Search

Aim: This study evaluated associations between CYP3A4*22 and variants in other pharmacogenes ( CYP3A5 , SULT2A1 , ABCB1 , ABCG2 , ERCC1 ) and the risk for palbociclib-associated toxicities. Materials & methods: Two hundred cancer patients who received standard-of-care palbociclib were genotyped and associations with toxicity were evaluated retrospectively. Results: No significant associations were found for CYP3A4*22 , CYP3A5*3 , ABCB1 _rs1045642, ABCG2 _rs2231142, ERCC1 _rs3212986 and ERCC1 _rs11615. Homozygous variant carriers of SULT2A1 _rs182420 had higher incidence of dose modifications due to palbociclib toxicity (odds ratio [OR]: 4.334, 95% CI: 1.057-17.767, p  = 0.042). ABCG2_rs2231137 variant carriers had borderline higher incidence of grade 3-4 neutropenia (OR: 4.14, 95% CI: 0.99-17.37, p  = 0.052). Conclusion: Once validated, SULT2A1 and ABCG2 variants may be useful to individualize palbociclib dosing to minimize toxicities and improve treatment outcomes.

In the last decade, reliable scientific evidence has emerged to support the concept that undetectable viral loads prevent human immunodeficiency virus (HIV). Undetectable equals untransmissible (U = U) is a simple message that everyone can understand. The success of this concept depends on strict adherence to antiretroviral therapy (ART) and the attainment of suppressed viral loads (VLs). To achieve U = U in sub-Saharan Africa (SSA), poor adherence to ART, persistent low-level viremia, and the emergence of drug-resistant mutants are challenges that cannot be overlooked. Short of a cure for HIV, U = U can substantially reduce the burden and change the landscape of HIV epidemiology on the continent. From a public health perspective, the U = U concept will reduce stigmatization in persons living with HIV (PLWHIV) in SSA and strengthen public opinion to accept that HIV infection is not a death sentence. This will also promote ART adherence because PLWHIV will aim to achieve U = U within the shortest possible time. This article highlights challenges and barriers to achieving U = U and suggests how to promote the concept to make it beneficial and applicable in SSA. This concept, if expertly packaged by policy-makers, clinicians, health service providers, and HIV control programs, will help to stem the tide of the epidemic in SSA.

Introduction: Vertical transmission of Cytomegalovirus (CMV), resulting in congenital CMV (cCMV) infection could have disabling and potentially fatal effects on the foetus or neonate. Although primary infection probably has a higher risk of leading to cCMV, in highly seropositive populations, a significant risk of vertical transmission is thought to be due to CMV reactivation and or reinfection during pregnancy. In this narrative review, we summarise the prevalence of CMV infection and associated risk factors among pregnant African women, in a setting where primary CMV infection usually occurs during infancy., Methodology: A systematic search of literature published between January 2000 and January 2019, retrieved on five bibliographic databases was performed. Search for relevant articles was performed using the following keywords: cytomegalovirus, CMV, infection, antenatal infections, pregnancy, pregnant women, gravidity, developing countries and Africa, with appropriate qualifiers such as OR, AND., Results: Systematic searching retrieved 11 relevant original research papers. Prevalence of anti-CMV IgG and IgM antibodies ranged from 60-100% and 0-15.5%, respectively. Prevalence of CMV DNA ranged from 0-29%, depending on the specimen used. However, there was no geographic trend for CMV seroprevalence or CMV DNA prevalence across the African continent. Overall, a substantial percentage of women of reproductive-age were CMV seronegative and at risk of primary infection. Associations of sociodemographic factors with CMV infection were inconsistent across all reviewed studies., Conclusions: The limited data and inconsistency of findings from the few studies carried out in Africa calls for prospective studies comparing prevalence and outcomes of cCMV in infants born to women with both primary and reactivated CMV in Africa., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2019 Doreen Mhandire, Sarah Rowland-Jones, Kudakwashe Mhandire, Mamadou Kaba, Collet Dandara.)

This study aimed to investigate the seroprevalence of cytomegalovirus (CMV) infection and risk factors associated with CMV acquisition among pregnant women in Zimbabwe. In a cross-sectional study, pregnant women were recruited in late gestation, seeking antenatal care at council clinics in three high-density suburbs in Harare, Zimbabwe. Anti-CMV IgM and IgG antibodies were quantified in serum using an enzyme-linked immunosorbent assay. Antibody avidity tests were used to distinguish active infection from viral reactivation in anti-CMV IgM-positive cases. Five hundred and twenty four women were recruited: 278 HIV infected and 246 HIV uninfected. Current or active CMV infection defined as IgM positive+low avidity was detected in 4.6% (24/524), 95% confidence interval (CI): 3-6.9 in all women, 5.8% (16/278) in the HIV infected and 3.3% (8/246), 95% CI: 1.4-6.3 in the HIV uninfected. IgG seroprevalence was 99.6% (522/524), 95% CI: 98.6-99.9 in all women. Notably, the difference in the prevalence of active CMV infection between the HIV-infected and HIV-uninfected women was not statistically significant ( p  = 0.173). The study shows a low prevalence of primary or active CMV infection among the pregnant women, but the IgG seroprevalence suggests high previous CMV exposure. Importantly, CMV seroprevalence was not associated with the HIV status of the women, perhaps due to the ubiquitous exposure of the population to CMV.

Background: Antiretroviral therapy (ART) to suppress HIV replication has reduced morbidity and mortality yet effectiveness of current HIV drugs is threatened by HIV drug resistance (HIVDR) mutations., Objective: To determine HIVDR mutations using proviral DNA from specimens of patients presenting to an HIV treatment clinic., Methods: DNA from 103 patients, 86 treatment-experienced, 17 treatment-naïve, were genotyped for the HIV-1C reverse transcriptase gene (RT; codons 21-304) using Sanger sequencing and sequences analyzed using Sequencher software. Resistance mutations were interpreted using Stanford HIVDR reference database., Results: Median age was 39 (IQR, 33-46) years and 80% of patients were female. Six-percent (n=6) had at least one HIVDR mutation, comprising NRTI-associated mutations, (M184V, T69D, T69N and V75I); NNRTI-associated mutations (G190A, K103N, V106M, Y181C) and thymidine analogue associated mutations (D67N, K70R, K219Q, L210W, M41L, T215Y). Of the six participants, with at least one HIVDR mutation, all were treatment experienced, five were on tenofovir, lamivudine and nevirapine and one was on tenofovir, lamivudine and atazanavir. There was no difference in median CD4 count and viral loads when patients were compared by presence of HIVDR mutations., Conclusion: We demonstrated the use of proviral DNA in HIVDR testing in adult patients and present that all the patients with various kinds of HIVDR mutations were treatment experienced, pointing to the role of drug regimens in driving viral mutations. Thus, the use of proviral DNA has potential to help provide surveillance on risk of HIVDR in HIV-infected individuals who are on treatment, which may assist in corrective treatment.

The extremely high prevalence of HIV/AIDS in sub-Saharan Africa and limitations of current antiretroviral medicines demand new tools to optimize therapy such as pharmacogenomics for person-to-person variations. African populations exhibit greater genetic diversity than other world populations, thus making it difficult to extrapolate findings from one population to another. Nevirapine, an antiretroviral medicine, displays large plasma concentration variability which adversely impacts therapeutic virological response. This study, therefore, aimed to identify sources of variability in nevirapine pharmacokinetics and pharmacodynamics, focusing on genetic variation in CYP2B6 and CYP1A2. Using a cross-sectional study design, 118 HIV-infected adult Zimbabwean patients on nevirapine-containing highly active antiretroviral therapy (HAART) were characterized for three key functional single nucleotide polymorphisms (SNPs), CYP2B6 c.516G>T (rs3745274), CYP2B6 c.983T>C (rs28399499), and CYP1A2 g.-163C>A (rs762551). We investigated whether genotypes at these loci were associated with nevirapine plasma concentration, a therapeutic biomarker, and CD4 cell count, a biomarker of disease progression. CYP2B6 and CYP1A2 were chosen as the candidate genes based on reports in literature, as well as their prominence in the metabolism of efavirenz, a drug in the same class with nevirapine. Nevirapine plasma concentration was determined using LC-MS/MS. The mean nevirapine concentration for CYP2B6 c.516T/T genotype differed significantly from that of 516G/G (p < 0.001) and 516G/T (p < 0.01) genotypes, respectively. There were also significant differences in mean nevirapine concentration between CYP2B6 c.983T > C genotypes (p = 0.04). Importantly, the CYP1A2 g.-163C>A SNP was significantly associated with the pharmacodynamics endpoint, the CD4 cell count (p = 0.012). Variant allele frequencies for the three SNPs observed in this Zimbabwean group were similar to other African population groups but different to observations among Caucasian and Asian populations. We conclude that CYP2B6 c.516G>T and CYP2B6 c.983T>C could be important sources of nevirapine pharmacokinetic variability that could be considered for dosage optimization, while CYP1A2 g.-163C>A seems to be associated with HIV disease progression. These inter- and intra-population pharmacokinetic and pharmacodynamics differences suggest that a single prescribed dosage may not be appropriate for the treatment of disease. Further research into a personalized nevirapine regimen is required.