Christopher M. Bositis

Effectiveness of efavirenz-based regimens in young HIV-infected children treated for tuberculosis: a treatment option for resource-limited settings.

Background Antiretroviral treatment (ART) options for young children co-infected with HIV and tuberculosis are limited in resource-poor settings due to limited data on the use of efavirenz (EFV). Using available pharmacokinetic data, an EFV dosing schedule was developed for young co-infected children and implemented as the standard of care at Macha Hospital in Southern Province, Zambia. Treatment outcomes inchildren younger than 3 years of age or weighing less than 10 kg receiving either EFV-based ART plus anti-tuberculous treatment or nevirapine-based (NVP) ART were compared. Methods Treatment outcomes were measured in a cohort of HIV-infected children seeking care at Macha Hospital in rural Zambia from 2007 to 2010. Informationon the diagnosis and treatment of tuberculosis was abstracted from medical records. Results Forty-five children treated for tuberculosis initiated an EFV-based regimen and 69 children initiated a NVP-based regimen, 7 of whom also were treated for tuberculosis. Children receiving both regimens were comparable in age, but children receiving EFV started ART with a lower CD4+ T-cell percentage and weight-for-age z-score. Children receiving EFV experienced increases in both CD4+ T-cell percentage and weight-for-age z-score during follow-up, such that levels were comparable to children receiving NVP after two years of ART. Cumulative survival after 12 months of ART did not differ between groups (NVP:87%;EFV:80%;p = 0.25). Eleven children experienced virologic failure during follow-up.The adjusted hazard ratio of virologic failure comparing EFV to NVP was 0.25 (95% CI:0.05,1.24) and 0.13 (95% CI:0.03,0.62) using thresholds of 5000 and 400 copies/mL, respectively.Five children receiving EFV were reported to have had convulsions after ART initiation compared to only one child receiving NVP (p = 0.04). Conclusions Despite poorer health at ART initiation, children treated for tuberculosis and receiving EFV-based regimens showed significant improvements comparable to children receiving NVP-based regimens. EFV-based regimens should be considered for young HIV-infected children co-infected with tuberculosis in resource-limited settings.

Acute EEG findings in HIV-infected Zambian adults with new-onset seizure

Objective: To describe acute EEG findings in HIV-infected adults with new-onset seizure, assess baseline clinical characteristics associated with EEG abnormalities, and evaluate the relationship between EEG abnormalities and recurrent seizure. Methods: Eighty-one HIV-infected adults with new-onset seizure had EEG recordings during their index admission. Baseline characteristics assessed included HIV stage, seizure semiology, serum and CSF studies, neuroimaging, cognitive function based on the Zambian Mini-Mental State Examination and International HIV Dementia Scale, and psychiatric symptoms using the Shona Symptom Questionnaire. We evaluated the relationship between baseline characteristics and EEG abnormalities. Patients were followed for seizure recurrence, and the association between acute EEG abnormalities and seizure recurrence was assessed. Death was a secondary outcome. Results: Fifty-five patients had abnormal EEGs (68%): 18 (22%) had interictal spikes (12) or a recorded seizure (6). Among baseline clinical characteristics, more advanced HIV disease (p = 0.039) and any imaging abnormality (p = 0.027) were associated with abnormal EEGs. Cortical (p = 0.008) and white matter (p = 0.004) abnormalities were associated with slow posterior dominant rhythm. Patients were followed for a median of 303 days (interquartile range 103–560). Twenty-four (30%) died and 23 (28%) had recurrent seizures. EEG abnormalities were not associated with recurrent seizure. There was a nonsignificant association between seizures recorded during EEG and death (67% vs 26%, p = 0.051). Conclusions: EEG abnormalities are common in this population, particularly in patients with imaging abnormalities and advanced HIV. Acute EEG abnormalities were not associated with recurrent seizure, but high mortality rates during follow-up limited this analysis.

Biophysical mechanism of the scavenger site near T cell-presented epitopes

We seek to identify consensus sequences in digested fragments of antigenic proteins regulating selection and major histocompatibility complex (MHC)-restricted presentation to T cells of epitopes within those fragments. One such pattern, of recurrent, hydrophobic sidechains forming a longitudinal hydrophobic strip when a sequence is coiled as an alpha-helix, is found in or near most T cell-presented epitopes. Such recurrent hydrophobicity may lead to protease-protected coiling of the fragment against endosomal membranes and transfer to MHC molecules. This concept leads to better identification of T cell-presented sequences and possible to engineering of T cell-presented vaccines to affect their potency and MHC restriction.

HIV and new onset seizures: slipping through the cracks in HIV care and treatment

The aim of the study was to describe patient characteristics and outcomes among HIV‐positive adults presenting to a Zambian tertiary care hospital with new‐onset seizures.

Neuroimaging abnormalities and seizure recurrence in a prospective cohort study of Zambians with human immunodeficiency virus and first seizure

In HIV-positive individuals with first seizure, we describe neuroimaging findings, detail clinical and demographic risk factors for imaging abnormalities, and evaluate the relationship between imaging abnormalities and seizure recurrence to determine if imaging abnormalities predict recurrent seizures. Among 43 participants (mean 37.4 years, 56% were male), 16 (37%) were on antiretroviral drugs, 32 (79%) had advanced HIV disease, and (28) 66% had multiple seizures and/or status epilepticus at enrollment. Among those with cerebrospinal fluid studies, 14/31 (44%) had opportunistic infections (OIs). During follow-up, 9 (21%) died and 15 (35%) experienced recurrent seizures. Edema was associated with OIs (odds ratio: 8.79; confidence interval: 1.03-236) and subcortical atrophy with poorer scores on the International HIV Dementia Scale) (5.2 vs. 9.3; P=0.002). Imaging abnormalities were not associated with seizure recurrence or death (P>0.05). Seizure recurrence occurred in at least a third and over 20% died during follow-up. Imaging was not predictive of recurrent seizure or death, but imaging abnormalities may offer additional diagnostic insights in terms of OI risk and cognitive impairment.

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.

New-onset seizure in HIV-infected adult Zambians: A search for causes and consequences

Objective: To identify the etiology of new-onset seizure in HIV-infected Zambian adults and identify risk factors for seizure recurrence. Methods: A prospective cohort study enrolling HIV-infected adults with new-onset seizure within 2 weeks of index seizure obtained clinical, laboratory, and neuroimaging data to determine seizure etiology. Participants were followed to identify risk factors for seizure recurrence. Risk factors for mortality were examined as mortality rates were unexpectedly high. Results: Eighty-one patients with CSF for analysis were enrolled and followed for a median of 306 days (interquartile range 61–636). Most (91%) were at WHO stage III/IV and 66 (81%) had a pre-seizure Karnofsky score ≥50. Prolonged or multiple seizures occurred in 46 (57%), including 12 (15%) with status epilepticus. Seizure etiologies included CNS opportunistic infections (OI) in 21 (26%), hyponatremia in 23 (28%), and other infections in 8 (10%). OIs included Cryptococcus (17%), JC virus (7%) and 5% each for tuberculosis, cytomegalovirus, and varicella-zoster virus. No etiology could be identified in 16 (20%). Thirty (37%) patients died during follow-up and 20 (25%) had recurrent seizures with survival being the only identifiable risk factor. Conclusions: HIV-infected adults with new-onset seizure in Zambia often have advanced HIV disease with OI being the most frequent seizure etiology. Seizure recurrence is common but no risk factors for recurrence other than survival were identified. These findings suggest an urgent need for immune reconstitution in this population. Initiating treatment for seizure prophylaxis where only enzyme-inducing antiepileptic medications are available could threaten antiretroviral efficacy.

The Arc of Human Immunodeficiency Virus Capacity Development: Insights from a Decade of Partnership for Medical Education in Zambia

AbstractZambia and other sub-Saharan nations suffer from a critical shortage of trained health-care professionals to combat the human immunodeficiency virus/acquired immunodeficiency syndrome crisis. The University of Maryland and the Zambian Ministry of Health have partnered over the past decade to develop health-care capacity among physicians, nurses, and community health workers. We describe novel interventions to train health-care workers at all levels and argue that our collaboration represents a successful model for such partnerships between western medical institutions and African governmental health agencies.

Patient-Reported Adverse Effects Associated with Combination Antiretroviral Therapy and Coadministered Enzyme-Inducing Antiepileptic Drugs

AbstractConcurrent treatment with combination antiretroviral therapy (cART) and an enzyme-inducing antiepileptic drug (EI-AED) is common in resource-limited settings; however, the incidence and impact of adverse effects in cotreated patients is largely unknown. Symptoms of adverse effects were assessed by both spontaneous report and checklist for 145 human immunodeficiency virus (HIV)-infected Zambian adults initiating various treatment combinations, such as cART with an EI-AED (N = 20), cART only (N = 43), or neither drug (untreated; N = 82). At study baseline, the cART + EI-AED group reported more headache, generalized fatigue, problems with concentration, and depression than the untreated group (P < 0.01 for all). At 2 weeks, a greater proportion of cART + EI-AED participants reported increased nausea or vomiting compared with baseline (P < 0.05). Adverse effects did not appear to impact self-reported adherence at 2 weeks as 100% cART adherence was reported in 19 of 20 (95%) and 42 of 43 (98%) cART + EI-AED and cART-only participants, respectively; 100% EI-AED adherence was reported in 19 of 20 (95%) participants. However, adherence at 6 months was suboptimal in both groups with 18 of 33 (56%) participants on cART experiencing greater than 1-week lapse in pharmacy-reported medication supply. Our results highlight the need to educate patients about the increased potential for nausea and vomiting with cART + EI-AED cotreatment. Although adherence was high early during treatment, adherence should be reinforced overtime to minimize the potential for HIV and/or epilepsy treatment failure.

Assessment of homology with the helical mimicry algorithm

Homologies based on structural motifs characterize conserved structures and mechanisms of maintaining function. An algorithm was developed to quantitate homology among segments of two proteins based upon structural characteristics of an amphipathic alpha-helix. This helical mimicry algorithm scored homology among sequences of two proteins in terms of: (i) presence of Leu, Ile, Val, Phe, or Met in a longitudinal, hydrophobic strip-of-helix at positions n, n + 4, n + 7, n + 11, etc. in the primary sequence, (ii) identity or chemical similarity of amino acids at intervening positions and (iii) exchanges of amino acids from positions n to n - 1, n + 3, n + 4, n + 1, n - 3, n - 4 around n (on the surface of a putative helix). While such exchanges of amino acids on the surfaces of homologous helices may conserve function, they did not maintain specific interactions of those residues with apposing groups.