Effect of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of P. carinii pneumonia in patients with HIV-1: a prospective study.

Navin, Thomas R; Beard, Charles B; Huang, Laurence; del Rio, Carlos; Lee, Sherline; Pieniazek, Norman J; Carter, Jane L; Le, Thuy; Hightower, Allen; Rimland, David

doi:10.1016/s0140-6736(01)05705-1

Cited by 117Pneumocystis jirovecii pneumonia detection and treatmentPneumonia and Respiratory InfectionsHIV/AIDS drug development and treatment

Effect of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of P. carinii pneumonia in patients with HIV-1: a prospective study.

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Navin, Thomas R, Beard, Charles B, Huang, Laurence, del Rio, Carlos, Lee, Sherline, Pieniazek, Norman J, Carter, Jane L, Le, Thuy +2 more·2001·The Lancet

DOI 10.1016/s0140-6736(01)05705-1

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Abstract

Background Investigators have reported that patients infected with Pneumocystis carinii containing mutations in the DHPS (dihydropteroate synthase) gene have a worse outcome than those infected with P carinii containing wild-type DHPS. We investigated patients with HIV-1 infection and P carinii pneumonia to determine if DHPS mutations were associated with poor outcomes in these patients.Methods We compared presence of mutations at the DHPS locus with survival and response of patients to co-trimoxazole or other drugs.Findings For patients initially given co-trimoxazole, nine (14%) of 66 with DHPS mutant died, compared with nine (25%) of 36 with wild type (risk ratio50.55 [95% CI=0.24-1.25]; p=0.15). Ten (15%) of 66 patients with a DHPS mutant did not respond to treatment, compared with 13 (36%) of 36 patients with the wild type (0.42 [0.20-0.86]; p=0.02). For patients aged 40 years or older, four (14%) of 29 with the mutant and nine (56%) of 16 with the wild type died (0.25 [0.09-0.67]; p=0.005).Interpretation These results, by contrast with those of previous studies, suggest that patients with wild-type P carinii do not have a better outcome than patients with the mutant when given co-trimoxazole. Our results suggest that presence of a DHPS mutation should be only one of several criteria guiding the choice of initial drug treatment of P carinii pneumonia in patients with HIV-1 infection.

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In Navin et al., the TMP-SMX response rate among PCP patients with DHPS mutations (56/66, 85%) was significantly better than the rate for those with DHPS mutations treated with intravenous pentamidine or clindamycin plus primaquine (14/28, 50%).
“This noted TMP-SMX response rate was significantly better than the rate for patients with DHPS mutation who were treated with intravenous pentamidine or clindamycin plus primaquine (14 [50%] of 28) and for patients with the wild-type DHPS who were treated with TMP-SMX (23 [64%] of 36).”
From Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance (2004) · cites this paper as [39]
In Navin et al., the TMP-SMX response rate among PCP patients with DHPS mutations (56/66, 85%) was significantly better than the rate for those with wild-type DHPS treated with TMP-SMX (23/36, 64%).
“This noted TMP-SMX response rate was significantly better than the rate for patients with DHPS mutation who were treated with intravenous pentamidine or clindamycin plus primaquine (14 [50%] of 28) and for patients with the wild-type DHPS who were treated with TMP-SMX (23 [64%] of 36).”
From Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance (2004) · cites this paper as [39]
In Navin et al., 16 (17%) of 94 PCP patients with DHPS mutations died compared to 9 (25%) of 36 PCP patients with wild-type DHPS (p = 0.30).
“Overall, 16 (17%) of 94 PCP patients with DHPS mutations died compared to 9 (25%) of 36 PCP patients with wild-type DHPS (p = 0.30).”
From Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance (2004) · cites this paper as [39]
In Navin et al., there was no association between the presence of DHPS mutations and overall number of deaths at 6 weeks.
“In contrast to these prior two studies, Navin and colleagues found no association between the presence of DHPS mutations and overall number of deaths at 6 weeks, death attributable specifically to PCP, or PCP treatment failure (39).”
From Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance (2004) · cites this paper as [39]
In Navin et al., the three patient groups did not differ in age, CD4-cell count, serum albumin, LDH, or proportion requiring corticosteroids.
“Although these three patient groups did not differ in terms of age, CD4-cell count, serum albumin, serum lactate dehydrogenase (LDH), or proportion who required corticosteroids, no multivariate analysis was performed to determine independent predictors associated with death (or PCP treatment failure).”
From Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance (2004) · cites this paper as [39]

In Navin et al., stratified analyses failed to detect any subsets of PCP patients in whom DHPS mutations were associated with a worse outcome.
“Instead, a series of stratified analyses were performed and failed to detect any subsets of PCP patients in whom DHPS mutations were associated with a worse outcome.”
From Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance (2004) · cites this paper as [39]
In Navin et al., there was no association between the presence of DHPS mutations and PCP treatment failure.
“In contrast to these prior two studies, Navin and colleagues found no association between the presence of DHPS mutations and overall number of deaths at 6 weeks, death attributable specifically to PCP, or PCP treatment failure (39).”
From Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance (2004) · cites this paper as [39]
In Navin et al., 7 (7%) of PCP patients with DHPS mutations died as a result of PCP compared to 4 (11%) with wild-type DHPS.
“Similarly, seven patients (7%) with PCP with DHPS mutations died as a result of PCP compared to four patients (11%) with wild-type DHPS.”
From Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance (2004) · cites this paper as [39]
In Navin et al., no multivariate analysis was performed to determine independent predictors associated with death or PCP treatment failure.
“Although these three patient groups did not differ in terms of age, CD4-cell count, serum albumin, serum lactate dehydrogenase (LDH), or proportion who required corticosteroids, no multivariate analysis was performed to determine independent predictors associated with death (or PCP treatment failure).”
From Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance (2004) · cites this paper as [39]
In Navin et al., there was no association between the presence of DHPS mutations and death attributable specifically to PCP.
“In contrast to these prior two studies, Navin and colleagues found no association between the presence of DHPS mutations and overall number of deaths at 6 weeks, death attributable specifically to PCP, or PCP treatment failure (39).”
From Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance (2004) · cites this paper as [39]
In Navin et al., results were similar when the analysis was restricted to patients who had been treated for at least 7 days with their initial therapy.
“These results were similar when the analysis was restricted to patients who had been treated for at least 7 days with their initial therapy.”
From Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance (2004) · cites this paper as [39]
In Navin et al., among 66 PCP patients with DHPS mutations treated with TMP-SMX, 56 (85%) responded.
“Among the 66 patients with PCP with DHPS mutations who were treated with TMP-SMX, 56 (85%) responded to this treatment.”
From Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance (2004) · cites this paper as [39]

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Authors: Navin, T. R., Beard, C. B., Huang, L., del Rio, C., Lee, S., Pieniazek, N. J., Carter, J. L., Le, T., Hightower, A., & Rimland, D.
Affiliations: Centers for Disease Control and Prevention (US)
San Francisco General Hospital (US)
Emory University (US)
Corresponding author: Navin, Thomas R
ORCID: Huang, Laurence
Hightower, Allen
Venue: The Lancet
Publisher: Elsevier BV
Published: 2001-08
Volume: 358
Issue: 9281
Pages: 545-549
ISSN: 0099-5355 (ISSN-L)
0140-6736
DOI: 10.1016/s0140-6736(01)05705-1
OpenAlex: W1974027540
Cited by: 117
References: 14
Citations by year: 2023: 4 · 2022: 2 · 2021: 4 · 2020: 2 · 2018: 2 · 2017: 4 · 2016: 6 · 2015: 4 · 2014: 6 · 2013: 3 · 2012: 4
FWCI: 7.03
Type: journal article
Language: en
Open access: green
hdl.handle.net
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: The Lancet (publishedVersion)
PubMed (publishedVersion)
DukeSpace (Duke University) (submittedVersion, cc-by-nc-nd)
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, trimethoprim-sulfamethoxazole, sulfonamide resistance, treatment response, survival, drug resistance, antifungal drug selection
MeSH terms: Adult, Anti-Infective Agents, Dapsone, Dihydropteroate Synthase, Drug Resistance, Microbial, Genotype, Humans, Male, Middle Aged, Mutation, Pneumocystis, Pneumonia, Pneumocystis, Prognosis, Prospective Studies, Trimethoprim, HIV-1, Trimethoprim, Sulfamethoxazole Drug Combination, Survival Analysis, AIDS-Related Opportunistic Infections

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Effect of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of P. carinii pneumonia in patients with HIV-1: a prospective study.

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