Browsing by Author "Norman, Jennifer"

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    Detectable HIV-1 in semen in individuals with very low blood viral loads
    (BioMed Central, 2020-03-05) Kariuki, Samuel Mundia; Selhorst, Philippe; Norman, Jennifer; Cohen, Karen; Rebe, Kevin; Williamson, Carolyn; Dorfman, Jeffrey R
    Background: Several reports indicate that a portion (5–10%) of men living with HIV-1 intermittently shed HIV-1 RNA into seminal plasma while on long term effective antiretroviral therapy (ART). This is highly suggestive of an HIV-1 reservoir in the male genital tract. However, the status of this reservoir in men living with HIV-1 who are not under treatment is underexplored and has implications for understanding the origins and evolution of the reservoir. Finding: Forty-three HIV-1 positive, antiretroviral therapy naïve study participants attending a men’s health clinic were studied. Semen viral loads and blood viral loads were generally correlated, with semen viral loads generally detected in individuals with blood viral loads > 10,000 cp/ml. However, we found 1 individual with undetectable viral loads (<20cp/ml) and 2 individuals with very low blood viral load (97 and 333cp/ml), but with detectable HIV-1 in semen (485–1157 copies/ semen sample). Blood viral loads in the first individual were undetectable when tested three times over the prior 5 years. Conclusions: Semen HIV-1 viral loads are usually related to blood viral loads, as we confirm. Nonetheless, this was not true in a substantial minority of individuals suggesting unexpectedly high levels of replication in the male genital tract in a few individuals, despite otherwise effective immune control. This may reflect establishment of a local reservoir of HIV-1 populations.
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    Pharmacokinetics and drug-drug interactions of abacavir and lamuvudine co-administered with antituberculosis drugs in HIV-positive children treated for multidrug-resistant tuberculosis
    (Frontiers Media S.A, 2021-10-08) Van der Laan, Louvina E.; Garcia-Prats, Anthony J.; Schaaf, H. Simon; Winckler, Jana L.; Draper, Heather; Norman, Jennifer; Wiesner, Lubbe; McIlleron, Helen; Denti, Paolo; Hesseling, Anneke C.
    Given the high prevalence of multidrug-resistant (MDR)-TB in high HIV burden settings, it is important to identify potential drug-drug interactions between MDR-TB treatment and widely used nucleoside reverse transcriptase inhibitors (NRTIs) in HIV-positive children. Population pharmacokinetic models were developed for lamivudine (n = 54) and abacavir (n = 50) in 54 HIV-positive children established on NRTIs; 27 with MDR-TB (combinations of high-dose isoniazid, pyrazinamide, ethambutol, ethionamide, terizidone, fluoroquinolones, and amikacin), and 27 controls without TB. Two-compartment models with first-order elimination and transit compartment absorption described both lamivudine and abacavir pharmacokinetics, respectively. Allometric scaling with body weight adjusted for the effect of body size. Clearance was predicted to reach half its mature value ∼2 (lamivudine) and ∼3 (abacavir) months after birth, with completion of maturation for both drugs at ∼2 years. No significant difference was found in key pharmacokinetic parameters of lamivudine and abacavir when co-administered with routine drugs used for MDR-TB in HIV-positive children.
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    Pharmacokinetics and Drug-Drug Interactions of Isoniazid and Efavirenz in Pregnant Women Living With HIV in High TB Incidence Settings: Importance of Genotyping
    (John Wiley & Sons, Ltd, 2020) Gausi, Kamunkhwala; Wiesner, Lubbe; Norman, Jennifer; Wallis, Carole L
    The World Health Organization guidelines recommend that individuals living with HIV receive ≥ 6 months of isoniazid preventive therapy, including pregnant women. Yet, plasma isoniazid exposure during pregnancy, in the antiretroviral therapy era, has not been well-described. We investigated pregnancy-induced and pharmacogenetic-associated pharmacokinetic changes and drug-drug interactions between isoniazid and efavirenz in pregnant women. Eight hundred forty-seven women received isoniazid for 28 weeks, either during pregnancy or at 12 weeks postpartum, and 786 women received efavirenz. After adjusting for NAT2 and CYP2B6 genotype and weight, pregnancy increased isoniazid and efavirenz clearance by 26% and 15%, respectively. Isoniazid decreased efavirenz clearance by 7% in CYP2B6 normal metabolizers and 13% in slow and intermediate metabolizers. Overall, both isoniazid and efavirenz exposures were reduced during pregnancy, but the main determinants of drug concentration were NAT2 and CYP2B6genotypes, which resulted in a five-fold difference for both drugs between rapid and slow metabolizers.