Zidovudine plus sulfamethoxazole–trimethoprim adversely affects B lymphocyte maturation in bone marrow of normal mice

Feola, David J.; Garvy, Beth A.

doi:10.1016/j.intimp.2005.06.011

Cited by 4 publications

(16 citation statements)

References 53 publications

(53 reference statements)

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“…Additionally, our group demonstrated that T-cell expansion and activation were reduced in the TBLNs and in the lungs of B-cell-deficient and CD40-knockout mice in response to Pneumocystis infection (46). These data support the findings of our previous work, which show that ZDV plus SMX-TMP affects only the frequencies of the cell types that mature in the bone marrow (18). This suggests that the CD4 ϩ -cell depletion seen here is directly due to reduced lymphatic B-lymphocyte populations.…”

Section: Discussionsupporting

confidence: 87%

“…Cells that mature in the bone marrow, including B cells, neutrophils, and monocytes, were all affected. These cells undergo a higher apoptosis rate as a result of drug treatment, and this leads to significantly diminished populations by day 14 of exposure (18). B-lymphocyte and monocyte populations in the spleen were also decreased, consistent with the work of other investigators (18,22).…”

supporting

confidence: 87%

“…We and others have previously reported that this drug combination did not affect the peripheral T-cell numbers in the spleen (18,22). Here, in the context of infection, total and activated CD4 ϩ T-cell frequencies were lower in the TBLNs of the animals receiving the combination treatment.…”

Section: Discussionsupporting

confidence: 41%

“…Our previous work demonstrated that ZDV plus SMX-TMP exposure significantly impairs developing B-lymphocyte popu- (18). We have now shown that this toxicity alters the humoral immune response to an infectious challenge, although the overall clearance of the infection was not significantly affected.…”

Section: Discussionmentioning

confidence: 78%

“…We have previously shown that the coadministration of ZDV and SMX-TMP results in the depletion of several cell types from the bone marrow of healthy mice (18). Cells that mature in the bone marrow, including B cells, neutrophils, and monocytes, were all affected.…”

mentioning

confidence: 95%

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Combination Exposure to Zidovudine plus Sulfamethoxazole-Trimethoprim Diminishes B-Lymphocyte Immune Responses toPneumocystis murinaInfection in Healthy Mice

Feola

Garvy

2006

Clin Vaccine Immunol

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We have previously shown that zidovudine plus sulfamethoxazole-trimethoprim exposure decreases immune cell populations in the bone marrow of healthy mice by inducing apoptosis. The hypothesis of the current work was that this toxicity would have an adverse impact on the immune response. To determine this, BALB/c mice were treated with zidovudine, sulfamethoxazole-trimethoprim, the combination of both drugs, or vehicle only (control) via oral gavage for 21 days. On day 4 after dosing completion, the mice were infected intratracheally with 1 ؋ 10 7 Pneumocystis murina organisms. Immune cell populations (in lung digest, bronchoalveolar lavage fluid, tracheobronchial lymph node, and bone marrow samples), the lung Pneumocystis burden, and serum Pneumocystis-specific antibody titers were determined at days 6, 10, and 20 postinfection. While total bone marrow cellularity was recovered by day 6 postinfection in the combination exposure group, B-cell numbers did not recover until 10 days postinfection, primarily due to the persistent depletion of the late pre-B-cell phenotype. The numbers of CD4 ؉ and CD8 ؉ T cells, as well as the numbers of total B cells and activated B cells in tracheobronchial lymph nodes, were decreased at days 10 and 20 as a result of zidovudine plus sulfamethoxazole-trimethoprim exposure compared to the numbers in the control group. No significant differences in lung lavage or lung digest cell populations were observed. There was a trend of a delay in Pneumocystis clearance in the combination treatment group, and Pneumocystis-specific serum immunoglobulin G titers were reduced at day 20 postinfection. Together, these data indicate that the combination of zidovudine and sulfamethoxazole-trimethoprim adversely affects the humoral immune response to Pneumocystis.

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Section: Discussionsupporting

confidence: 87%

supporting

confidence: 87%

Section: Discussionsupporting

confidence: 41%

Section: Discussionmentioning

confidence: 78%

mentioning

confidence: 95%

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Combination Exposure to Zidovudine plus Sulfamethoxazole-Trimethoprim Diminishes B-Lymphocyte Immune Responses toPneumocystis murinaInfection in Healthy Mice

Feola

Garvy

2006

Clin Vaccine Immunol

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Extended prophylaxis with nevirapine and cotrimoxazole among HIV-exposed uninfected infants is well tolerated

Aizire

Fowler

Wang

et al. 2012

Aids

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Objective Nevirapine and cotrimoxazole are associated with hematologic toxicities and skin-rash. Safety of their concurrent use for prophylaxis over extended periods among HIV-exposed uninfected infants has not been previously assessed. Design Secondary data analysis of the ‘HIV Prevention Trials Network-046 protocol’ (version 2.0), a phase-III, randomized, placebo-controlled trial that assessed efficacy and safety of nevirapine prophylaxis against breast milk transmission of HIV-1. Methods Trial infants received 6-month study nevirapine/placebo, and standard-of-care peripartum single-dose nevirapine+/– zidovudine ‘tail’, and cotrimoxazole prophylaxis from 6 weeks through breastfeeding cessation. Adverse events were monitored using United States Division of AIDS Toxicity Tables (2004). Risk of neutropenia, anemia and skin-rash in the cotrimoxazole+nevirapine and the cotrimoxazole+placebo groups were compared using negative-binomial regression. Results Incidence of neutropenia and/or anemia, and skin-rash was highest during the first 6 weeks of life and declined, thereafter, regardless of study group. Time to first adverse event after 6 weeks was similar in cotrimoxazole+nevirapine and cotrimoxazole+placebo groups: hazard ratio (95% confidence interval) was 1.26 (0.96–1.66) for neutropenia and/or anemia (all grades), 1.27 (0.80–2.03) for neutropenia and/or anemia (grade ≥3) and 1.16 (0.46–2.90) for skin-rash (grade ≥2). There were no statistically significant differences in immediate (6 weeks–6 months) and long-term (6–12 months) adverse event risk among infants on cotrimoxazole+nevirapine versus cotrimoxazole+placebo. Conclusion Extended nevirapine and cotrimoxazole prophylaxis through 6 months of age among HIV-exposed uninfected infants did not appear to increase the immediate or long-term risk of neutropenia, anemia or skin-rash. Concurrent use beyond 6 months, however, needs to be evaluated.

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Blunted Humoral Response to Influenza Vaccination in Patients Exposed to Zidovudine plus Trimethoprim‐Sulfamethoxazole

Feola¹,

Garvy²,

Rapp³

et al. 2007

Pharmacotherapy

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Zidovudine plus sulfamethoxazole–trimethoprim adversely affects B lymphocyte maturation in bone marrow of normal mice

Cited by 4 publications

References 53 publications

Combination Exposure to Zidovudine plus Sulfamethoxazole-Trimethoprim Diminishes B-Lymphocyte Immune Responses toPneumocystis murinaInfection in Healthy Mice

Combination Exposure to Zidovudine plus Sulfamethoxazole-Trimethoprim Diminishes B-Lymphocyte Immune Responses toPneumocystis murinaInfection in Healthy Mice

Extended prophylaxis with nevirapine and cotrimoxazole among HIV-exposed uninfected infants is well tolerated

Blunted Humoral Response to Influenza Vaccination in Patients Exposed to Zidovudine plus Trimethoprim‐Sulfamethoxazole

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