Evaluation of four chemotherapy regimens for treatment of advanced AIDS-associated Kaposi sarcoma in Kenya: a cost-effectiveness analysis.

BACKGROUND: The most effective treatment for advanced AIDS-associated Kaposi sarcoma is paclitaxel or pegylated liposomal doxorubicin (PLD); neither is routinely used in sub-Saharan Africa due to limited availability and high cost. We examined the clinical impact, costs, and cost-effectiveness of paclitaxel or PLD in Kenya, compared with etoposide or bleomycin-vincristine. METHODS: In this study, we use the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-International Model to project clinical outcomes and costs among people living with HIV and advanced Kaposi sarcoma on antiretroviral therapy. We compared four different treatment strategies: etoposide, bleomycin-vincristine, paclitaxel, or PLD. We derived cohort characteristics and costs from the Kenyan Academic Model for Providing Access to Healthcare network, and adverse events, efficacy, and mortality from clinical trials. We projected model outcomes over a lifetime and included life expectancy, per-person lifetime costs, and incremental cost-effectiveness ratios (ICERs). We conducted budget impact analysis for 5-year total costs and did deterministic and probabilistic sensitivity analyses to evaluate the effect of uncertainty in input parameters. FINDINGS: We found that paclitaxel would be more effective than bleomycin-vincristine and would increase life expectancy by 4·2 years per person. PLD would further increase life expectancy by 0·6 years per person. Paclitaxel would be the most cost-effective strategy (ICER US$380 per year-of-life-saved compared with bleomycin-vincristine) and would remain cost-effective across a range of scenarios. PLD would be cost-effective compared with paclitaxel if its price were reduced to $100 per cycle (base case $180 per cycle). Implementing paclitaxel instead of bleomycin-vincristine would save approximately 6400 life-years and would increase the overall 5-year Kenyan health-care costs by $3·7 million; increased costs would be primarily related to ongoing HIV care given improved survival. INTERPRETATION: Paclitaxel would substantially increase life expectancy and be cost-effective compared with bleomycin-vincristine for advanced AIDS-associated Kaposi sarcoma in Kenya and should be the standard of care. PLD would further improve survival and be cost-effective with a 44% price reduction. FUNDING: US National Institutes of Health and Massachusetts General Hospital. TRANSLATION: For the Swahili translation of the abstract see Supplementary Materials section.

Clinical sequelae among individuals with pauci-symptomatic or asymptomatic Ebola virus infection and unrecognised Ebola virus disease in Liberia: a longitudinal cohort study.

BACKGROUND: Whether or not individuals with pauci-symptomatic or asymptomatic Ebola virus infection and unrecognised Ebola virus disease develop clinical sequelae is unknown. We assessed current symptoms and physical examination findings among individuals with pauci-symptomatic or asymptomatic infection and unrecognised Ebola virus disease compared with Ebola virus disease survivors and uninfected contacts. METHODS: Between June 17, 2015, and June 30, 2017, we studied a cohort of Ebola virus disease survivors and their contacts in Liberia. Surveys, current symptoms and physical examination findings, and serology were used to characterise disease status of reported Ebola virus disease, unrecognised Ebola virus disease, pauci-symptomatic or asymptomatic Ebola virus infection, or no infection. We pre-specified findings known to be differentially prevalent among Ebola virus disease survivors versus their contacts (urinary frequency, headache, fatigue, muscle pain, memory loss, joint pain, neurological findings, chest findings, muscle findings, joint findings, abdominal findings, and uveitis). We estimated the prevalence and incidence of selected clinical findings by disease status. FINDINGS: Our analytical cohort included 991 reported Ebola virus disease survivors and 2688 close contacts. The median time from acute Ebola virus disease onset to baseline was 317 days (IQR 271-366). Of 222 seropositive contacts, 115 had pauci-symptomatic or asymptomatic Ebola virus infection and 107 had unrecognised Ebola virus disease. At baseline, prevalent findings of joint pain, memory loss, muscle pain, and fatigue were lowest among those with pauci-symptomatic or asymptomatic infection or no infection, higher among contacts with unrecognised Ebola virus disease, and highest in reported survivors of Ebola virus disease. Joint pain was the most prevalent finding, and was reported in 434 (18%) of 2466 individuals with no infection, 14 (12%) of 115 with pauci-symptomatic or asymptomatic infection, 31 (29%) of 107 with unrecognised Ebola virus disease, and 476 (48%) of 991 with reported Ebola virus disease. In adjusted analyses, this pattern remained for joint pain and memory loss. Survivors had an increased odds of joint pain compared with unrecognised Ebola virus disease contacts (adjusted odds ratio [OR] 2·13, 95% CI 1·34-3·39); unrecognised Ebola virus disease contacts had an increased odds of joint pain compared with those with pauci-symptomatic or asymptomatic infection and uninfected contacts (adjusted OR 1·89, 95% CI 1·21-2·97). The adjusted odds of memory loss was more than four-times higher among survivors than among unrecognised Ebola virus disease contacts (adjusted OR 4·47, 95% CI 2·41-8·30) and two-times higher among unrecognised Ebola virus disease contacts than in those with pauci-symptomatic or asymptomatic infection and uninfected contacts (adjusted OR 2·05, 95% CI 1·10-3·84). By 12 months, prevalent findings had decreased in the three infected groups. INTERPRETATION: Our findings provide evidence of post-Ebola virus disease clinical sequelae among contacts with unrecognised Ebola virus disease but not in people with pauci-symptomatic or asymptomatic Ebola virus infection. FUNDING: National Cancer Institute and National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

Smartphone confocal microscopy for imaging cellular structures in human skin in vivo.

We report development of a low-cost smartphone confocal microscope and its first demonstration of in vivo human skin imaging. The smartphone confocal microscope uses a slit aperture and diffraction grating to conduct two-dimensional confocal imaging without using any beam scanning devices. Lateral and axial resolutions of the smartphone confocal microscope were measured as 2 and 5 µm, respectively. In vivo confocal images of human skin revealed characteristic cellular structures, including spinous and basal keratinocytes and papillary dermis. Results suggest that the smartphone confocal microscope has a potential to examine cellular details in vivo and may help disease diagnosis in resource-poor settings, where conducting standard histopathologic analysis is challenging.

Heavy Cannabis Use Associated With Reduction in Activated and Inflammatory Immune Cell Frequencies in Antiretroviral Therapy-Treated Human Immunodeficiency Virus-Infected Individuals.

Background: Cannabis is a widely used drug in the United States, and the frequency of cannabis use in the human immunodeficiency virus (HIV)-infected population is disproportionately high. Previous human and macaque studies suggest that cannabis may have an impact on plasma viral load; however, the relationship between cannabis use and HIV-associated systemic inflammation and immune activation has not been well defined. Methods: The impact of cannabis use on peripheral immune cell frequency, activation, and function was assessed in 198 HIV-infected, antiretroviral-treated individuals by flow cytometry. Individuals were categorized into heavy, medium, or occasional cannabis users or noncannabis users based on the amount of the cannabis metabolite 11-nor-carboxy-tetrahydrocannabinol (THC-COOH) detected in plasma by mass spectrometry. Results: Heavy cannabis users had decreased frequencies of human leukocyte antigen (HLA)-DR+CD38+CD4+ and CD8+ T-cell frequencies, compared to frequencies of these cells in non-cannabis-using individuals. Heavy cannabis users had decreased frequencies of intermediate and nonclassical monocyte subsets, as well as decreased frequencies of interleukin 23- and tumor necrosis factor-α-producing antigen-presenting cells. Conclusions: While the clinical implications are unclear, our findings suggest that cannabis use is associated with a potentially beneficial reduction in systemic inflammation and immune activation in the context of antiretroviral-treated HIV infection.

A combined chemometric and quantitative NMR analysis of HIV/AIDS serum discloses metabolic alterations associated with disease status.

Individuals infected with the human immunodeficiency virus (HIV) often suffer from concomitant metabolic complications. Treatment with antiretroviral therapy has also been shown to alter the metabolism of patients. Although chemometric analysis of nuclear magnetic resonance (NMR) spectra of human sera can distinguish normal sera (HIVneg) from HIV-infected sera (HIVpos) and sera from HIV-infected patients on antiretroviral therapy (ART), quantitative analysis of the discriminating metabolites and their relationship to disease status has yet to be determined. The objectives of the study were to analyze NMR spectra of HIVneg, HIVpos, and ART serum samples with a combination of chemometric and quantitative methods and to compare the NMR data with disease status as measured by viral load and CD4 count. High-resolution magic angle spinning (HRMAS) NMR spectroscopy was performed on HIVneg (N = 10), HIVpos (N = 10), and ART (N = 10) serum samples. Chemometric linear discriminant analysis classified the three groups of spectra with 100% accuracy. Concentrations of 12 metabolites were determined with a semi-parametric metabolite quantification method named high-resolution quantum estimation (HR-QUEST). CD4 count was directly associated with alanine (p = 0.008), and inversely correlated with both glutamine (p = 0.017) and glucose (p = 0.022) concentrations. A multivariate linear model using alanine, glutamine and glucose as covariates demonstrated an association with CD4 count (p = 0.038). The combined chemometric and quantitative analysis of the data disclosed previously unknown associations between specific metabolites and disease status. The observed associations with CD4 count are consistent with metabolic disorders that are commonly seen in HIV-infected patients.

Viral dynamics and in vivo fitness of HIV-1 in the presence and absence of enfuvirtide.

OBJECTIVES: To estimate the in vivo fitness cost of enfuvirtide (ENF) resistance, we analyzed dynamic shifts in the HIV-1 quasispecies under changing selective pressure in 3 subjects on failing ENF-based regimens who interrupted ENF while maintaining stable background regimens. Subsequently, ENF was readministered for 4 weeks as "pulse intensification." METHODS: The proportion of plasma virus carrying the V38A mutation in gp41 was quantified by allele-specific real-time polymerase chain reaction in serial samples collected from 3 subjects at 1- to 4-week intervals. Fitness differences were calculated using a method that corrected for time dependence of the viral replication rate. RESULTS: The V38A mutant made up >or=85% of the quasispecies at baseline and decayed to <5% over 12-24 weeks; plasma HIV-1 RNA levels remained stable during this time. Fitness differences for mutant versus wild type ranged from -25% to -65%, providing in vivo evidence for the reduced fitness of ENF-resistant HIV-1. The V38A mutant virus reemerged rapidly during the ENF pulse. CONCLUSIONS: These results demonstrate that the HIV-1 quasispecies undergoes dynamic changes in response to withdrawal and reinitiation of fusion inhibitor therapy. The relative stability of plasma HIV-1 titers during decay of V38A suggests that factors other than viral fitness likely define viral load set-point in patients with advanced disease.

Loss of T cell responses following long-term cryopreservation.

Although cryopreservation of peripheral blood mononuclear cells (PBMC) is a commonly used technique, the degree to which it affects subsequent functional studies has not been well defined. Here we demonstrate that long-term cryopreservation has detrimental effects on T cell IFN-gamma responses in human immunodeficiency virus (HIV) infected individuals. Long-term cryopreservation caused marked decreases in CD4(+) T cell responses to whole proteins (HIV p55 and cytomegalovirus (CMV) lysate) and HIV peptides, and more limited decreases in CD8(+) T cell responses to whole proteins. These losses were more apparent in cells stored for greater than one year compared to less than six months. CD8(+) T cell responses to peptides and peptide pools were well preserved. Loss of both CD4(+) and CD8(+) T cell responses to CMV peptide pools were minimal in HIV-negative individuals. Addition of exogenous antigen presenting cells (APC) did not restore CD4(+) T cell responses to peptide stimulation and partially restored T cell IFN-gamma responses to p55 protein. Overnight resting of thawed cells did not restore T cell IFN-gamma responses to peptide or whole protein stimulation. A selective loss of phenotypically defined effector cells did not explain the decrement of responses, although cryopreservation did increase CD4(+) T cell apoptosis, possibly contributing to the loss of responses. These data suggest that the impact of cryopreservation should be carefully considered in future vaccine and pathogenesis studies. In HIV-infected individuals short-term cryopreservation may be acceptable for measuring CD4(+) and CD8(+) T cell responses. Long-term cryopreservation, however, may lead to the loss of CD4(+) T cell responses and mild skewing of T cell phenotypic marker expression.