Faculty Bibliography

BACKGROUND:The scarcity of physicians in sub-Saharan Africa - particularly in rural clinics staffed only by non-physician health workers - is constraining access to HIV treatment, as only they are legally allowed to start antiretroviral therapy in the HIV-positive patient. Here we present a pilot study from Uganda assessing agreement between non-physician clinicians (nurses and clinical officers) and physicians in their decisions as to whether to start therapy. METHODS:We conducted the study at 12 government antiretroviral therapy sites in three regions of Uganda, all of which had staff trained in delivery of antiretroviral therapy using the WHO Integrated Management of Adult and Adolescent Illness guidelines for chronic HIV care. We collected seven key variables to measure patient assessment and the decision as to whether to start antiretroviral therapy, the primary variable of interest being the Final Antiretroviral Therapy Recommendation. Patients saw either a clinical officer or nurse first, and then were screened identically by a blinded physician during the same clinic visit. We measured inter-rater agreement between the decisions of the non-physician health workers and physicians in the antiretroviral therapy assessment variables using simple and weighted Kappa analysis. RESULTS:Two hundred fifty-four patients were seen by a nurse and physician, while 267 were seen by a clinical officer and physician. The majority (>50%) in each arm of the study were in World Health Organization Clinical Stages I and II and therefore not currently eligible for antiretroviral therapy according to national antiretroviral therapy guidelines. Nurses and clinical officers both showed moderate to almost perfect agreement with physicians in their Final Antiretroviral Therapy Recommendation (unweighted kappa=0.59 and kappa=0.91, respectively). Agreement was also substantial for nurses versus physicians for assigning World Health Organization Clinical Stage (weighted kappa=0.65), but moderate for clinical officers versus physicians (kappa=0.44). CONCLUSION/CONCLUSIONS:Both nurses and clinical officers demonstrated strong agreement with physicians in deciding whether to initiate antiretroviral therapy in the HIV patient. This could lead to immediate benefits with respect to antiretroviral therapy scale-up and decentralization to rural areas in Uganda, as non-physician clinicians--particularly clinical officers--demonstrated the capacity to make correct clinical decisions to start antiretroviral therapy. These preliminary data warrant more detailed and multicountry investigation into decision-making of non-physician clinicians in the management of HIV disease with antiretroviral therapy, and should lead policy-makers to more carefully explore task-shifting as a shorter-term response to addressing the human resource crisis in HIV care and treatment.

BACKGROUND:No more than 8% of HIV positive children needing treatment in low- and middle-income countries have access to antiretroviral drugs (ARVs). Children presently account for about 4% of all treated patients, while for equitable access they should make up at least 13%. AIMS/OBJECTIVE:This study explores key issues, implications and interaction dynamics to boost production of easy-to-use and affordable fixed-dose combination (FDC) ARVs for children in the developing world. Potentials for equitable solutions are examined including priority steps and actions, appropriate treatment options and reliable forecasting methods for paediatric ARVs, as well as combination incentives to generic companies against market unattractiveness and enforced intellectual property (IP) rights. Moreover, implementation strategies to enhance the development and production of affordable ARV paediatric formulations and appropriate supply systems to ensure availability are investigated. RESULTS:The current market for FDC paediatric ARVs is already substantial and will only grow with improved and scaled up diagnosis and monitoring of children. This provides an argument for immediate increase of production and development of FDC ARVs for children. These formulations must be low cost and included in the list of Essential Medicines to avoid children continuing to lag behind in access to treatment. Access-oriented, long-term drug policy strategies with the ability to pass muster of governments, the UN system, as well as generic and research-based enterprises are needed to let children gain expanded and sustained access to FDC ARVs. Under the requirements listed above, IP-bound Voluntary License (VL) flexibilities do appear, if coupled with substantial combination incentives to generic firms, as a fitting tool into the needs. Policies must consider enhancing human resource capacity in the area of caregivers and social and health workers aiming to spread correct information and awareness on effectiveness and rationale of FDC ARVs for children. Policies should urge that paediatric ARV treatment programmes entwine with extant interventions on prevention of mother-to-child transmission, as well as with HIV treatment initiatives focused on mothers and household members. Policies, again, should consider centralising functions and pooling resources to help overcome drug supply barriers. WHO's brokering role in VL-based agreements between wealthy and developing country industries, as well as its technical guidance in setting international standards should not be waived while looking for sustained access to optimised ARV treatments for children. Strategies discussed in this paper, while taking unavoidability of marketing and profit rules into account, look closely into the trade and drug policy directions of China and India according to frontier crossing implications of their IP management trends as well as their multi-faceted penetration strategies of both the wealthy and under-served markets the world over.

OBJECTIVES/OBJECTIVE:To present direct manufacturing costs and price calculations of individual antiretroviral drugs, enabling those responsible for their procurement to have a better understanding of the cost structure of their production, and to indicate the prices at which these antiretroviral drugs could be offered in developing country markets. METHODS:Direct manufacturing costs and factory prices for selected first and second-line antiretroviral drugs were calculated based on cost structure data from a state-owned company in Brazil. Prices for the active pharmaceutical ingredients (API) were taken from a recent survey by the World Health Organization (WHO). The calculated prices for antiretroviral drugs are compared with quoted prices offered by privately-owned, for-profit manufacturers. RESULTS:The API represents the largest component of direct manufacturing costs (55-99%), while other inputs, such as salaries, equipment costs, and scale of production, have a minimal impact. The calculated prices for most of the antiretroviral drugs studied fall within the lower quartile of the range of quoted prices in developing country markets. The exceptions are those drugs, primarily for second-line therapy, for which the API is either under patent, in short supply, or in limited use in developing countries (e.g. abacavir, lopinavir/ritonavir, nelfinavir, saquinavir). CONCLUSION/CONCLUSIONS:The availability of data on the cost of antiretroviral drug production and calculation of factory prices under a sustainable business model provide benchmarks that bulk purchasers of antiretroviral drugs could use to negotiate lower prices. While truly significant price decreases for antiretroviral drugs will depend largely on the future evolution of API prices, the present study demonstrates that for several antiretroviral drugs price reduction is currently possible. Whether or not these reductions materialize will depend on the magnitude of indirect cost and profit added by each supplier over the direct production costs. The ability to achieve price reductions in line with production costs will have critical implications for sustainable treatment for HIV/AIDS in the developing world.

The Purchase price report released in August 2004 by the Global Fund to Fight AIDS, Tuberculosis, and Malaria (Global Fund) was the first publication of a significant amount of real transaction purchase data for antiretrovirals (ARVs). We did an observational study of the ARV transaction data in the Purchase price report to examine the procurement behaviour of principal recipients of Global Fund grants in developing countries. We found that, with a few exceptions for specific products (e.g. lamivudine) and regions (e.g. eastern Europe), prices in low-income countries were broadly consistent or lower than the lowest differential prices quoted by the research and development sector of the pharmaceutical industry. In lower middle-income countries, prices were more varied and in several instances (lopinavir/ritonavir, didanosine, and zidovudine/lamivudine) were very high compared with the per capita income of the country. In all low- and lower middle-income countries, ARV prices were still significantly high given limited local purchasing power and economic strength, thus reaffirming the need for donor support to achieve rapid scale-up of antiretroviral therapy. However, the price of ARVs will have to decrease to render scale-up financially sustainable for donors and eventually for governments themselves. An important first step in reducing prices will be to make available in the public domain as much ARV transaction data as possible to provide a factual basis for discussions on pricing. The price of ARVs has considerable implications for the sustainability of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) treatment in the developing world.

BACKGROUND:Many different subtypes of human immunodeficiency virus (HIV) type 1 have been identified, particularly in sub-Saharan Africa. However, much remains unknown regarding the relative pathogenicity of these subtypes and their influence on the clinical progression of HIV infection. We examined prospectively the associations between HIV-1 subtypes A, C, and D and recombinant viruses, as well as the rates of disease progression in a cohort of seropositive women from Dar es Salaam, Tanzania. METHODS:A total of 428 pregnant mothers participating in a larger controlled trial of the effect of vitamin supplements were selected for DNA sequencing of their HIV-1 subtype. Plasma viral load was measured at baseline, and CD4+ cell counts was assessed at baseline and at regular intervals throughout the follow-up period. Proportional hazards regression (hazards ratio [HR]) analysis was used to measure the association between viral subtype and the rate of disease progression. RESULTS:Relative to patients with subtype A, patients with subtype D experienced the most rapid progression to death (HR, 2.27; 95% confidence interval [CI], 1.46-3.52) or to the World Health Organization stage 4 of illness (HR, 1.94; 95% CI, 1.20-3.14) and to a CD4+ cell count of <200 cells/mm3 (HR, 2.12; 95% CI, 1.42-3.17). After adjustment for viral load, CD4+ cell count, and other baseline covariates, the associations remained similar. CONCLUSIONS:We observed heterogeneity in the rates of disease progression of HIV-1 disease in infected persons, on the basis of the infecting subtype. Subtype D was associated with the most rapid progression of the disease, relative to the other 3 categories of viruses in our cohort.

We have previously shown that systemic infusion of the bacterial toxins Staphylococcal enterotoxin B (SEB) and endotoxin (LPS) induces hepatic dysfunction as measured by decreased biliary indocyanine green (ICG) excretion. In this study, we compare the effects of these bacterial toxins after infusion into the portal and systemic circulation and directly measure biliary bile acid excretion as a measure of cholestasis. We hypothesized that bacterial toxins infused into the portal vein would induce greater hepatic dysfunction than toxins infused into the systemic circulation. Using a chronically catheterized rat model, biliary bile acid excretion was directly measured after infusion of LPS at 10 and 100 microg/kg with and without 50 microg/kg SEB into the portal vein (IPV) or inferior vena cava (IV) at baseline, and at 6 and 24 h. We found that when LPS was infused alone, only IPV administration caused a significant decrease in bile acid excretion at 6 h. There was no change in bile acid excretion after IV administration of LPS. In contrast, when the combination of LPS and SEB was infused, both IV and IPV administration significantly decreased bile acid excretion at 6 and 24 h. At 6 h post-LPS and -SEB administration, the decrease in bile acid excretion was significantly greater after IPV than IV administration. There was no site-specific difference in IFN-gamma release after infusion of toxins. However, peak TNFalpha release was decreased in IPV-infused rats [10 microg/kg (P < 0.05) or 100 microg/kg (P = ns) LPS with SEB] compared with the same doses in IV-infused rats. These data question the role of systemic TNF-alpha and IFN-gamma in regulating hepatic dysfunction and suggest a differential functional response of the liver to systemic and gut-derived septic events. This study also further explains the frequent development of liver dysfunction in patients with sepsis, multisystem organ failure, and other diseases with altered intestinal permeability.