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Michael D Hughes

Publications and source records attributed to Michael D Hughes.

10 recordsLinked to original sources
PubMed2026

Effect of inhaled interferon-β1a on SARS-CoV-2 diversity and evolution.

Interferon resistance has been implicated in SARS-CoV-2 escape from innate immunity, but exogenous interferon's impact on viral evolution and diversity is unknown. SNG001, an inhaled interferon-β1a treatment, was evaluated in the ACTIV-2/A5401 randomized controlled trial of therapeutics for COVID-19. We measured viral kinetics and performed whole-genome sequencing on longitudinal nasal swabs collected from ACTIV-2 participants who received either SNG001 or placebo to assess viral sequence diversity. No difference in nasal viral load decay was detected between study arms when stratifying by SARS-CoV-2 variant or by viral culture conversion. Compared to placebo participants, the SNG001-treated participants displayed significantly lower nonsynonymous amino acid average pairwise distance, indicating lower sequence diversity. Similarly, SNG001-treated individuals also developed numerically fewer nonsynonymous mutations during their infection in ORF1a, ORF1b, Spike, and Nucleocapsid. No specific emerging SARS-CoV-2 nonsynonymous amino acid changes indicating signatures of viral escape were enriched in those receiving SNG001. These in vivo data provide an intriguing signal that exogenous interferon-β1a may restrict SARS-CoV-2 viral diversity and add to growing evidence that interferon levels play a critical role in antiviral responses during COVID-19.IMPORTANCESARS-CoV-2 encodes several genes which can antagonize the interferon signaling cascade, preventing it from activating antiviral responses and thereby facilitating viral establishment and dissemination. It is unknown how the administration of exogenous interferon might affect viral evolution and immune escape. ACTIV-2/A5401 represents a unique opportunity to study the virologic effects of interferon treatment in a rigorous randomized, placebo-controlled clinical trial setting. Our characterization of longitudinal nasal samples shows that interferon-treated individuals had lower viral diversity and no evidence of viral escape mutations.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04518410.

Humans↗
PubMed2003

Delayed onset of pubertal development in children and adolescents with perinatally acquired HIV infection.

OBJECTIVE: To examine whether greater severity of HIV infection is associated with delayed initiation of pubertal development among perinatally HIV-infected children, and to compare sexual maturation of perinatally HIV-infected children with children in the general US population using the National Health and Nutrition Examination Survey III. METHODS: In a prospective cohort study, the authors studied 983 HIV-infected children aged 6 to 18 years, who had Tanner stage assessed on at least two occasions between 1995 and 2000. Analyses were conducted separately for girls and boys to identify factors associated with onset of puberty or adrenarche (progression beyond Tanner stage 1). RESULTS: Among children who were in Tanner stage 1 at their first assessment, 185 of 413 (45%) girls and 144 of 434 (33%) boys entered puberty during the observation period. In multivariate longitudinal regression analyses adjusted for age, race/ethnicity, time interval between study visits, and other clinical factors, girls with severe immunosuppression (CD4% <15) were significantly less likely to enter adrenarche (odds ratio [OR], 0.48; 95% confidence interval [CI], 0.29-0.83) and puberty (OR, 0.57; 95% CI, 0.33-0.96) compared with girls who were not immunosuppressed (CD4% > or =25). For boys, those with severe immunosuppression were significantly less likely to enter adrenarche (OR, 0.52; 95% CI, 0.28-0.96) and tended to be less likely to begin puberty (OR, 0.69; 95% CI, 0.39-1.22) compared with boys who were not immunosuppressed. Qualitative comparisons suggested that HIV-infected children may experience delayed puberty and adrenarche compared with similarly aged children in the general US population. CONCLUSIONS: Immunosuppression was associated with delayed pubertal onset in perinatally HIV-infected children. Further studies of perinatally HIV-infected and uninfected children are needed to better quantify the delay in pubertal onset and to compare the pace of pubertal maturation.

Adolescent↗
PubMed2002

Subtle decreases in stavudine phenotypic susceptibility predict poor virologic response to stavudine monotherapy in zidovudine-experienced patients.

To identify the level of phenotypic susceptibility for stavudine (d4T) that is associated with a diminished virologic response to d4T therapy, phenotyping was performed on archived baseline HIV isolates from 26 subjects who received d4T monotherapy in AIDS Clinical Trials Group (ACTG) 302 who had received >3 years of prior zidovudine (ZDV) monotherapy. Seven of 26 subjects achieved a virologic response of >0.3-log10 copies/mL reduction in plasma HIV RNA after 8 weeks of d4T. Responders had lower fold changes in susceptibility to d4T (1.0 vs. 1.6, p=.003), lower baseline viral loads (4.26 vs. 4.74 log10 copies/mL, p=.004), and fewer thymidine analog mutations (TAMS) (1 vs. 2, p=.059). Lower baseline d4T fold change in susceptibility predicted greater reductions in HIV RNA from baseline to week 8 after adjusting for baseline HIV RNA, ZDV fold change in susceptibility, and number of TAMS. Using the same phenotypic assay, drug susceptibility among 240 antiretroviral-naive patients found all HIV isolates to have d4T susceptibility <or=1.4-fold change. Using <or=1.4 as the d4T cutoff, the positive predictive value for a virologic response in this study was 44%, and the negative predictive value was 100%. d4T susceptibility greater than 1.4-fold change was associated with failure to achieve significant viral load reduction after 8 weeks of d4T monotherapy.

Adult↗
PubMed2002

Antiretroviral therapy during pregnancy and the risk of an adverse outcome.

BACKGROUND: Some studies suggest that combination antiretroviral therapy in pregnant women with human immunodeficiency virus type 1 (HIV-1) infection increases the risk of premature birth and other adverse outcomes of pregnancy. METHODS: We studied pregnant women with HIV-1 infection who were enrolled in seven clinical studies and delivered their infants from 1990 through 1998. The cohort comprised 2123 women who received antiretroviral therapy during pregnancy (monotherapy in 1590, combination therapy without protease inhibitors in 396, and combination therapy with protease inhibitors in 137) and 1143 women who did not receive antiretroviral therapy. RESULTS: After standardization for the CD4+ cell count and use or nonuse of tobacco, alcohol, and illicit drugs, the rate of premature delivery (<37 weeks of gestation) was similar among the women who received antiretroviral therapy and those who did not (16 percent and 17 percent, respectively); the rate of low birth weight (<2500 g) was 16 percent among the infants born to both groups; and the rate of very low birth weight (<1500 g) was 2 percent for the group that received antiretroviral therapy and 1 percent for the group that did not. The rates of low Apgar scores (<7) and stillbirth were also similar or the same in the two groups. After adjustment for multiple risk factors, combination antiretroviral therapy was not associated with an increased risk of premature delivery as compared with monotherapy (odds ratio, 1.08; 95 percent confidence interval, 0.71 to 1.62) or delivery of an infant with low birth weight (odds ratio, 1.03; 95 percent confidence interval, 0.64 to 1.63). Seven of the women who received combination therapy with protease inhibitors (5 percent) had infants with very low birth weight, as compared with nine women who received combination therapy without protease inhibitors (2 percent) (adjusted odds ratio, 3.56; 95 percent confidence interval, 1.04 to 12.19). CONCLUSIONS: As compared with no antiretroviral therapy or monotherapy, combination therapy for HIV-1 infection in pregnant women is not associated with increased rates of premature delivery or with low birth weight, low Apgar scores, or stillbirth in their infants. The association between combination therapy with protease inhibitors and an increased risk of very low birth weight requires confirmation.

Adolescent↗
PubMed2002

Is severity of necrotizing pancreatitis increased in extended necrosis and infected necrosis?

INTRODUCTION: We previously reported that organ failure occurs in 50% of patients with necrotizing pancreatitis, that extended pancreatic necrosis (greater than 50% necrosis) is not associated with an increased prevalence of organ failure or infected necrosis, and that the prevalence of organ failure is similar in sterile necrosis and infected necrosis. AIMS To analyze these relations in a larger group of patients and to evaluate other factors that might have prognostic significance. METHODOLOGY: We reviewed 1,110 consecutive cases of acute pancreatitis between January 1, 1995, and January 1, 2000. Necrosis was documented by contrast-enhanced CT. A value less than 0.05 was considered significant. RESULTS: Ninety-nine patients (9%) had necrotizing pancreatitis; 52% had organ failure. Patients with extended pancreatic necrosis did not have increased prevalence of organ failure or infected necrosis but did have an increased need for intubation and an increased mortality rate associated with multiple organ failure. Patients with infected necrosis did not have an increased prevalence of organ failure but did have a marginally increased prevalence of multiple organ failure and increased need for intubation. Overall mortality was 14% and was markedly increased among patients with organ failure at admission (47%) and among patients who had multiple organ failure during the hospitalization (49%). CONCLUSION: Although severity of necrotizing pancreatitis was somewhat increased in extended pancreatic necrosis and infected necrosis, mortality was more strongly linked to organ failure at admission and multiple organ failure during hospitalization.

Female↗
PubMed2002

Detection of replication-competent human immunodeficiency virus type 1 (HIV-1) in cultures from patients with levels of HIV-1 RNA in plasma suppressed to less than 500 or 50 copies per milliliter.

We determined the frequency with which human immunodeficiency virus (HIV) peripheral blood mononuclear cell cultures convert from positive to negative in subjects enrolled in a substudy of AIDS Clinical Trials Group (ACTG) 320, which compared the efficacy of treatment with a combination of indinavir, zidovudine, and lamivudine (indinavir arm) to that of a combination of zidovudine and lamivudine (dual-nucleoside arm). All subjects included for study had positive baseline HIV cultures. Cultures were performed in real time with 10(7) fresh patient peripheral blood mononuclear cells, using the ACTG consensus method. We found lower rates of positive HIV cultures in the indinavir treatment arm than in the dual-nucleoside treatment arm (64 versus 96% at week 24, P < 0.001). Within the indinavir arm of the study, we found that positive cultures were less likely to occur in samples with a plasma HIV type 1 (HIV-1) RNA level of <500 copies/ml than in those with a level of >or=500 copies/ml (44 versus 90%, P < 0.001). In addition, HIV cultures from samples with HIV-1 RNA levels of >or=500 copies/ml turned positive 8.5 days earlier, on average, than those from samples with levels of <500 copies/ml (P < 0.001). However, 38% of samples with plasma RNA levels of <50 copies/ml still were positive for HIV by culture. Thus, the rates of HIV isolation by standard culture procedures decrease as the plasma viral load decreases below 1,000 copies/ml; however, HIV isolates were still obtained from a substantial proportion of subjects with RNA levels of <50 copies/ml. The delay in the time required for HIV cultures to turn positive should be considered when attempting to obtain an HIV isolate from patients with suppression of plasma viral load.

Adult↗
PubMed2002

Can fluid resuscitation prevent pancreatic necrosis in severe acute pancreatitis?

BACKGROUND/AIMS: In previous studies, we have demonstrated that hemoconcentration was an early marker for necrotizing pancreatitis. The aim of the present study was to determine whether fluid resuscitation could prevent pancreatic necrosis among patients with hemoconcentration at the time of admission. METHODS: Data was pooled from the prior two studies of all patients with necrotizing pancreatitis and interstitial pancreatitis with a hematocrit of > or = 44 on admission. Hematocrit values in necrotizing pancreatitis and interstitial pancreatitis were compared at admission and at 24 h. Statistical analyses were performed using the Wilcoxon rank-sum test. RESULTS: A total of 39 patients satisfied our inclusion criteria, 28 with necrotizing pancreatitis and 11 with interstitial pancreatitis. Patients with necrotizing pancreatitis presented earlier than patients with interstitial pancreatitis (median 18 vs. 38 h, respectively) (p = 0.005). There was no significant difference between the intergroup median hematocrits on admission and at 24 h. All patients with hematocrits that failed to decrease at 24 h developed necrotizing pancreatitis (12/28 with necrotizing pancreatitis vs. 0/11 with interstitial pancreatitis) (p = 0.009). There was no significant difference at 24 h in rehydration among the three groups: 4.0 liters among the 12 patients with necrotizing pancreatitis whose hematocrits increased and 4.5 liters among the 16 whose hematocrits decreased at 24 h, and 4.1 liters among the 11 patients with interstitial pancreatitis (p = 0.81). CONCLUSION: Patients who presented early were more likely to have necrotizing pancreatitis than interstitial pancreatitis. While fluid resuscitation was not shown to prevent pancreatic necrosis, all patients with inadequate fluid resuscitation as evidenced by persistence of hemoconcentration at 24 h developed necrotizing pancreatitis.

Acute Disease↗
PubMed2002

Osteonecrosis of the hip (Legg-Calvé-Perthes disease) in human immunodeficiency virus-infected children.

OBJECTIVE: Osteonecrosis of the hip has been reported in human immunodeficiency virus (HIV)-infected adults; whether this is related to HIV infection or its treatment is unknown. There has been 1 report of osteonecrosis among HIV-infected children. Specifically, avascular necrosis of the hip consistent with Legg-Calvé-Perthes disease (LCPD) was reported in 3 HIV-infected children with AIDS from Spain in 1992. We evaluated the prevalence and incidence of LCPD, the pediatric equivalent of adult osteonecrosis of the hip, in HIV-infected children participating in a prospective cohort study of long-term outcomes in HIV-infected and HIV-exposed children-Pediatric AIDS Clinical Trials Group (PACTG) protocol 219. METHODS: PACTG 219 enrolled 2014 HIV-infected and 849 HIV-exposed, uninfected children between April 1993 and September 2000. Children had periodic examinations with collection of clinical and laboratory data. The database was reviewed for reports of LCPD and other bone disorders. A prevalent case was defined as LCPD diagnosis preceding PACTG 219 enrollment and an incident case had to have occurred between enrollment and September 2000. A case-control study (matching on age, gender, and race/ethnicity, which are known to be associated with risk of LCPD and HIV infection status) was performed to investigate factors possibly associated with LCPD. RESULTS: Six cases of LCPD (4 prevalent cases reported at study entry; 2 diagnosed during 5837 person-years of follow-up) were observed; LCPD was seen only in children with perinatal HIV infection. LCPD prevalence was 199 per 100 000 compared with an estimated general pediatric population prevalence of 23 per 100 000. Based on age-adjusted general population rates, the expected number of prevalent cases at PACTG 219 study entry would have been 0.44; the age-adjusted LCPD prevalence rate ratio was 9.0 (95% confidence interval [CI]: 8.3-9.7) for HIV-infected children compared with the general population. LCPD incidence was 34 per 100 000 person-years (95% CI: 0.42-124) compared with the estimated general population incidence of 6 per 100 000 person-years (95% CI: 5-7). Based on age-adjusted general population rates, the expected incidence of LCPD in PACTG 219 would have been 0.42; the age-adjusted relative risk of LCPD in HIV-infected PACTG 219 children was 4.8 (95% CI: 0.56-10.4). No cases were observed in uninfected children during 1919 person-years of follow-up on PACTG 219; the age-adjusted expected number of cases was 0.09. Median onset age was 7 years; 67% were of Hispanic or black race/ethnicity and 33% were female. Four of the 6 LCPD cases had received antiretroviral therapy before diagnosis; treatment was primarily with nucleoside reverse transcriptase inhibitors, and 2 had received protease inhibitors. Three of the LCPD cases had corticosteroid exposure before the diagnosis, but only 1 child had systemic exposure and the remaining 2 had topical exposure exclusively. In the case-control study, antiretroviral and corticosteroid therapy, CD4 cell percentage, birth weight, height for age and gender percentile, and triglyceride levels were not significantly associated with LCPD. However, the case-control study had limited power to evaluate possible associations. CONCLUSION: Similar to HIV-infected adults, children with perinatal HIV infection have an increased risk for osteonecrosis of the hip, and clinicians should be alert to this diagnosis when HIV-infected children present with limp or hip pain. Whether LCPD is attributable to HIV infection itself, HIV-associated complications that could predispose to hypercoagulopathy, HIV-related therapies, or to the growth abnormalities in HIV-infected children is unknown and deserves additional evaluation.

Adrenal Cortex Hormones↗
PubMed2002

The prevalence of pain in pediatric human immunodeficiency virus/acquired immunodeficiency syndrome as reported by participants in the Pediatric Late Outcomes Study (PACTG 219).

OBJECTIVES: As the life expectancy of children with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) increases, quality-of-life outcomes are of increasing concern. The prevalence of pain in adults with AIDS ranges from 40% to 60%, depending on stage of illness. There is limited research concerning pain in HIV-infected children and youth. DESIGN: The General Health Assessment for Children was administered to caregivers of HIV-infected children and youth enrolled in the Pediatric Late Outcomes Study (PACTG 219), a prospective cohort study. Pain is assessed over the previous month with 7 questions. For the purpose of this analysis, we defined pain as the presence of pain of at least moderate intensity. Participants were observed from January 1, 1996, to December 31, 1999. RESULTS: A total of 985 HIV-positive participants had a baseline pain evaluation in 1995. The prevalence of pain remained relatively constant during each year of observation, averaging 20%. Lower CD4+ T-lymphocyte percentage, female gender, and an HIV/AIDS-related diagnosis were highly associated with an increased risk of reported pain. Pain was also independently associated with increased risk of death. After adjusting for CD4 percentage, use of combination therapy including protease inhibitors, comorbid diagnoses, and other sociodemographic characteristics, individuals reporting pain were over 5 times more likely to die than those not reporting pain (hazard ratio = 5.07; 95% confidence interval = 3.23-7.95). CONCLUSIONS: Pain is a frequently encountered symptom in children and youth with HIV disease and is also associated with increased mortality. These findings emphasize the importance of pain management in this population.

Acquired Immunodeficiency Syndrome↗