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