First name
Gregory
Middle name
P
Last name
Bisson

Title

Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana.

Year of Publication

2018

Date Published

2018 Jun 01

ISSN Number

1473-1150

Abstract

<p>Inter-individual variability in efavirenz (EFV) pharmacokinetics and dynamics is dominantly driven by the polymorphism in cytochrome P450 (CYP) isoenzyme 2B6 516G&gt;T. We hypothesized that additional CYP polymorphisms mediate the relationship between CYP2B6 516G&gt;T, EFV metabolism, and clinical events. We investigated 21 SNPs in 814 HIV-infected adults initiating EFV-based therapy in Botswana for population pharmacokinetics, CNS toxicities, and treatment outcomes. Two SNPs (rs28399499 and rs28399433) showed reduced apparent oral EFV clearance. Four SNPs (rs2279345, rs4803417, rs4802101, and rs61663607) showed extensive clearance. Composite CYP2B-mediated EFV metabolism was significantly associated with CNS toxicity (p = 0.04), with extensive metabolizers reporting more and slow and very slow metabolizers reporting less toxicity after 1 month compared to intermediate metabolizers. Composite CYP2B6 metabolism was not associated with composite early treatment failure. In conclusion, our data suggest that CNS-related toxicities might not be solely the result of super-therapeutic parent EFV concentrations in HIV-infected individuals in patients of African ancestry.</p>

DOI

10.1038/s41397-018-0028-2

Alternate Title

Pharmacogenomics J.

PMID

29855606

Title

Effects of sex and alcohol use on antiretroviral therapy outcomes in Botswana: a cohort study.

Year of Publication

2017

Number of Pages

73-81

Date Published

2017 Jan

ISSN Number

1360-0443

Abstract

<p><strong>AIMS: </strong>To determine alcohol use effect on HIV treatment success and whether alcohol use mediates the relation between male sex and treatment failure.</p>

<p><strong>DESIGN: </strong>Longitudinal cohort study.</p>

<p><strong>SETTING: </strong>Eight HIV clinics in and near Gaborone, Botswana.</p>

<p><strong>PARTICIPANTS: </strong>A total of 938 HIV-infected treatment-naive adults initiating regimens containing the antiretroviral medication efavirenz between June 2009 and February 2013, including 478 (51%) males, median age 38&nbsp;years, and plasma HIV RNA 4.9 logcopies/ml.</p>

<p><strong>MEASUREMENTS: </strong>Primary outcome was a composite of treatment failure over 6&nbsp;months including death, lost to care or plasma HIV RNA &gt; 25 copies/ml. Exposures included alcohol use and gender.</p>

<p><strong>FINDINGS: </strong>Failure in 339 (36%) participants included 40 (4%) deaths, 194 (21%) lost to care and 105 (11%) with HIV RNA&nbsp;&gt;&nbsp;25 copies/ml. Both hazardous alcohol use in the past year [adjusted odds ratio (aOR)&nbsp;=&nbsp;1.4, 95% confidence interval (CI)&nbsp;=&nbsp;1.0, 1.9] and male sex (aOR&nbsp;=&nbsp;2.1, 95% CI&nbsp;=&nbsp;1.5, 2.9) were associated with failure. Hazardous alcohol use in the year prior to enrollment was more common in men (57%) than women (24%), P&nbsp;&lt;&nbsp;0.001. There was no difference in alcohol use effect on failure between sexes (P for interaction&nbsp;&gt;&nbsp;0.5). Controlling for hazardous alcohol use did not change the relation between sex and failure.</p>

<p><strong>CONCLUSION: </strong>Alcohol use among HIV-infected adults in Botswana appears to worsen HIV treatment outcomes. Alcohol use does not appear to have either a mediating or a moderating effect on the relation between gender and HIV treatment outcome failure.</p>

DOI

10.1111/add.13538

Alternate Title

Addiction

PMID

27447841

Title

Elevated Pre-Antiretroviral Therapy CD39+CD8+ T Cell Frequency Is Associated With Early Mortality in Advanced Human Immunodeficiency Virus/Tuberculosis Co-infection.

Year of Publication

2017

Number of Pages

1453-1456

Date Published

2017 May 15

ISSN Number

1537-6591

Abstract

<p>Correlates of death soon after antiretroviral therapy (ART) initiation remain unclear. We investigated the association between expression of CD39, a novel immune exhaustion marker, and early mortality in patients with human immunodeficiency virus/tuberculosis co-infection. Elevated pre-ART CD39+CD8+ T cell frequency was independently associated with mortality within 6 months of ART initiation.</p>

DOI

10.1093/cid/cix155

Alternate Title

Clin. Infect. Dis.

PMID

28203772

Title

CYP2B6 genotypes and early efavirenz-based hiv treatment outcomes in botswana.

Year of Publication

2017

Date Published

2017 Jul 07

ISSN Number

1473-5571

Abstract

<p><strong>OBJECTIVES: </strong>To determine the association between cytochrome p450 2B6 genotypes and efavirenz-based HIV treatment outcomes.</p>

<p><strong>DESIGN: </strong>Observational cohort study of HIV infected adults initiating efavirenz-based regimens in Botswana.</p>

<p><strong>METHODS: </strong>The primary endpoint was a composite of death or loss to care or HIV RNA&gt;25 copies/ml at 6 months. CYP2B6 516G&gt;T and 983T&gt;C genotyping was done with Taqman Open Array platform. Adverse experiences were measured using the Subject Experience Questionnaire. Metabolism alleles were included in logistic regression models of the composite endpoint.</p>

<p><strong>RESULTS: </strong>801 individuals included 406 (51%) males, median age 37 years, median baseline CD4 count 195 cells/mm and plasma HIV RNA 4·9 log10 copies/ml. 277 (35%) reached the endpoint including 34 (4%) deaths, 151 (19%) lost to care, and 92 (11%) with plasma HIV RNA&gt;25 copies/ml. Metabolism variant alleles were common with 396 (49%) intermediate and 192 (24%) slow metabolizers. There were no statistically significant associations between metabolism and treatment endpoints. However, slower metabolism was associated with fewer adverse experiences.</p>

<p><strong>CONCLUSIONS: </strong>Slow metabolism alleles were associated with lower efavirenz clearance but not any of the treatment endpoints. Slow efavirenz metabolism did not exacerbate CNS toxicity. These results should allay concern that slow efavirenz metabolism adversely impacts individuals in sub-Saharan African settings in which these alleles are common.</p>

DOI

10.1097/QAD.0000000000001593

Alternate Title

AIDS

PMID

28692529

Title

CYP2B6 516G>T Minor Allele Protective of Late Virologic Failure in Efavirenz-treated HIV-Infected Patients in Botswana.

Year of Publication

2017

Date Published

2017 May 05

ISSN Number

1944-7884

Abstract

<p><strong>BACKGROUND: </strong>CYPB2B6 polymorphisms that affect efavirenz (EFV) concentrations are common, but the effect of this polymorphism on HIV virologic failure in clinical practice settings has not fully been elucidated. Our objective was to investigate the relationship between the CYPB2B6 516G&gt;T genotype and late virologic failure in patients treated with EFV in Gaborone, Botswana.</p>

<p><strong>SETTING: </strong>We performed a case-control study that included 1,338 HIV-infected black Batswana on EFV-based antiretroviral therapy (ART). Patients were approached for enrollment during regular visits at one of the outpatient HIV clinics between 7/2013-4/2014.</p>

<p><strong>METHODS: </strong>Cases experienced late HIV failure, defined as plasma HIV RNA &gt;1000 copies/mL after maintaining viral suppression (&lt;400 copies/mL) for at least 6 months. For each case, a total of 4 control patients were randomly sampled from the same population. Controls had plasma HIV RNA &lt;400 copies/mL on ART for at least 6 months. Logistic regression was used to determine the adjusted odds of late HIV failure by 516G&gt;T genotype.</p>

<p><strong>RESULTS: </strong>After adjustment for the confounding variables age and CD4 count, the CYPB2B6 516 T-allele was protective against late HIV virologic breakthrough, adjusted OR 0.70; 95%CI 0.50-0.97.</p>

<p><strong>CONCLUSION: </strong>The CYPB2B6 516 T-allele was protective against late virologic breakthrough in patients with initial (6 month) HIV RNA suppression on EFV-based ART. Future studies are needed to assess long-term viral benefits of identifying and offering EFV containing ART to black African HIV-infected patients with CYPB2B6 T-alleles, especially given the wider availability of a single pill EFV in this setting.</p>

DOI

10.1097/QAI.0000000000001442

Alternate Title

J. Acquir. Immune Defic. Syndr.

PMID

28481785

Title

Impact of the human immunodeficiency virus on early multidrug-resistant tuberculosis treatment outcomes in Botswana.

Year of Publication

2013

Number of Pages

348-53

Date Published

2013 Mar

ISSN Number

1815-7920

Abstract

<p><strong>SETTING: </strong>The impact of the human immunodeficiency virus (HIV) on multidrug-resistant tuberculosis (MDR-TB) treatment outcomes in sub-Saharan Africa, where extensive rollout of highly active antiretroviral therapy (HAART) has occurred, remains unclear.</p>

<p><strong>OBJECTIVE: </strong>To compare the time to initial culture conversion among patients with and those without HIV infection in a setting of individualized MDR-TB care in Botswana.</p>

<p><strong>DESIGN: </strong>Prospective cohort study of MDR-TB patients receiving ambulatory, integrated TB-HIV care at two public clinics in Botswana. The time to culture conversion was compared by HIV status using Cox proportional hazard ratios (HRs).</p>

<p><strong>RESULTS: </strong>A total of 40 HIV-infected and 30 non-HIV-infected patients with MDR-TB and follow-up cultures were identified. The median time to initial culture conversion was 78 days (interquartile range [IQR] 42-186) for HIV-infected and 95 days (IQR 70-133) for non-HIV-infected individuals (log rank P &gt; 0.5; unadjusted HR 0.9, 95%CI 0.5-1.5). Adjusting for age, sex, treatment history and number of active anti-tuberculosis drugs did not change this result (adjusted HR 0.8, 95%CI 0.4-1.4).</p>

<p><strong>CONCLUSION: </strong>We found no difference in the proportion of or time to initial sputum culture conversion between an HIV-infected and a non-infected cohort of MDR-TB patients in Botswana, suggesting that outcomes may be comparable in similar settings with access to individualized anti-tuberculosis treatment and HAART.</p>

DOI

10.5588/ijtld.12.0100

Alternate Title

Int. J. Tuberc. Lung Dis.

PMID

23321297

Title

Early antiretroviral therapy is protective against epilepsy in children with human immunodeficiency virus infection in botswana.

Year of Publication

2015

Number of Pages

193-9

Date Published

06/2015

ISSN Number

1944-7884

Abstract

<p><strong>BACKGROUND: </strong>Seizures are common among patients with HIV/AIDS in the developing world and are associated with significant morbidity and mortality. Early treatment with combination antiretroviral therapy (cART) may reduce this risk by decreasing rates of central nervous system infections and HIV encephalopathy.</p>

<p><strong>METHODS: </strong>A case-control study of new-onset epilepsy among children aged 0-18 years with perinatally acquired HIV/AIDS followed in Gaborone, Botswana, during the period 2003-2009 was conducted. Children with epilepsy were identified and compared with age- and sex-matched controls without epilepsy with respect to timing of cART initiation. Early treatment was defined as treatment with cART before the age of 12 months, at a CD4% of greater than 25 in children aged 1-5 years, or at an absolute CD4 count of &gt;350 cell per cubic millimeter in children aged 5 years and older.</p>

<p><strong>RESULTS: </strong>We identified 29 cases of new-onset epilepsy and 58 age- and sex-matched controls. The most common identified etiologies for epilepsy were central nervous system infections and direct HIV neurotoxicity. Only 8 (28%) of the children who developed epilepsy received early treatment compared with 31 (53%) controls (odds ratio: 0.36, 95% confidence interval: 0.14 to 0.92, P = 0.03). This effect was primarily driven by differences in rates of epilepsy among children who initiated treatment with cART between the ages of 1 and 5 years (11% vs. 53%, odds ratio: 0.11, 95% confidence interval: 0.01 to 1.1, P = 0.06).</p>

<p><strong>CONCLUSIONS: </strong>Earlier initiation of cART may be protective against epilepsy in children with HIV.</p>

DOI

10.1097/QAI.0000000000000563

Alternate Title

J. Acquir. Immune Defic. Syndr.

PMID

25647527

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