Cost-effectiveness of single-dose AmBisome pre-emptive treatment for the prevention of cryptococcal meningitis in African low and middle-income countries.

Cryptococcal antigen (CrAg) screening is recommended for patients with advanced HIV to reduce AIDS-related mortality. For asymptomatic CrAg-positive persons, fluconazole pre-emptive therapy is standard, despite a ∼25% failure rate. Single-dose liposomal amphotericin B (AmBisome) is non-inferior to standard treatment for cryptococcal meningitis. We evaluate the threshold of efficacy necessary for AmBisome + fluconazole to be cost-effective as pre-emptive therapy for CrAg-positive persons.We created a decision analytic model to evaluate CrAg screening and treatment in HIV-infected persons with CD4 < 100 cells/µL. Costs were estimated for screening, pre-emptive therapy, and hospitalization for an example low-income country (Uganda) and middle-income country (South Africa). We used a discounted price range of AmBisome® at ${\$}$16.25 to ${\$}$40 per 50 mg vial for both Uganda and South Africa. We estimated AmBisome efficacy from 75 to 95%. Parameter assumptions were based on prospective CrAg screening studies and clinical trials in Africa. Disability adjusted life years (DALYs) were calculated using the age-specific life expectancy in Uganda, per WHO Global Health Observatory data. We modeled the theoretical efficacy of adjunctive AmBisome to determine cost per DALY averted.In South Africa, at ${\$}$16.25 per vial cost and a minimum efficacy of 85%, adjunctive AmBisome is cost-saving compared to fluconazole monotherapy. Compared to fluconazole pre-emptive therapy in Uganda, AmBisome + fluconazole would cost ${\$}$475, ${\$}$220, or ${\$}$136 per DALY averted if meningitis-free survival efficacy was 80, 85, or 90% at ${\$}$24 per vial cost.Investing in AmBisome may be cost-effective in low-income settings compared to using fluconazole pre-emptive therapy alone, if efficacy is 85% or greater. AmBisome pre-emptive therapy appears more cost-efficient in middle-income settings where hospitalization costs for meningitis, and GDP per capita are higher. LAY SUMMARY: We evaluate the efficacy necessary for AmBisome + fluconazole to be cost-effective to prevent cryptococcal meningitis. We found that if AmBisome pre-emptive therapy has an efficacy of 85% or greater, it is likely to be cost-effective in low-income settings.

mHealth for HIV Treatment & Prevention: A Systematic Review of the Literature.

This systematic review assesses the published literature to describe the landscape of mobile health technology (mHealth) for HIV/AIDS and the evidence supporting the use of these tools to address the HIV prevention, care, and treatment cascade. The speed of innovation, broad range of initiatives and tools, and heterogeneity in reporting have made it difficult to uncover and synthesize knowledge on how mHealth tools might be effective in addressing the HIV pandemic. To do address this gap, a team of reviewers collected literature on the use of mobile technology for HIV/AIDS among health, engineering, and social science literature databases and analyzed a final set of 62 articles. Articles were systematically coded, assessed for scientific rigor, and sorted for HIV programmatic relevance. The review revealed evidence that mHealth tools support HIV programmatic priorities, including: linkage to care, retention in care, and adherence to antiretroviral treatment. In terms of technical features, mHealth tools facilitate alerts and reminders, data collection, direct voice communication, educational messaging, information on demand, and more. Studies were mostly descriptive with a growing number of quasi-experimental and experimental designs. There was a lack of evidence around the use of mHealth tools to address the needs of key populations, including pregnant mothers, sex workers, users of injection drugs, and men who have sex with men. The science and practice of mHealth for HIV are evolving rapidly, but still in their early stages. Small-scale efforts, pilot projects, and preliminary descriptive studies are advancing and there is a promising trend toward implementing mHealth innovation that is feasible and acceptable within low-resource settings, positive program outcomes, operational improvements, and rigorous study design.

Time to clearance of Chlamydia trachomatis ribosomal RNA in women treated for chlamydial infection.

BACKGROUND: The dynamics of chlamydia clearance after treatment administration for chlamydial urogenital infection are unknown. We estimated the time to clearance of Chlamydia trachomatis (CT) ribosomal RNA (rRNA) after administration of azithromycin for cervical chlamydial infection using APTIMA Combo 2 (Gen-Probe, Inc., San Diego, CA, USA). METHODS: A total of 115 women diagnosed with urogenital chlamydial infection, defined as a positive APTIMA urine or endocervical specimen, were enrolled in the present study. Vaginal swabs on the day of treatment (Day 0) and on Days 3, 7, 10 and 14 after treatment with 1 g of azithromycin were self-obtained by participants. Specimens were tested in a single laboratory. Our analysis was limited to women who were CT-confirmed by vaginal swab at baseline, who returned all follow-up swabs, and who reported sexual abstinence during the follow-up period (n = 61). RESULTS: Among 61 participants, 48 (79%) had a negative APTIMA at Day 14. Subjects with a negative APTIMA at each time-point were as follows: 0/61 (0%) on Day 0, 7/61 (12%) on Day 3, 28/61 (46%) on Day 7, 40/61 (66%) on Day 10, and 48/61 (79%) on Day 14. Multiple linear regression analysis predicted time to clearance at 17 days (95% confidence interval, 16-18 days) after administration of azithromycin. Seventeen of the 94 participants (18.1%) who screened positive for chlamydia had a negative vaginal swab on Day 0, indicating possible spontaneous clearance of CT. CONCLUSIONS: After treatment, CT rRNA declined with time. As rRNA was still detectable in 21% of the women 14 days after treatment, APTIMA should not be used as a test-of-cure in the 14-day period following azithromycin administration.

Validation of Microcapillary Flow Cytometry for Community-Based CD4+ T Lymphocyte Enumeration in Remote Burkina Faso.

BACKGROUND: CD4+ T lymphocyte enumeration plays a critical role in the initiation and monitoring of HIV-infected patients on antiretroviral therapy. There is an urgent need for low-cost CD4+ enumeration technologies, particularly for use in dry, dusty climates characteristic of many small cities in Sub-Saharan Africa. DESIGN: Cross-sectional study. METHODS: Blood samples from 98 HIV-infected patients followed in a community HIV clinic in Ouahigouya, Burkina Faso were obtained for routine CD4+ T lymphocyte count monitoring. The blood samples were divided into two aliquots, on which parallel CD4+ measurements were performed using microcapillary (Guava EasyCD4) and dedicated (Becton Dickinson FACSCount) CD4+ enumeration systems. Spearman rank correlation coefficient was calculated, and the sensitivity, specificity and positive predictive value (PPV) for EasyCD4 <200 cells/µL were determined compared to the reference standard FACSCount CD4 <200 cells/µL. RESULTS: Mean CD4 counts for the EasyCD4 and FACSCount were 313.75 cells/µL and 303.47 cells/µL, respectively. The Spearman rank correlation coefficient was 0.92 (p<0.001). Median values using EasyCD4 were higher than those with the FACSCount (p=0.004). For a CD4<350 cells/uL, sensitivity of the EasyCD4 was 93.9% (95%CI 85.2-98.3%), specificity was 90.6% (95% CI 75.0-98.0%), and PPV was 95.4% (95%CI 87.1-99.0%). CONCLUSION: Use of the EasyCD4 system was feasible and highly accurate in the harsh conditions of this remote city in Sub-Saharan Africa, demonstrating acceptable sensitivity and specificity compared to a standard operating system. Microcapillary flow cytometry offers a cost-effective alternative for community-based, point-of-care CD4+ testing and could play a substantial role in scaling up HIV care in remote, resource-limited settings.

Detection of HIV-1 in Saliva: Implications for Case-Identification, Clinical Monitoring and Surveillance for Drug Resistance.

BACKGROUND: Saliva tests that detect antibodies are used to diagnose HIV infection. The goal of this study was to determine whether saliva could be used for nucleic acid-based tests to measure HIV-1 virus load (VL) and detect drug resistance. METHODS: 69 HIV infected individuals provided 5-10 ml of saliva and blood samples. Viral RNA was isolated from saliva and dried blood spots using the Nuclisens extraction. Saliva VL was measured using a modified Amplicor assay, and genotyping was performed using an in-house RT-PCR/sequencing protocol. Plasma VLs were obtained from concurrently drawn clinical tests. RESULTS: Thirty-six of 47 (77%) plasma viremic patients had measurable saliva HIV-1 RNA. Paired plasma and saliva HIV RNA levels were significantly correlated (Spearman's correlation = .6532, p<.0001), but saliva VL was typically lower. Three of 22 patients with undetectable plasma VL (<50 copies/ml) had detectable saliva HIV RNA. Eleven of 30 patients with undetectable saliva RNA had detectable plasma HIV-1 RNA. Comparison of the protease and reverse transcriptase gene sequences from paired saliva and plasma of 20 patients showed less than 1% difference overall, and few resistance-related amino acid differences CONCLUSIONS: Most patients with plasma virus >50 copies/mL had detectable saliva HIV RNA, and the genotypic data was highly concordant between saliva and plasma. In patients with high levels of plasma HIV RNA, saliva might be useful in identifying viremia and evaluating drug resistance.

Single-cell, phosphoepitope-specific analysis demonstrates cell type- and pathway-specific dysregulation of Jak/STAT and MAPK signaling associated with in vivo human immunodeficiency virus type 1 infection.

Despite extensive evidence of cell signaling alterations induced by human immunodeficiency virus type 1 (HIV-1) in vitro, the relevance of these changes to the clinical and/or immunologic status of HIV-1-infected individuals is often unclear. As such, mapping the details of cell type-specific degradation of immune function as a consequence of changes to signaling network responses has not been readily accessible. We used a flow cytometric-based assay of signaling to determine Janus kinase/signal transducers and activators of transcription (Jak/STAT) signaling changes at the single-cell level within distinct cell subsets from the primary immune cells of HIV-1-infected donors. We identified a specific defect in granulocyte-macrophage colony-stimulating factor (GM-CSF)-driven Stat5 phosphorylation in the monocytes of HIV-1+ donors. This inhibition was statistically significant in a cohort of treated and untreated individuals. Ex vivo Stat5 phosphorylation levels varied among HIV-1+ donors but did not correlate with CD4(+) T-cell counts or HIV-1 plasma viral load. Low Stat5 activation occurred in HIV-1-infected donors despite normal GM-CSF receptor levels. Investigation of mitogen-activated protein kinase (MAPK) pathways, also stimulated by GM-CSF, led to the observation that lipopolysaccharide-stimulated extracellular signal-regulated kinase phosphorylation is enhanced in monocytes. Thus, we have identified a specific, imbalanced monocyte signaling profile, with inhibition of STAT and enhancement of MAPK signaling, associated with HIV-1 infection. This understanding of altered monocyte signaling responses that contribute to defective antigen presentation during HIV-1 infection could lead to immunotherapeutic approaches that compensate for the deficiency.

Proteomic analysis of serum cytokine levels in response to highly active antiretroviral therapy (HAART).

A 30-cytokine protein microarray was used to screen for cytokine profile changes in HIV-infected patients in response to highly active antiretroviral therapy (HAART). Serum cytokines showing significant changes were confirmed by enzyme immunoassay. Monokine induced by gamma-interferon (MIG) and interferon-inducible protein-10 (IP-10) levels significantly decreased after 24 weeks of HAART. Protein microarrays are useful for initial screening of novel cytokine expression. Further studies are needed to elucidate the role of MIG and IP-10 in response to HAART.

Marijuana use and its association with adherence to antiretroviral therapy among HIV-infected persons with moderate to severe nausea.

BACKGROUND: Adherence to antiretroviral therapy (ART) is essential to successful treatment of HIV infection. Two recent studies reported a negative correlation between marijuana use and adherence to ART. Some patients, however, report that smoking marijuana improves adherence to ART. This study therefore sought to identify which subgroups of patients may have differential adherence to ART in association with recent marijuana use. METHODS: Cross-sectional survey design within a public health care system for HIV/AIDS. RESULTS: With a 5% refusal rate, 252 patients completed the interview, 175 (69%) were on ART, and 168 (67%) provided ART adherence data. Forty-one subjects (24%), predominantly whites, used marijuana. In bivariate analysis, no association between ART adherence and marijuana use was found (odds ratio [OR] = 0.92, 95% CI = 0.4-1.9). Adherence was positively associated with undetectable plasma virus and negatively associated with alcohol and other illicit drug use. Examining subgroups of patients, among those with nausea, marijuana users were more likely to show an association with adherence than nonusers (OR = 3.3), while among those without nausea, marijuana use was lower associated with adherence (OR = 0.52, P for homogeneity 0.02). This relationship was confirmed in multivariate analyses controlling for the interactions between nausea and marijuana use, in which other illicit drug use remained a factor related to nonadherence. DISCUSSION: These data suggest that medicinal use of marijuana may facilitate, rather than impede, ART adherence for patients with nausea, in contrast to the use of other illicit substances, which were associated with lower rates of ART adherence. To demonstrate any causal relationship between marijuana and adherence would require a longitudinal or controlled study.

Patterns of marijuana use among patients with HIV/AIDS followed in a public health care setting.

OBJECTIVES: To examine prevalence and patterns of smoked marijuana and perceived benefit and to assess demographic and clinical factors associated with marijuana use among HIV patients in a public health care setting. METHODS: Participants (n = 252) were recruited via consecutive sampling in public health care clinics. Structured interviews assessed patterns of recent marijuana use, including its perceived benefit for symptom relief. Associations between marijuana use and demographic and clinical variables were examined using univariate and multivariate regression analyses. RESULTS: Overall prevalence of smoked marijuana in the previous month was 23%. Reported benefits included relief of anxiety and/or depression (57%), improved appetite (53%), increased pleasure (33%), and relief of pain (28%). Recent use of marijuana was positively associated with severe nausea (odds ratio [OR] = 4.0, P = 0.004) and recent use of alcohol (OR = 7.5, P < 0.001) and negatively associated with being Latino (OR = 0.07, P < 0.001). No associations between marijuana use and pain symptoms were observed. CONCLUSIONS: The findings suggest that providers be advised to assess routinely and better understand patients' "indications" for self-administration of cannabis. Given the estimated prevalence, more formal characterization of the patterns and impact of cannabis use to alleviate HIV-associated symptoms is warranted. Clinical trials of smoked and noncombustible marijuana are needed to determine the role of cannabinoids as a class of agents with potential to improve quality of life and health care outcomes among patients with HIV/AIDS.

Clinical management of tuberculosis in the context of HIV infection.

Globally, the HIV and tuberculosis epidemics are stoking each other, creating a public health crisis of enormous proportions. At the level of individuals, contemporaneous infection with M. tuberculosis and HIV poses great challenges to clinical management. This chapter provides an overview of active and latent tuberculosis treatment in HIV-infected and -uninfected individuals. The discussion focuses on medication issues, including interactions between antitubercular drugs, antiretroviral drugs, and medicines used for opportunistic infections and treatment in the face of comorbidities. Clinical questions specific to coinfection are discussed, including duration and timing initiation of therapy and immune reconstitution. Most of the data presented were generated in industrialized settings and are presented to assist patient management in such settings. However, given the disproportionate amount of TB/HIV in less-developed nations and the increasing availability of antiretroviral therapy in resource-limited settings, the issues presented will become increasingly relevant globally.

Social support, substance use, and denial in relationship to antiretroviral treatment adherence among HIV-infected persons.

This study examined the relationship of adherence to antiretroviral treatment with three types of social support (partner, friends, and family) and use of two coping strategies (denial and substance use). Participants were 73 men and women with HIV infection drawn from a larger sample of 186 clinical trial patients. Based on inclusion criteria, parent trial participants taking antiretroviral therapies, and those with complete data on self-reported measures of adherence were considered eligible for the present study. Overall, 26% of participants were found to be nonadherent, which was defined as one or more missed doses of treatment in the prior 4-day period. Logistic regression analysis was conducted to determine associations of sociodemographic and psychosocial variables with adherence to antiretroviral regimen. Results indicated that heterosexual participants (p < 0.01) and participants of Latino ethnicity (p < 0.05) were significantly more likely to report missed medications. Perceived satisfaction with support from a partner was associated with taking antiretroviral therapy as prescribed, whereas satisfaction with support from friends and from family was not significantly related to adherence. Examination of coping strategies showed that participants reporting drug and alcohol use (p <.05) to cope with HIV-related stress were more likely to be nonadherent. These findings call for adherence interventions designed to address barriers and strengths, such as community norms or traditional cultural values, specific to certain populations. Furthermore, couple-based approaches enlisting partner support may help persons living with HIV to adhere to antiretroviral regimens.

HIV: effectiveness of complementary and alternative medicine.

Outcome studies examining the efficacy of CAM among people living with HIV-AIDS are often conducted among small sample sizes with very little follow-up data or time points. Generalizability of many of the study findings is further limited by participant attrition. It is difficult to conduct clinical studies on chronically ill patients without participants dropping out, typically because the study demands coupled with their illness become too burdensome. Several studies have been conducted that include control groups, double-blind designs, and randomization. These scientifically sound studies have demonstrated promising results that strongly indicate a need for further research with larger samples in a prospective research design so that safety and efficacy can be determined over time. Many of the studies with small sample sizes reported trends, but did not find statistical significance. Increasing sample sizes in future studies is necessary to evaluate the scientific merit of these trends. Moreover, researchers need to evaluate the clinical and statistical significance in CAM use. The psychologic benefits of taking CAM should not be underestimated. For the purposes of this article, the authors did not include psychologic outcomes; however, there is evidence suggesting that decreasing depression can decrease HIV-related somatic complaints [69]. Studies need also to examine the effectiveness of CAM on psychologic outcomes and physical outcomes. This article and the authors' own research (Gore-Felton C et al, unpublished data) have revealed a high prevalence of alternative supplement use in conjunction with HIV medication, indicating an urgent need to understand the health benefits and the health risks of alternative supplements among patients with HIV and AIDS. Patients and physicians need more empirically based research to examine the toxicities, interactions, and health benefits of CAM. Many patients do not report the use of CAM to their physicians and very few physicians record treatments in the clinical record [70]. This will likely change as CAM becomes more widely recognized as a legitimate medical intervention; however, controlled outcome studies among large, diverse samples of people living with HIV-AIDS are needed. Health care providers need to assess the use of herbal and alternative therapy practices by their patients. Some patients may not be aware that they are taking a supplement or plant-based herb. Furthermore, some patients may believe that they are using something innocuous and even healthy simply because it came from a health food store. Understanding the contraindications of alternative therapies is necessary to prevent deleterious outcomes and to facilitate the safe and efficacious use of CAM in the management of HIV disease and related symptoms. As the epidemic in the United States continues to rise among women and minority populations, clinical research trials must include ethnically diverse patient populations that are gender balanced. Current available studies indicate that many CAM interventions may improve the quality of life of people living with HIV-AIDS; however, further studies using longitudinal, controlled designs are needed to accurately assess the safety of such interventions.