Department of Global Health Faculty Papers

Permanent URI for this collectionhttps://digital.lib.washington.edu/handle/1773/15643

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Persisting with prevention: The importance of adherence for HIV prevention
(2008) Weiss, Helen A.; Wasserheit, Judith N.; Barnabas, Ruanne V.; Hayes, Richard J.; Abu-Raddad, Laith J.
Background: Only four out of 31 completed randomized controlled trials (RCTs) of HIV prevention strategies against sexual transmission have shown significant efficacy. Poor adherence may have contributed to the lack of effect in some of these trials. In this paper we explore the impact of various levels of adherence on measured efficacy within an RCT. Analysis: We used simple quantitative methods to illustrate the impact of various levels of adherence on measured efficacy by assuming a uniform population in terms of sexual behavior and the binomial model for the transmission probability per partnership. At 100% adherence the measured efficacy within an RCT is a reasonable approximation of the true biological efficacy. However, as adherence levels fall, the efficacy measured within a trial substantially under-estimates the true biological efficacy. For example, at 60% adherence, the measured efficacy can be less than half of the true biological efficacy. Conclusion: Poor adherence during a trial can substantially reduce the power to detect an effect, and improved methods of achieving and maintaining high adherence within trials are needed. There are currently 12 ongoing HIV prevention trials, all but one of which require ongoing useradherence. Attention must be given to methods of maximizing adherence when piloting and designing RCTs and HIV prevention programmes.
Comparative analysis of the kinomes of three pathogenic trypanosomatids: Leishmania major, Trypanosoma brucei and Trypanosoma cruzi
(2005) Parsons, Marilyn; Worthey, Elizabeth A.; Ward, Pauline N.; Mottram, Jeremy C.
Background: The trypanosomatids Leishmania major, Trypanosoma brucei and Trypanosoma cruzi cause some of the most debilitating diseases of humankind: cutaneous leishmaniasis, African sleeping sickness, and Chagas disease. These protozoa possess complex life cycles that involve development in mammalian and insect hosts, and a tightly coordinated cell cycle ensures propagation of the highly polarized cells. However, the ways in which the parasites respond to their environment and coordinate intracellular processes are poorly understood. As a part of an effort to understand parasite signaling functions, we report the results of a genome-wide analysis of protein kinases (PKs) of these three trypanosomatids. Results: Bioinformatic searches of the trypanosomatid genomes for eukaryotic PKs (ePKs) and atypical PKs (aPKs) revealed a total of 176 PKs in T. brucei, 190 in T. cruzi and 199 in L. major, most of which are orthologous across the three species. This is approximately 30% of the number in the human host and double that of the malaria parasite, Plasmodium falciparum. The representation of various groups of ePKs differs significantly as compared to humans: trypanosomatids lack receptor-linked tyrosine and tyrosine kinase-like kinases, although they do possess dual-specificity kinases. A relative expansion of the CMGC, STE and NEK groups has occurred. A large number of unique ePKs show no strong affinity to any known group. The trypanosomatids possess few ePKs with predicted transmembrane domains, suggesting that receptor ePKs are rare. Accessory Pfam domains, which are frequently present in human ePKs, are uncommon in trypanosomatid ePKs. Conclusion: Trypanosomatids possess a large set of PKs, comprising approximately 2% of each genome, suggesting a key role for phosphorylation in parasite biology. Whilst it was possible to place most of the trypanosomatid ePKs into the seven established groups using bioinformatic analyses, it has not been possible to ascribe function based solely on sequence similarity. Hence the connection of stimuli to protein phosphorylation networks remains enigmatic. The presence of numerous PKs with significant sequence similarity to known drug targets, as well as a large number of unusual kinases that might represent novel targets, strongly argue for functional analysis of these molecules.
Using nurses to identify HAART eligible patients in the Republic of Mozambique: results of a time series analysis
(2007) Gimbel-Sherr, Sarah O.; Micek, Mark A.; Gimbel-Sherr, Kenneth H.; Koepsell, Thomas; Hughes, James P.; Thomas, Katherine K.; Pfeiffer, James; Gloyd, Stephen S.
Background: The most pressing challenge to achieving universal access to highly active anti-retroviral therapy (HAART) in sub-Saharan Africa is the shortage of trained personnel to handle the increased service requirements of rapid roll-out. Overcoming the human resource challenge requires developing innovative models of care provision that improve efficiency of service delivery and rationalize use of limited resources. Methods: We conducted a time-series intervention trial in two HIV clinics in central Mozambique to discern whether expanding the role of basic-level nurses to stage HIV-positive patients using CD4 counts and WHO-defined criteria would lead to more rapid information on patient status (including identification of HAART eligible patients), increased efficiency in the use of higher-level clinical staff, and increased capacity to start HAART-eligible patients on treatment. Results: Overall, 1,880 of the HAART-eligible patients were considered in the study of whom 48.5% started HAART, with a median time of 71 days from their initial blood draw. After adjusting for time, expanding the role of nurses to stage patients was associated with more rational use of higher-level clinical staff at one site (Beira OR 1.9, 95% CI 1.1-3.3; Chimoio OR 0.2, 95% CI 0.1-0.5). In multivariate analyses, the rate of starting HAART in patients with CD4 counts of less than 200/mm3 increased over time (HR = 1.07, 95% CI 1.02-1.13), as did the total number of new patients initiating HAART ([Beta] = 7.3, 95% CI 1.3-13.3). However, the intervention was not independently associated with either of these outcomes in multivariate analyses (HR = 0.9, 95% CI 0.7-1.2) for starting HAART in patients with CD4 counts of less than 200/mm3; ([Beta] = -5.2, p = 0.75) for the total number of new patients initiating HAART per month. No effect of the intervention was found in these outcomes when stratifying by site. Conclusion: The CD4 nurse intervention, when implemented correctly, was associated with a more rational use of higherlevel clinical providers, which may improve overall clinic flow and efficient use of the limited supply of human resources. However, this intervention did not lead to an increase in the number of patients starting HAART or a reduction in the time to HAART initiation. Study month appears to play an important role in all outcomes, suggesting that general improvements in clinic efficiency may have overshadowed the effect of the intervention. The lack of observed effect in these outcomes may be due to additional health systems bottlenecks that delay the initiation of treatment in HAART-eligible patients.
Intent to migrate among nursing students in Uganda: Measures of the brain drain in the next generation of health professionals
(2008) Nguyen, Lisa; Ropers, Steven; Nderitu, Esther; Zuyderduin, Anneke; Luboga, Sam; Hagopian, Amy
Background: There is significant concern about the worldwide migration of nursing professionals from low-income countries to rich ones, as nurses are lured to fill the large number of vacancies in upper-income countries. This study explores the views of nursing students in Uganda to assess their views on practice options and their intentions to migrate. Methods: Anonymous questionnaires were distributed to nursing students at the Makerere Nursing School and Aga Khan University Nursing School in Kampala, Uganda, during July 2006, using convenience sampling methods, with 139 participants. Two focus groups were also conducted at one university. Results: Most (70%) of the participants would like to work outside Uganda, and said it was likely that within five years they would be working in the U.S. (59%) or the U.K. (49%). About a fourth (27%) said they could be working in another African country. Only eight percent of all students reported an unlikelihood to migrate within five years of training completion. Survey respondents were more dissatisfied with financial remuneration than with any other factor pushing them towards emigration. Those wanting to work in the settings of urban, private, or U.K./U.S. practices were less likely to express a sense of professional obligation and/or loyalty to country. Those who have lived in rural areas were less likely to report wanting to emigrate. Students with a desire to work in urban areas or private practice were more likely to report an intent to emigrate for financial reasons or in pursuit of country stability, while students wanting to work in rural areas or public practice were less likely to want to emigrate overall. Conclusion: Improving remuneration for nurses is the top priority policy change sought by nursing students in our study. Nursing schools may want to recruit students desiring work in rural areas or public practice to lead to a more stable workforce in Uganda.
What if we decided to take care of everyone who needed treatment? Workforce planning in Mozambique using simulation of demand for HIV/AIDS care
(2008) Hagopian, Amy; Micek, Mark A.; Vio, Ferruccio; Gimbel-Sherr, Kenneth; Montoya, Pablo
Background: The growing AIDS epidemic in southern Africa is placing an increased strain on health systems, which are experiencing steadily rising patient loads. Health care systems are tackling the barriers to serving large populations in scaled-up operations. One of the most significant challenges in this effort is securing the health care workforce to deliver care in settings where the manpower is already in short supply. Methods: We have produced a demand-driven staffing model using simple spreadsheet technology, based on treatment protocols for HIV-positive patients that adhere to Mozambican guidelines. The model can be adjusted for the volumes of patients at differing stages of their disease, varying provider productivity, proportion who are pregnant, attrition rates, and other variables. Results: Our model projects the need for health workers using three different kinds of goals: 1) the number of patients to be placed on anti-retroviral therapy (ART), 2) the number of HIV-positive patients to be enrolled for treatment, and 3) the number of patients to be enrolled in a treatment facility per month. Conclusion: We propose three scenarios, depending on numbers of patients enrolled. In the first scenario, we start with 8000 patients on ART and increase that number to 58 000 at the end of three years (those were the goals for the country of Mozambique). This would require thirteen clinicians and just over ten nurses by the end of the first year, and 67 clinicians and 47 nurses at the end of the third year. In a second scenario, we start with 34 000 patients enrolled for care (not all of them on ART), and increase to 94 000 by the end of the third year, requiring a growth in clinician staff from 18 to 28. In a third scenario, we start a new clinic and enrol 200 new patients per month for three years, requiring 1.2 clinicians in year 1 and 2.2 by the end of year 3. Other clinician types in the model include nurses, social workers, pharmacists, phlebotomists, and peer counsellors. This planning tool could lead to more realistic and appropriate estimates of workforce levels required to provide high-quality HIV care in a low-resource settings.
The migration of physicians from sub-Saharan Africa to the United States of America: measures of the African brain drain
(2004) Hagopian, Amy; Thompson, Matthew J.; Fordyce, Meredith; Johnson, Karin E.; Hart, L. Gary
Background: The objective of this paper is to describe the numbers, characteristics, and trends in the migration to the United States of physicians trained in sub-Saharan Africa. Methods: We used the American Medical Association 2002 Masterfile to identify and describe physicians who received their medical training in sub-Saharan Africa and are currently practicing in the USA. Results: More than 23% of America's 771 491 physicians received their medical training outside the USA, the majority (64%) in low-income or lower middle-income countries. A total of 5334 physicians from sub-Saharan Africa are in that group, a number that represents more than 6% of the physicians practicing in sub-Saharan Africa now. Nearly 86% of these Africans practicing in the USA originate from only three countries: Nigeria, South Africa and Ghana. Furthermore, 79% were trained at only 10 medical schools. Conclusions: Physician migration from poor countries to rich ones contributes to worldwide health workforce imbalances that may be detrimental to the health systems of source countries. The migration of over 5000 doctors from sub-Saharan Africa to the USA has had a significantly negative effect on the doctor-to-population ratio of Africa. The finding that the bulk of migration occurs from only a few countries and medical schools suggests policy interventions in only a few locations could be effective in stemming the brain drain.
Maternal peripheral blood level of IL-10 as a marker for inflammatory placental malaria
(2008) Kabyemela, Edward R.; Muehlenbachs, Atis; Fried, Michal; Kurtis, Jonathan D.; Mutabingwa, Theonest K.; Duffy, Patrick E.
Background: Placental malaria (PM) is an important cause of maternal and foetal mortality in tropical areas, and severe sequelae and mortality are related to inflammation in the placenta. Diagnosis is difficult because PM is often asymptomatic, peripheral blood smear examination detects parasitemia as few as half of PM cases, and no peripheral markers have been validated for placental inflammation. Methods: In a cohort of Tanzanian parturients, PM was determined by placental blood smears and placental inflammation was assessed by histology and TNF mRNA levels. Maternal peripheral blood levels of several immune mediators previously implicated in PM pathogenesis, as well as ferritin and leptin were measured. The relationship between the levels of these soluble factors to PM and placental inflammation was examined. Results: Peripheral levels of TNF, TNF-RI, TNF-RII, IL-1, IL-10, and ferritin were elevated during PM, whereas levels of IFN-[gamma], IL-4, IL-5 and IL-6 were unchanged and levels of leptin were decreased. In receiver operating characteristic curve analysis, IL-10 had the greatest area under the curve, and would provide a sensitivity of 60% with a false positive rate of 10%. At a cut off level of 15 pg/mL, IL-10 would detect PM with a sensitivity of 79.5% and a specificity of 84.3%. IL-10 levels correlated with placental inflammatory cells and placental TNF mRNA levels in first time mothers. Conclusion: These data suggest that IL-10 may have utility as a biomarker for inflammatory PM in research studies, but that additional biomarkers may be required to improve clinical diagnosis and management of malaria during pregnancy.
Low serum albumin and the acute phase response predict low serum selenium in HIV-1 infected women
(2006) Drain, Paul K.; Baeten, Jared; Overbaugh, Julie; Wener, Mark H.; Bankson, Daniel D.; Lavreys, Ludo; Mandaliya, Kishorchandra; O Ndinya-Achola, Jeckoniah; McClelland, R. Scott
Background: Low serum selenium has been associated with lower CD4 counts and greater mortality among HIV-1-seropositive individuals, but most studies have not controlled for serum albumin and the presence of an acute phase response. Methods: A cross-sectional study was conducted to evaluate relationships between serum selenium concentrations and CD4 count, plasma viral load, serum albumin, and acute phase response markers among 400 HIV-1-seropositive women. Results: In univariate analyses, lower CD4 count, higher plasma viral load, lower albumin, and the presence of an acute phase response were each significantly associated with lower serum selenium concentrations. In multivariate analyses including all four of these covariates, only albumin remained significantly associated with serum selenium. For each 0.1 g/dl increase in serum albumin, serum selenium increased by 0.8 [micro]g/l (p less than 0.001). Women with an acute phase response also had lower serum selenium (by 5.6 [micro]g/l, p = 0.06). Conclusion: Serum selenium was independently associated with serum albumin, but not with CD4 count or plasma viral load, in HIV-1-seropositive women. Our findings suggest that associations between lower serum selenium, lower CD4 count, and higher plasma viral load may be related to the frequent occurrence of low serum albumin and the acute phase response among individuals with more advanced HIV-1 infection.
Higher pre-infection vitamin E levels are associated with higher mortality in HIV-1-infected Kenyan women: a prospective study
(2007) Graham, Susan M.; Baeten, Jared; Richardson, Barbra A.; Bankson, Daniel D.; Lavreys, Ludo; O Ndinya-Achola, Jeckoniah; Mandaliya, Kishorchandra; Overbaugh, Julie; McClelland, R. Scott
Background: Low vitamin E levels are often found in HIV-1 infection, and studies have suggested that higher levels may decrease the risk of disease progression. However, vitamin E supplementation has also been reported to increase CCR5 expression, which could increase HIV- 1 replication. We hypothesized that vitamin E levels at HIV-1 acquisition may influence disease progression. Methods: Vitamin E status was measured in stored samples from the last pre-infection visit for 67 Kenyan women with reliably estimated dates of HIV-1 acquisition. Regression analyses were used to estimate associations between pre-infection vitamin E and plasma viral load, time to CD4 count less than 200 cells/[micro]L, and mortality. Results: After controlling for potential confounding factors, each 1 mg/L increase in pre-infection vitamin E was associated with 0.08 log[sub]10 copies/mL (95% CI -0.01 to +0.17) higher set point viral load and 1.58-fold higher risk of mortality (95% CI 1.15�2.16). The association between higher preinfection vitamin E and mortality persisted after adjustment for set point viral load (HR 1.55, 95% CI 1.13�2.13). Conclusion: Higher pre-infection vitamin E levels were associated with increased mortality. Further research is needed to elucidate the role vitamin E plays in HIV-1 pathogenesis.

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