Time to Treatment Initiation and Retrospective Analysis of Antiretroviral Therapy Outcomes among HIV-positive Methadone Maintenance Therapy Clients in Primary Health-care Centers, Kuantan, Pahang.

INTRODUCTION: Methadone maintenance therapy (MMT) program helped to improve access to antiretroviral therapy (ART) among people who inject drugs (PWID) with human immunodeficiency virus (HIV). However, the time to treatment initiation (TTI) and outcomes of ART intervention in this population have scarcely been analyzed. OBJECTIVES: The aim of this study was to analyze the TTI and outcomes of ART among MMT clients in primary health-care centers in Kuantan, Pahang. MATERIALS AND METHODS: This was a retrospective evaluation of MMT clients from 2006 to 2019. The TTI was calculated from the day of MMT enrolment to ART initiation. The trends of CD4 counts and viral loads were descriptively evaluated. Cox proportional hazard model was used to analyze the survival and treatment retention rate. RESULTS: A total of 67 MMT clients from six primary health-care centers were HIV-positive, of which 37 clients were started on ART. The mean TTI of ART was 27 months. The clients who were given ART had a mean CD4 count of 119 cells/mm3 at baseline and increased to 219 cells/mm3 after 6 months of ART. Only two patients (5.4%) in the ART subgroup had an unsuppressed viral load. The initiation of ART had reduced the risk of death by 72.8% (hazard ratio = 0.27, P = 0.024), and they are 13.1 times more likely to remain in treatment (P < 0.01). CONCLUSION: The TTI of ART was delayed in this population. MMT clients who were given ART have better CD4 and viral load outcomes, helped reduced death risk and showed higher retention rates in MMT program.

A map of human PRDM9 binding provides evidence for novel behaviors of PRDM9 and other zinc-finger proteins in meiosis.

PRDM9 binding localizes almost all meiotic recombination sites in humans and mice. However, most PRDM9-bound loci do not become recombination hotspots. To explore factors that affect binding and subsequent recombination outcomes, we mapped human PRDM9 binding sites in a transfected human cell line and measured PRDM9-induced histone modifications. These data reveal varied DNA-binding modalities of PRDM9. We also find that human PRDM9 frequently binds promoters, despite their low recombination rates, and it can activate expression of a small number of genes including CTCFL and VCX. Furthermore, we identify specific sequence motifs that predict consistent, localized meiotic recombination suppression around a subset of PRDM9 binding sites. These motifs strongly associate with KRAB-ZNF protein binding, TRIM28 recruitment, and specific histone modifications. Finally, we demonstrate that, in addition to binding DNA, PRDM9's zinc fingers also mediate its multimerization, and we show that a pair of highly diverged alleles preferentially form homo-multimers.

Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination.

Although present in both humans and chimpanzees, recombination hotspots, at which meiotic crossover events cluster, differ markedly in their genomic location between the species. We report that a 13-base pair sequence motif previously associated with the activity of 40% of human hotspots does not function in chimpanzees and is being removed by self-destructive drive in the human lineage. Multiple lines of evidence suggest that the rapidly evolving zinc-finger protein PRDM9 binds to this motif and that sequence changes in the protein may be responsible for hotspot differences between species. The involvement of PRDM9, which causes histone H3 lysine 4 trimethylation, implies that there is a common mechanism for recombination hotspots in eukaryotes but raises questions about what forces have driven such rapid change.