Cognitive Impairment and Psychiatric Morbidity in HIV+ Zambians with New-Onset Seizure

A prospective cohort study of new-onset seizure in people with human immunodeficiency virus (HIV) in Zambia is ongoing to determine the incidence of subsequent epilepsy and risk factors for epileptogenesis in this population. At enrollment, we evaluated this cohort for cognitive impairment and psychiatric morbidity. Over 50% of participants had cognitive impairment and significant psychiatric morbidity. Most participants had advanced HIV disease based on CD4+ T-cell count and World Health Organization stage, but we found no association between cognitive impairment or psychiatric morbidity and HIV disease staging.     

Improving abortion care in Zambia.

In this commentary, the impact of the introduction of manual vacuum aspiration (MVA) for incomplete abortion patients and for early uterine evacuation is discussed for the University Teaching Hospital in Lusaka, Zambia. This 3-year training and service delivery program was begun in 1988 after it was clear that 15% of maternal deaths were due to illegally induced abortion. The prior procedure of dilation and curettage (D and C) required use of the main operating room and general anesthesia, which resulted in severe congestion and treatment delays. As a result of the new MVA procedure, congestion has decreased substantially, treatment is safer and more timely, and the staff's ability to provide abortions has increased. Family planning counseling is provided to postabortion patients in a more thorough fashion, and the savings in time has improved the quality of patient-staff interactions. Specifically, the patient flow has improved from a 12-hour wait to a 4-6 hour wait and rarely requires overnight hospitalization. The demand for the main operating room had decreased which frees space, time, and commodities for other gynecological treatment. The shorter procedure and release time means a minimal loss of earnings and productivity, and allows for greater privacy in explaining absences to families, schools, or employers. The improved quality of are is reflected in the figures for number treated, i.e., in 1989, 74% were treated with MVA for incomplete abortion 12 weeks and pregnancy termination 8 weeks compared with 26% treated with D and C. In 1990, the figures were 86% with MVA and 14% with D and C. The likelihood of complications from hemorrhage and sepsis have also been reduced. The MVA procedure is also less traumatic for the patient. The increased access to safe legal abortion services is reflected in the ratio of induced to incomplete abortions between 1988-1990 (1:25 to 1:5). Family planning counseling is provided by a full-time counselor who counsels preabortion and postabortion and schedules 2-week follow-up appointment. These achievements have been made in spite of a declining economy and difficulties in the health sector. Unfortunately, conditions throughout Zambia are such that access to safe abortion is restricted. Effort is underway to expand this MVA training and service delivery in provincial hospitals and to conduct research on other effective strategies to reduced unsafe abortion and improve family planning care.     

Binding of sulfonyl-containing arylalkylamines at human 5-HT6 serotonin receptors

Various sulfonyl-containing compounds (e.g. sulfonamides, sulfones) bind at human 5-HT6 serotonin receptors, but it has been difficult relating the binding mode(s) of such agents to one another, even though many possess a common SO2 moiety, to identify a common pharmacophore model(s). On the basis of the hypothesis that an ergoline-type conformation might be important for the binding of some sulfonamide-containing arylalkylamines, we prepared for examination at h5-HT6 receptors a series of compounds, including phenylethylamines 6, pyrroloethylamine 7, and phenylpiperazines 9. The results (with Ki values ranging from about 1 nM to >1000 nM) suggest that many of these agents likely bind in a related fashion, and structure-affinity studies indicate that the benzenesulfonamide portion of the phenylethylamine and phenylpiperazine analogues can be "reversed", abbreviated to a sulfone, and moved to an adjacent position with relatively little impact on affinity. Although a benzenesulfonamide (or related arylsulfonamide) group might be common to various 5-HT6 ligands, there appears to be some latitude with regard to the specific constitution and location of the sulfonamide moiety even within the same arylalkylamine structural framework. A pharmacophore model is presented to account for some of the current findings.     

Trajectories of re-engagement: factors and mechanisms enabling patient return to HIV care in Zambia

Introduction

While disengagement from HIV care threatens the health of persons living with HIV (PLWH) and incidence-reduction targets, re-engagement is a critical step towards positive outcomes. Studies that establish a deeper understanding of successful return to clinical care among previously disengaged PLWH and the factors supporting re-engagement are essential to facilitate long-term care continuity.

Methods

We conducted narrative, patient-centred, in-depth interviews between January and June 2019 with 20 PLWH in Lusaka, Zambia, who had disengaged and then re-engaged in HIV care, identified through electronic medical records (EMRs). We applied narrative analysis techniques, and deductive and inductive thematic analysis to identify engagement patterns and enablers of return.

Results

We inductively identified five trajectories of care engagement, suggesting patterns in patient characteristics, experienced barriers and return facilitators that may aid intervention targeting including: (1) intermittent engagement;(2) mostly engaged; (3) delayed linkage after testing; (4) needs time to initiate antiretroviral therapy (ART); and (5) re-engagement with ART initiation. Patient-identified periods of disengagement from care did not always align with care gaps indicated in the EMR. Key, interactive re-engagement facilitators experienced by participants, with varied importance across trajectories, included a desire for physical wellness and social support manifested through verbal encouragement, facility outreach or personal facility connections and family instrumental support. The mechanisms through which facilitators led to return were: (1) the promising of living out one's life priorities; (2) feeling valued; (3) fostering interpersonal accountability; (4) re-entry navigation support; (5) facilitated care and treatment access; and (6) management of significant barriers, such as depression.

Conclusions

While preliminary, the identified trajectories may guide interventions to support re-engagement, such as offering flexible ART access to patients with intermittent engagement patterns instead of stable patients only. Further, for re-engagement interventions to achieve impact, they must activate mechanisms underlying re-engagement behaviours. For example, facility outreach that reminds a patient to return to care but does not affirm a patient's value or navigate re-entry is unlikely to be effective. The demonstrated importance of positive health facility connections reinforces a growing call for patient-centred care. Additionally, interventions should consider the important role communities play in fostering treatment motivation and overcoming practical barriers.     

Design, synthesis, and evaluation of metabolism-based analogues of haloperidol incapable of forming MPP+-like species

The long-term, irreversible, Parkinsonism-like side effects of haloperidol have been speculated to involve several mechanisms. More recently, it has been speculated that the metabolic transformation to MPP+-like species may contribute to the Parkinsonism-like side effects. Because BCPP+ and its reduced analogue have been shown to possess the potential to destroy dopamine receptors in the nigrostriatum, we have designed new analogues of haloperidol lacking the structural features necessary to form neurotoxic quaternary species but retaining their dopamine-binding capacity. The most potent agent at the D2 receptor, the homopiperidine analogue 11, was found to be equipotent to haloperidol. It was also of interest to identify analogues with DA binding profiles similar to that of clozapine at the dopamine receptor subtypes. Evaluation of the proposed agents shows that the ratio of D2 to D4 (2) binding of clozapine was mimicked by 7 [K(i)(D2) = 33, K(i)(D3) = 200, K(i)(D4) = 11 nM; K(i)(D2)/K(i)(D4) = 3] and 9 [K(i)(D2) = 44, K(i)(D3) = 170, K(i)(D4) = 24 nM; K(i)(D2)/K(i)(D4) = 2]. A preliminary in-vivo testing of compound 7 shows that its behavioral profile is similar to that of clozapine. This profile suggests that there is a need for further evaluation of these two synthetic agents and their enantiomers for efficacy and lack of catalepsy in animal models.     

The effect of tracer contact on return to care among adult, “lost to follow‐up” patients living with HIV in Zambia: an instrumental variable analysis

IntroductionTracing patients lost to follow‐up (LTFU) from HIV care is widely practiced, yet we have little knowledge of its causal effect on care engagement. In a prospective, Zambian cohort, we examined the effect of tracing on return to care within 2 years of LTFU.MethodsWe traced a stratified, random sample of LTFU patients who had received HIV care between August 2013 and July 2015. LTFU was defined as a gap of >90 days from last scheduled appointment in the routine electronic medical record. Extracting 2 years of follow‐up visit data through 2017, we identified patients who returned. Using random selection for tracing as an instrumental variable (IV), we used conditional two‐stage least squares regression to estimate the local average treatment effect of tracer contact on return. We examined the observational association between tracer contact and return among patient sub‐groups self‐confirmed as disengaged from care.ResultsOf the 24,164 LTFU patients enumerated, 4380 were randomly selected for tracing and 1158 were contacted by a tracer within a median of 14.8 months post‐loss. IV analysis found that patients contacted by a tracer because they were randomized to tracing were no more likely to return than those not contacted (adjusted risk difference [aRD]: 3%, 95% CI: –2%, 8%, p = 0.23). Observational data showed that among contacted, disengaged patients, the rate of return was higher in the week following tracer contact (IR 5.74, 95% CI: 3.78–8.71) than in the 2 weeks to 1‐month post‐contact (IR 2.28, 95% CI: 1.40–3.72). There was a greater effect of tracing among patients lost for >6 months compared to those contacted within 3 months of loss.ConclusionsOverall, tracer contact did not causally increase LTFU patient return to HIV care, demonstrating the limited impact of tracing in this program, where contact occurred months after patients were LTFU. However, observational data suggest that tracing may speed return among some LTFU patients genuinely out‐of‐care. Further studies may improve tracing effectiveness by examining the mechanisms underlying the impact of tracing on return to care, the effect of tracing at different times‐since‐loss and using more accurate identification of patients who are truly disengaged to target tracing.     

Simultaneous Detection of Major Drug Resistance Mutations in the Protease and Reverse Transcriptase Genes for HIV-1 Subtype C by Use of a Multiplex Allele-Specific Assay

High-throughput, sensitive, and cost-effective HIV drug resistance (HIVDR) detection assays are needed for large-scale monitoring of the emergence and transmission of HIVDR in resource-limited settings. Using suspension array technology, we have developed a multiplex allele-specific (MAS) assay that can simultaneously detect major HIVDR mutations at 20 loci. Forty-five allele-specific primers tagged with unique 24-base oligonucleotides at the 5′ end were designed to detect wild-type and mutant alleles at the 20 loci of HIV-1 subtype C. The MAS assay was first established and optimized with three plasmid templates (C-wt, C-mut1, and C-mut2) and then evaluated using 148 plasma specimens from HIV-1 subtype C-infected individuals. All the wild-type and mutant alleles were unequivocally distinguished with plasmid templates, and the limits of detection were 1.56% for K219Q and K219E, 3.13% for L76V, 6.25% for K65R, K70R, L74V, L100I, K103N, K103R, Q151M, Y181C, and I47V, and 12.5% for M41L, K101P, K101E, V106A, V106M, Y115F, M184V, Y188L, G190A, V32I, I47A, I84V, and L90M. Analyses of 148 plasma specimens revealed that the MAS assay gave 100% concordance with conventional sequencing at eight loci and >95% (range, 95.21% to 99.32%) concordance at the remaining 12 loci. The differences observed were caused mainly by 24 additional low-abundance alleles detected by the MAS assay. Ultradeep sequencing analysis confirmed 15 of the 16 low-abundance alleles. This multiplex, sensitive, and straightforward result-reporting assay represents a new efficient genotyping tool for HIVDR surveillance and monitoring.