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1.  Schistosomiasis Elimination Strategies and Potential Role of a Vaccine in Achieving Global Health Goals 
In March 2013, the National Institute of Allergy and Infectious Diseases and the Bill and Melinda Gates Foundation co-sponsored a meeting entitled “Schistosomiasis Elimination Strategy and Potential Role of a Vaccine in Achieving Global Health Goals” to discuss the potential role of schistosomiasis vaccines and other tools in the context of schistosomiasis control and elimination strategies. It was concluded that although schistosomiasis elimination in some focal areas may be achievable through current mass drug administration programs, global control and elimination will face several significant scientific and operational challenges, and will require an integrated approach with other, additional interventions. These challenges include vector (snail) control; environmental modification; water, sanitation, and hygiene; and other future innovative tools such as vaccines. Defining a clear product development plan that reflects a vaccine strategy as complementary to the existing control programs to combat different forms of schistosomiasis will be important to develop a vaccine effectively.
doi:10.4269/ajtmh.13-0467
PMCID: PMC3886428  PMID: 24402703
2.  Use of Principal Components Analysis and Protein Microarray to Explore the Association of HIV-1-Specific IgG Responses with Disease Progression 
Abstract
The role of HIV-1-specific antibody responses in HIV disease progression is complex and would benefit from analysis techniques that examine clusterings of responses. Protein microarray platforms facilitate the simultaneous evaluation of numerous protein-specific antibody responses, though excessive data are cumbersome in analyses. Principal components analysis (PCA) reduces data dimensionality by generating fewer composite variables that maximally account for variance in a dataset. To identify clusters of antibody responses involved in disease control, we investigated the association of HIV-1-specific antibody responses by protein microarray, and assessed their association with disease progression using PCA in a nested cohort design. Associations observed among collections of antibody responses paralleled protein-specific responses. At baseline, greater antibody responses to the transmembrane glycoprotein (TM) and reverse transcriptase (RT) were associated with higher viral loads, while responses to the surface glycoprotein (SU), capsid (CA), matrix (MA), and integrase (IN) proteins were associated with lower viral loads. Over 12 months greater antibody responses were associated with smaller decreases in CD4 count (CA, MA, IN), and reduced likelihood of disease progression (CA, IN). PCA and protein microarray analyses highlighted a collection of HIV-specific antibody responses that together were associated with reduced disease progression, and may not have been identified by examining individual antibody responses. This technique may be useful to explore multifaceted host–disease interactions, such as HIV coinfections.
doi:10.1089/aid.2013.0088
PMCID: PMC3931433  PMID: 24134221
3.  Species-specific treatment effects of helminth/HIV-1 co-infection: a systematic review and meta-analysis 
Parasitology  2011;138(12):1546-1558.
SUMMARY
In sub-Saharan Africa, over 22 million people are estimated to be co-infected with both helminths and HIV-1. Several studies have suggested that de-worming individuals with HIV-1 may delay HIV-1 disease progression, and that the benefit of de-worming may vary by individual helminth species. We conducted a systematic review and meta-analysis of the published literature to determine the effect of treatment of individual helminth infections on markers of HIV-1 progression (CD4 count and HIV viral load). There was a trend towards an association between treatment for Schistosoma mansoni and a decrease in HIV viral load (Weighted mean difference (WMD)=−0·10; 95% Confidence interval (CI): −0·24, 0·03), although this association was not seen for Ascaris lumbricoides, hookworm or Trichuris trichiura. Treatment of A. lumbricoides, S. mansoni, hookworm or T. trichiura was not associated with a change in CD4 count. While pooled data from randomized trials suggested clinical benefit of de-worming for individual helminth species, these effects decreased when observational data were included in the pooled analysis. While further trials are needed to confirm the role of anthelmintic treatment in HIV-1 co-infected individuals, providing anthelmintics to individuals with HIV-1 may be a safe, inexpensive and practical intervention to slow progression of HIV-1.
doi:10.1017/S0031182011000357
PMCID: PMC3387276  PMID: 21729353
Helminth; HIV-1; co-infection; meta-analysis; Kenya
4.  Treatment of helminth co-infection in HIV-1 infected individuals in resource-limited settings 
Background
The HIV-1 pandemic has disproportionately affected individuals in resource-constrained settings. These areas often also have high prevalence of other infectious diseases, such as helminth infections. It is important to determine if helminth infection affects the progression of HIV-1 in these co-infected individuals. There are biologically plausible reasons for possible effects of helminth infection in HIV-1 infected individuals and findings from some observational studies suggest that helminth infection may adversely affect HIV-1 progression. We sought to evaluate the available evidence from published and unpublished studies to determine if treatment of helminth infection in HIV-1 co-infected individuals impacts HIV-1 progression.
Objectives
Our objective was to determine if treating helminth infection in individuals with HIV-1 can reduce the progression of HIV-1 as determined by changes in CD4 count, viral load, or clinical disease progression (including mortality).
Search strategy
We searched online for published and unpublished studies in The Cochrane Library (Issue 3, 2006), MEDLINE (November 2006), EMBASE (November 2006), CENTRAL (July 2006), AIDSEARCH (August 2006). We also searched databases listing conference abstracts, scanned reference lists of articles, and contacted authors of included studies.
Selection criteria
We searched for randomized and quasi-randomized controlled trials that compared HIV-1 progression as measured by changes in CD4 count, viral load, or clinical disease progression in HIV-1 infected individuals receiving anti-helminth therapy. Observational studies with relevant data were also included.
Data collection and analysis
Data regarding changes in CD4 count, HIV-1 RNA levels, clinical staging and/or mortality after treatment of helminth co-infection were extracted from the reports of the studies.
Main results
Of 6,384 abstracts identified, 15 met criteria for potential inclusion, of which five were eligible for inclusion. In the single randomized controlled trial (RCT) identified, HIV-1 and schistosomiasis co-infected individuals receiving treatment for schistosomiasis had a significantly lower change in plasma HIV-1 RNA over three months (−0.001 log10 copies/mL) compared to those receiving no treatment (+0.21 log10 copies/mL), (p=0.03). Four observational studies met inclusion criteria and all of these suggested a possible beneficial effect of helminth eradication on plasma HIV-1 RNA levels when compared to plasma HIV-1 RNA changes prior to helminth treatment or to helminth-uninfected or persistently helminth-infected individuals. Follow-up duration in these studies ranged from three to six months. The reported magnitude of effect on HIV-1 RNA was variable, ranging from 0.07–1.05 log10 copies/mL. None of the included studies showed a significant benefit of helminth treatment on CD4 decline, clinical staging, or mortality.
Authors' conclusions
There are insufficient data available to determine the potential benefit of helminth eradication in HIV-1 and helminth co-infected adults. Data from a single RCT and multiple observational studies suggest possible benefit in reducing plasma viral load. The impact of de-worming on markers of HIV-1 progression should be addressed in larger randomized studies evaluating species-specific effects and with a sufficient duration of follow-up to document potential differences on clinical outcomes and CD4 decline.
doi:10.1002/14651858.CD006419.pub2
PMCID: PMC3372409  PMID: 18254104
CD4 Lymphocyte Count; Disease Progression; *Health Resources; Helminthiasis [complications; *drug therapy]; *HIV-1 [genetics]; HIV Infections [*complications;parasitology;virology]; Poverty Areas; RNA, Viral [analysis]; Schistosomiasis [drug therapy]; Viral Load; Humans
5.  Morbidity Among HIV-1–Infected Mothers in Kenya 
Background
Much of the burden of morbidity affecting women of childbearing age in sub-Saharan Africa occurs in the context of HIV-1 infection. Understanding patterns of illness and determinants of disease in HIV-1–infected mothers may guide effective interventions to improve maternal health in this setting.
Methods
We describe the incidence and cofactors of comorbidities affecting peripartum and postpartum HIV-1–infected women in Kenya. Women were evaluated by clinical examination and standardized questionnaires during pregnancy and for up to 2 years after delivery.
Results
Five hundred thirty-five women were enrolled in the cohort (median CD4 count of 433 cells/mm3) and accrued 7736 person-months of follow-up. During 1-year follow-up, the incidence of upper respiratory tract infections was 161 per 100 person-years, incidence of pneumonia was 33 per 100 person-years, incidence of tuberculosis (TB) was 11 per 100 person-years, and incidence of diarrhea was 63 per 100 person-years. Immunosuppression and HIV-1 RNA levels were predictive for pneumonia, oral thrush, and TB but not for diarrhea; CD4 counts <200 cells/mm3 were associated with pneumonia (relative risk [RR] = 2.87, 95% confidence interval [CI]: 1.71 to 4.83), TB (RR = 7.14, 95% CI: 2.93 to 17.40) and thrush. The risk of diarrhea was significantly associated with crowding (RR = 1.86, 95% CI: 1.19 to 2.92) and breast-feeding (RR = 1.71, 95% CI: 1.19 to 2.44). Less than 10% of women reported hospitalization during 2-year follow-up; mortality risk in the cohort was 1.9% and 4.8% for 1 and 2 years, respectively.
Conclusions
Mothers with HIV-1, although generally healthy, have substantial morbidity as a result of common infections, some of which are predicted by immune status or by socioeconomic factors. Enhanced attention to maternal health is increasingly important as HIV-1–infected mothers transition from programs targeting the prevention of mother-to-child transmission to HIV care clinics.
doi:10.1097/QAI.0b013e318141fcc0
PMCID: PMC3372412  PMID: 17667334
HIV/AIDS; HIV-1 progression; maternal health; morbidity; postpartum; pregnancy; prevention of mother-to-child transmission; women
6.  Changes in Plasma Cytokines Following Treatment of Ascaris lumbricoides in HIV-1 Infected Individuals 
The Journal of infectious diseases  2010;201(12):1816-1821.
Albendazole treatment of HIV-1/Ascaris lumbricoides co-infected individuals led to significantly improved CD4 cell counts and a trend for lower plasma HIV-1 RNA levels in a previous randomized placebo-controlled trial. To define mechanisms by which deworming contributed to changes in markers of HIV-1 disease progression, plasma cytokine levels were evaluated. Albendazole treatment was associated with significantly decreased plasma IL-10 levels when compared to placebo (P = 0.04), but not with significant changes in levels of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12p70, IL-13, IFN-γ, TNF-α, or TSLP. Treatment of A. lumbricoides co-infection may delay HIV-1 disease progression by reducing helminth-induced, IL-10-mediated immunosuppression.
doi:10.1086/652784
PMCID: PMC2946624  PMID: 20441516
HIV-1; Ascaris lumbricoides; helminth; co-infection; CD4 T cell count; IL-10; cytokines; albendazole
7.  Deworming helminth co-infected individuals for delaying HIV disease progression 
Background
The HIV-1 pandemic has disproportionately affected individuals in resource-constrained settings where other infectious diseases, such as helminth infections, also are highly prevalent. There are biologically plausible reasons for possible effects of helminth infection in HIV-1-infected individuals, and findings from multiple studies suggest that helminth infection may adversely affect HIV-1 progression. Since initial publication of this review (Walson 2007), additional data from randomized controlled trials (RCTs) has become available. We sought to evaluate all currently available evidence to determine if treatment of helminth infection in HIV-1 co-infected individuals impacts HIV-1 progression.
Objectives
To determine if treating helminth infection in individuals with HIV-1 can reduce the progression of HIV-1 as determined by changes in CD4 count, viral load, or clinical disease progression.
Search strategy
In this 2008 update, we searched online for published and unpublished studies in The Cochrane Library, MEDLINE, EMBASE, CENTRAL, and AIDSEARCH. We also searched databases listing conference abstracts, scanned reference lists of articles, and contacted authors of included studies.
Selection criteria
We searched for RCTs and quasi-RCTs that compared HIV-1 progression as measured by changes in CD4 count, viral load, or clinical disease progression in HIV-1 infected individuals receiving anti-helminthic therapy.
Data collection and analysis
Data regarding changes in CD4 count, HIV-1 RNA levels, and/or clinical staging after treatment of helminth co-infection were extracted from identified studies.
Main results
Of 7,019 abstracts identified (6,384 from original searches plus 635 from updated searches), 17 abstracts were identified as meeting criteria for potential inclusion (15 from previous review plus an additional two RCTs). After restricting inclusion to RCTs, a total of three studies were eligible for inclusion in this updated review.
All three trials showed individual beneficial effects of helminth eradication on markers of HIV-1 disease progression (HIV-1 RNA and/or CD4 counts). When data from these trials were pooled, the analysis demonstrated significant benefit of deworming on both plasma HIV-1 RNA and CD4 counts.
Authors’ conclusions
To date, three RCTs have evaluated the effects of deworming on markers of HIV-1 disease progression in helminth and HIV-1 co-infected individuals. All trials demonstrate benefit in attenuating or reducing plasma viral load and/or increasing CD4 counts. When taken together, there is evidence of benefit for deworming HIV-1 co-infected adults. Given that these studies evaluated different helminth species and different interventions, further trials are warranted to evaluate species-specific effects and to document long-term clinical outcomes following deworming.
doi:10.1002/14651858.CD006419.pub3
PMCID: PMC2871762  PMID: 19588389
Medical Subject Headings (MeSH); *Health Resources; *HIV-1 [genetics]; CD4 Lymphocyte Count; Disease Progression; Helminthiasis [complications; *drug therapy]; HIV Infections [*complications; parasitology; virology]; Poverty Areas; RNA; Viral [analysis]; Schistosomiasis [drug therapy]; Viral Load; MeSH check words; Humans
8.  Albendazole treatment of HIV-1 and helminth co-infection: A randomized, double blind, placebo-controlled trial 
AIDS (London, England)  2008;22(13):1601-1609.
OBJECTIVE
Several co-infections have been shown to impact the progression of HIV-1 infection. We sought to determine if treatment of helminth co-infection in HIV-1 infected adults impacted markers of HIV-1 disease progression.
DESIGN
To date there have been no randomized trials to examine the effects of soil-transmitted helminth eradication on markers of HIV-1 progression.
METHODS
A randomized, double-blind, placebo-controlled trial of albendazole (400mg daily for three days) in antiretroviral-naïve HIV-1 infected adults (CD4 >200 cells/mm3) with soil-transmitted helminth infection was conducted at ten sites in Kenya (Clinical Trials.gov NCT00130910). CD4 and plasma HIV-1 RNA levels at 12 weeks following randomization were compared in the trial arms using linear regression, adjusting for baseline values.
RESULTS
Of 1,551 HIV-1 infected individuals screened for helminth-infection, 299 were helminth-infected. 234 adults were enrolled and underwent randomization and 208 individuals were included in intent-to-treat analyses. Mean CD4 count was 557 cells/mm3 and mean plasma viral load was 4.75 log10 copies/mL at enrolment. Albendazole therapy resulted in significantly higher CD4 counts among individuals with Ascaris lumbricoides infection after 12 weeks of follow up (+109 cells/mm3; 95% CI +38.9 to +179.0, p=0.003) and a trend for 0.54 log10 lower HIV-1 RNA levels (p=0.09). These effects were not seen with treatment of other species of soil-transmitted helminths.
CONCLUSIONS
Treatment of A. lumbricoides with albendazole in HIV-1 co-infected adults resulted in significantly increased CD4 counts during 3-month follow-up. Given the high prevalence of A. lumbricoides infection worldwide, deworming may be an important potential strategy to delay HIV-1 progression.
doi:10.1097/QAD.0b013e32830a502e
PMCID: PMC2637615  PMID: 18670219
HIV-1 progression; helminth; co-infection
9.  Estimating the Burden of Paratyphoid A in Asia and Africa 
Despite the increasing availability of typhoid vaccine in many regions, global estimates of mortality attributable to enteric fever appear stable. While both Salmonella enterica serovar Typhi (S. Typhi) and serovar Paratyphi (S. Paratyphi) cause enteric fever, limited data exist estimating the burden of S. Paratyphi, particularly in Asia and Africa.
We performed a systematic review of both English and Chinese-language databases to estimate the regional burden of paratyphoid within Africa and Asia. Distinct from previous reviews of the topic, we have presented two separate measures of burden; both incidence and proportion of enteric fever attributable to paratyphoid. Included articles reported laboratory-confirmed Salmonella serovar classification, provided clear methods on sampling strategy, defined the age range of participants, and specified the time period of the study.
A total of 64 full-text articles satisfied inclusion criteria and were included in the qualitative synthesis. Paratyphoid A was commonly identified as a cause of enteric fever throughout Asia. The highest incidence estimates in Asia came from China; four studies estimated incidence rates of over 150 cases/100,000 person-years. Paratyphoid A burden estimates from Africa were extremely limited and with the exception of Nigeria, few population or hospital-based studies from Africa reported significant Paratyphoid A burden.
While significant gaps exist in the existing population-level estimates of paratyphoid burden in Asia and Africa, available data suggest that paratyphoid A is a significant cause of enteric fever in Asia. The high variability in documented incidence and proportion estimates of paratyphoid suggest considerable geospatial variability in the burden of paratyphoid fever. Additional efforts to monitor enteric fever at the population level will be necessary in order to accurately quantify the public health threat posed by S. Paratyphi A, and to improve the prevention and treatment of enteric fever.
Author Summary
Enteric fever due to Salmonella enterica serovar Typhi (S. Typhi) and serovar Paratyphi (S. Paratyphi A, B, C) remains a global public health concern. While numerous studies have estimated the levels or burden of S. Typhi, there are only limited data estimating the burden of S. Paratyphi A, particularly in Asia and Africa. We reviewed both English and Chinese-language databases for estimates of the regional burden within Africa and Asia, including new paratyphoid A cases/year and proportion of enteric fever cases attributable to paratyphoid A. S. Paratyphi A appears to constitute a significant proportion of all cases of enteric fever in Asia, though population level estimates are limited, especially in Africa. There was high variability in reported paratyphoid A burden estimates, which suggests considerable geospatial variability in the burden of paratyphoid fever. Improved efforts to monitor enteric fever at the population level are warranted in order to correctly measure the public health threat posed by S. Paratyphi A and to determine the potential need for S. Paratyphi specific prevention and treatment interventions.
doi:10.1371/journal.pntd.0002925
PMCID: PMC4046978  PMID: 24901439
10.  Prioritizing Countries for Interventions to Reduce Child Mortality: Tools for Maximizing the Impact of Mass Drug Administration of Azithromycin 
PLoS ONE  2014;9(5):e96658.
Background
As new interventions to reduce childhood mortality are identified, careful consideration must be given to identifying populations that could benefit most from them. Promising reductions in childhood mortality reported in a large cluster randomized trial of mass drug administration (MDA) of azithromycin (AZM) prompted the development of visually compelling, easy-to-use tools that synthesize country-specific data on factors that would influence both potential AZM benefit and MDA implementation success.
Methodology/Principal Findings
We assessed the opportunity to reduce mortality and the feasibility of implementing such a program, creating Opportunity and Feasibility Indices, respectively. Countries with high childhood mortality were included. A Country Ranking Index combined key variables from the previous two Indices and applied a scoring system to identify high-priority countries. We compared four scenarios with varying weights given to each variable.
Twenty-five countries met inclusion criteria. We created easily visualized tools to display the results of the Opportunity and Feasibility Indices. The Opportunity Index revealed substantial variation in the opportunity for an MDA of AZM program to reduce mortality, even among countries with high overall childhood mortality. The Feasibility Index demonstrated that implementing such a program would be most challenging in the countries that could see greatest benefit. Based on the Country Ranking Index, Equatorial Guinea would benefit the most from the MZA of AZM in three of the four scenarios we tested.
Conclusions/Significance
These visually accessible tools can be adapted or refined to include other metrics deemed important by stakeholders, and provide a quantitative approach to prioritization for intervention implementation. The need to explicitly state metrics and their weighting encourages thoughtful and transparent decision making. The objective and data-driven approach promoted by the three Indices may foster more efficient use of resources.
doi:10.1371/journal.pone.0096658
PMCID: PMC4023929  PMID: 24837459
11.  Impact of Helminth Diagnostic Test Performance on Estimation of Risk Factors and Outcomes in HIV-Positive Adults 
PLoS ONE  2013;8(12):e81915.
Background
Traditional methods using microscopy for the detection of helminth infections have limited sensitivity. Polymerase chain reaction (PCR) assays enhance detection of helminths, particularly low burden infections. However, differences in test performance may modify the ability to detect associations between helminth infection, risk factors, and sequelae. We compared these associations using microscopy and PCR.
Methods
This cross-sectional study was nested within a randomized clinical trial conducted at 3 sites in Kenya. We performed microscopy and real-time multiplex PCR for the stool detection and quantification of Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, Strongyloides stercoralis, and Schistosoma species. We utilized regression to evaluate associations between potential risk factors or outcomes and infection as detected by either method.
Results
Of 153 HIV-positive adults surveyed, 55(36.0%) and 20(13.1%) were positive for one or more helminth species by PCR and microscopy, respectively (p<0.001). PCR-detected infections were associated with farming (Prevalence Ratio 1.57, 95% CI: 1.02, 2.40), communal water source (PR 3.80, 95% CI: 1.01, 14.27), and no primary education (PR 1.54, 95% CI: 1.14, 2.33), whereas microscopy-detected infections were not associated with any risk factors under investigation. Microscopy-detected infections were associated with significantly lower hematocrit and hemoglobin (means of -3.56% and -0.77 g/dl) and a 48% higher risk of anemia (PR 1.48, 95% CI: 1.17, 1.88) compared to uninfected. Such associations were absent for PCR-detected infections unless infection intensity was considered, Infections diagnosed with either method were associated with increased risk of eosinophilia (PCR PR 2.42, 95% CI: 1.02, 5.76; microscopy PR 2.92, 95% CI: 1.29, 6.60).
Conclusion
Newer diagnostic methods, including PCR, improve the detection of helminth infections. This heightened sensitivity may improve the identification of risk factors for infection while reducing ability to discriminate infections associated with adverse clinical outcomes. Quantitative assays can be used to differentiate infection loads and discriminate infections associated with sequelae.
doi:10.1371/journal.pone.0081915
PMCID: PMC3852669  PMID: 24324729
12.  Systematic Review of the Performance of Rapid Rifampicin Resistance Testing for Drug-Resistant Tuberculosis 
PLoS ONE  2013;8(10):e76533.
Introduction
Rapid tests for rifampicin resistance may be useful for identifying isolates at high risk of drug resistance, including multidrug-resistant TB (MDR-TB). However, choice of diagnostic test and prevalence of rifampicin resistance may both impact a diagnostic strategy for identifying drug resistant-TB. We performed a systematic review to evaluate the performance of WHO-endorsed rapid tests for rifampicin resistance detection.
Methods
We searched MEDLINE, Embase and the Cochrane Library through January 1, 2012. For each rapid test, we determined pooled sensitivity and specificity estimates using a hierarchical random effects model. Predictive values of the tests were determined at different prevalence rates of rifampicin resistance and MDR-TB.
Results
We identified 60 publications involving six different tests (INNO-LiPA Rif. TB assay, Genotype MTBDR assay, Genotype MTBDRplus assay, Colorimetric Redox Indicator (CRI) assay, Nitrate Reductase Assay (NRA) and MODS tests): for all tests, negative predictive values were high when rifampicin resistance prevalence was ≤ 30%. However, positive predictive values were considerably reduced for the INNO-LiPA Rif. TB assay, the MTBDRplus assay and MODS when rifampicin resistance prevalence was < 5%.
Limitations
In many studies, it was unclear whether patient selection or index test performance could have introduced bias. In addition, we were unable to evaluate critical concentration thresholds for the colorimetric tests.
Discussion
Rapid tests for rifampicin resistance alone cannot accurately predict rifampicin resistance or MDR-TB in areas with a low prevalence of rifampicin resistance. However, in areas with a high prevalence of rifampicin resistance and MDR-TB, these tests may be a valuable component of an MDR-TB management strategy.
doi:10.1371/journal.pone.0076533
PMCID: PMC3789679  PMID: 24098523
13.  Humoral immune responses to Plasmodium falciparum among HIV-1-infected Kenyan adults 
Proteomics. Clinical applications  2011;5(11-12):613-623.
Introduction
Humoral immune responses play a pivotal role in naturally acquired immunity to malaria. Understanding which humoral responses are impaired among individuals at higher risk for malaria may improve our understanding of malaria immune control and contribute to vaccine development.
Methods
We compared humoral responses with 483 Plasmodium falciparum antigens between adults in, Kisumu (high, year-long malaria transmission leading to partial immunity), and adults in Kisii (low, seasonal malaria transmission). Then within each site, we compared malaria-specific humoral responses between those at higher risk for malaria (CD4+ ≤ 500) and those at lower risk for malaria (CD4+>500). A protein microarray chip containing 483 P. falciparum antigens and 71 HIV antigens was used. Benjamini–Hochberg adjustments were made to control for multiple comparisons.
Results
Fifty-seven antigens including CSP, MSP1, LSA1 and AMA1 were identified as significantly more reactive in Kisumu than in Kisii. Ten of these antigens had been identified as protective in an earlier study. CD4+ T-cell count did not significantly impact humoral responses.
Conclusion
Protein microarrays are a useful method to screen multiple humoral responses simultaneously. This study provides useful clues for potential vaccine candidates. Modest decreases in CD4 counts may not significantly impact malaria-specific humoral immunity.
doi:10.1002/prca.201100021
PMCID: PMC3406934  PMID: 21956928
HIV-1; Humoral Immunity; Malaria; Vaccine
14.  Use of Anti-Retroviral Therapy in Tuberculosis Patients on Second-Line Anti-TB Regimens: A Systematic Review 
PLoS ONE  2012;7(11):e47370.
Introduction
Use of antiretroviral therapy (ART) during treatment of drug susceptible tuberculosis (TB) improves survival. However, data from HIV infected individuals with drug resistant TB are lacking. Second line TB drugs when combined with ART may increase drug interactions and lead to higher rates of toxicity and greater noncompliance. This systematic review sought to determine the benefit of ART in the setting of second line drug therapy for drug resistant TB.
Methods
We included individual patient data from studies that evaluated treatment of drug-resistant tuberculosis in HIV-1 infected individuals published between January 1980 and December of 2009. We evaluated the effect of ART on treatment outcomes, time to smear and culture conversion, and adverse events.
Results
Ten observational studies, including data from 217 subjects, were analyzed. Patients using ART during TB treatment had increased likelihood of cure (hazard ratio (HR) 3.4, 95% CI 1.6–7.4) and decreased likelihood of death (HR 0.4, 95% CI 0.3–0.6) during treatment for drug resistant TB. These associations remained significant in patients with a CD4 less than 200 cells/mm3 and less than 50 cells/mm3, and when correcting for drug resistance pattern.
Limitations
We identified only observational studies from which individual patient data could be drawn. Limitations in study design, and heterogeneity in a number of the outcomes of interest had the potential to introduce bias.
Discussion
While there are insufficient data to determine if ART use increases adverse drug interactions when used with second line TB drugs, ART use during treatment of drug resistant TB appears to improve cure rates and decrease risk of death. All individuals with HIV appear to benefit from ART use during treatment for TB.
doi:10.1371/journal.pone.0047370
PMCID: PMC3489892  PMID: 23144818
16.  Assessment of the low cost Cavidi ExaVir™ Load assay for monitoring HIV viral load in pediatric and adult patients 
Background
Viral load (VL) is a critical marker for monitoring HIV disease progression and response to antiretroviral therapy. In resource-constrained settings, there is a need for a simple and inexpensive assay to monitor infected adults and children.
Methods
We compared versions 2 and 3 of the ExaVir™ Load assay, Cavidi AB (HIV RT) with the Roche, COBAS® Amplicor® HIV-1 Monitor assay (HIV RNA) for quantifying HIV VL.
Results
The HIV RT version 2 assay showed good sensitivity with detection in 94% of samples with HIV RNA >1000 copies/ml. Adult samples were tested using HIV RT version 2 (n=35) and version 3 (n=23) assays with plasma volumes of 1ml (recommended), 0.5ml and 0.25ml in comparison with HIV RNA. The HIV RT and HIV RNA assay results were comparable when tested using different volumes. Comparison of results from pediatric samples (n=27), tested using 1ml and a smaller volume by HIV RT version 2 were not significantly different.
Conclusion
The HIV RT assay was comparable to the HIV RNA assay with sensitivity approaching that of RT-PCR. Smaller volumes than the recommended 1ml can be used, improving utility of this assay for pediatric monitoring.
doi:10.1097/QAI.0b013e3181b05f62
PMCID: PMC2784031  PMID: 19617845
Monitoring HIV infection; HIV reverse transcriptase; viral load; resource constrained countries; pediatric testing
17.  The Charles R. Ream, MD, Award for excellence—2009 
doi:10.1016/j.curtheres.2010.03.005
PMCID: PMC3967275  PMID: 24683254
18.  Prevalence and Correlates of Helminth Co-infection in Kenyan HIV-1 Infected Adults 
Background
Deworming HIV-1 infected individuals may delay HIV-1 disease progression. It is important to determine the prevalence and correlates of HIV-1/helminth co-infection in helminth-endemic areas.
Methods
HIV-1 infected individuals (CD4>250 cells/ul) were screened for helminth infection at ten sites in Kenya. Prevalence and correlates of helminth infection were determined. A subset of individuals with soil-transmitted helminth infection was re-evaluated 12 weeks following albendazole therapy.
Results
Of 1,541 HIV-1 seropositive individuals screened, 298 (19.3%) had detectable helminth infections. Among individuals with helminth infection, hookworm species were the most prevalent (56.3%), followed by Ascaris lumbricoides (17.1%), Trichuris trichiura (8.7%), Schistosoma mansoni (7.1%), and Stongyloides stercoralis (1.3%). Infection with multiple species occurred in 9.4% of infections. After CD4 count was controlled for, rural residence (RR 1.40, 95% CI: 1.08–1.81), having no education (RR 1.57, 95% CI: 1.07–2.30), and higher CD4 count (RR 1.36, 95% CI: 1.07–1.73) remained independently associated with risk of helminth infection. Twelve weeks following treatment with albendazole, 32% of helminth-infected individuals had detectable helminths on examination. Residence, education, and CD4 count were not associated with persistent helminth infection.
Conclusions
Among HIV-1 seropositive adults with CD4 counts above 250 cells/mm3 in Kenya, traditional risk factors for helminth infection, including rural residence and lack of education, were associated with co-infection, while lower CD4 counts were not.
Trial Registration
ClinicalTrials.gov NCT00130910
Author Summary
Over one-third of people worldwide are currently infected with parasitic worms. The majority of these infections occur in sub-Saharan Africa, where over half of the population may be infected with at least one type of parasitic worm. HIV infection is also common in many of these countries, and there is significant geographic overlap in the presence of HIV and worm infection. Several studies have suggested that treatment of worm infections in people with HIV may delay the progression of HIV disease. Treatment has been shown to both decrease levels of the HIV virus in the blood of people with HIV and to increase the number of immune cells (CD4 cells) targeted by HIV. It is important to determine which populations of HIV-infected individuals are at greatest risk of worm infection in order to develop potential interventions for the treatment and prevention of worm infection in HIV-infected individuals. We report findings from a large study examining the prevalence and associated co-factors for worm infection among individuals at ten sites in Kenya.
doi:10.1371/journal.pntd.0000644
PMCID: PMC2846937  PMID: 20361031
19.  The Charles R. Ream, MD, award for excellence—2008 
doi:10.1016/j.curtheres.2009.04.001
PMCID: PMC3967342  PMID: 24683219
20.  The Charles R. Ream, MD, Award for Excellence—2007 
doi:10.1016/j.curtheres.2008.04.001
PMCID: PMC3969960  PMID: 24692789
21.  Treatment of Helminth Co-Infection in Individuals with HIV-1: A Systematic Review of the Literature 
Background and Objectives
The HIV-1 pandemic has disproportionately affected individuals in resource-constrained settings. It is important to determine if other prevalent infections affect the progression of HIV-1 in co-infected individuals in these settings. Some observational studies suggest that helminth infection may adversely affect HIV-1 progression. We sought to evaluate existing evidence on whether treatment of helminth infection impacts HIV-1 progression.
Review Methods
This review was conducted using the HIV/AIDS Cochrane Review Group (CRG) search strategy and guidelines. Published and unpublished studies were obtained from The Cochrane Library (Issue 3, 2006), MEDLINE (November 2006), EMBASE (November 2006), CENTRAL (July 2006), and AIDSEARCH (August 2006). Databases listing conference abstracts and scanned reference lists were searched, and authors of included studies were contacted. Data regarding changes in CD4 count, HIV-1 RNA levels, clinical staging and/or mortality were extracted and compared between helminth-treated and helminth-untreated or helminth-uninfected individuals.
Results
Of 6,384 abstracts identified, 15 met criteria for potential inclusion, of which 5 were eligible for inclusion. In the single randomized controlled trial (RCT) identified, HIV-1 and schistosomiasis co-infected individuals receiving treatment for schistosomiasis had a significantly lower change in plasma HIV-1 RNA over three months (−0.001 log10 copies/mL) compared to those receiving no treatment (+0.21 log10 copies/mL), (p = 0.03). Four observational studies met inclusion criteria, and all of these suggested a possible beneficial effect of helminth eradication on plasma HIV-1 RNA levels when compared to plasma HIV-1 RNA changes prior to helminth treatment or to helminth-uninfected or persistently helminth-infected individuals. The follow-up duration in these studies ranged from three to six months. The reported magnitude of effect on HIV-1 RNA was variable, ranging from 0.07–1.05 log10 copies/mL. None of the included studies showed a significant benefit of helminth treatment on CD4 decline, clinical staging, or mortality.
Conclusion
There are insufficient data available to determine the potential benefit of helminth eradication in HIV-1 and helminth co-infected adults. Data from a single RCT and multiple observational studies suggest possible benefit in reducing plasma viral load. The impact of de-worming on markers of HIV-1 progression should be addressed in larger randomized studies evaluating species-specific effects and with a sufficient duration of follow-up to document potential differences on clinical outcomes and CD4 decline.
Author Summary
Many people living in areas of the world most affected by the HIV/AIDS pandemic are also exposed to other common infections. Parasitic infections with helminths (intestinal worms) are common in Africa and affect over half of the population in some areas. There are plausible biological reasons why treating helminth infections in people with HIV may slow down the progression of HIV to AIDS. Thus, treating people with HIV for helminths in areas with a high prevalence of both HIV and helminth infections may be a feasible strategy to help people with HIV delay progression of their disease or initiation of antiretroviral therapy. After a comprehensive review of the available literature, we conclude that there is not enough evidence to determine whether treating helminth infections in people with HIV is beneficial.
doi:10.1371/journal.pntd.0000102
PMCID: PMC2154389  PMID: 18160978
22.  Global Theme Issue on Poverty and Human Development 
doi:10.1016/j.curtheres.2007.10.002
PMCID: PMC3969961  PMID: 24692760
23.  The Charles R. Ream, MD, Award for Excellence—2006 
doi:10.1016/j.curtheres.2007.04.003
PMCID: PMC3966003  PMID: 24678120
24.  Announcing trials from resource-limited settings 
doi:10.1016/j.curtheres.2006.08.001
PMCID: PMC3966009  PMID: 24678098
25.  The Charles R. Ream, MD, award for excellence—2005 
doi:10.1016/j.curtheres.2006.04.004
PMCID: PMC3965970  PMID: 24678086

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