An analysis of volumes, prices and pricing trends of the pediatric antiretroviral market in developing countries from 2004 to 2012.

BACKGROUND: The pediatric antiretroviral (ARV) market is poorly described in the literature, resulting in gaps in understanding treatment access. We analyzed the pediatric ARV market from 2004 to 2012 and assessed pricing trends and associated factors. METHODS: Data on donor funded procurements of pediatric ARV formulations reported to the Global Price Reporting Mechanism database from 2004 to 2012 were analyzed. Outcomes of interest were the volume and mean price per patient-year ARV formulation based on WHO ARV dosing recommendations for a 10 kg child. Factors associated with the price of formulations were assessed using linear regression; potential predictors included: country income classification, geographical region, market segment (originator versus generic ARVs), and number of manufacturers per formulation. All analyses were adjusted for type of formulations (single, dual or triple fixed-dose combinations (FDCs)) RESULTS: Data from 111 countries from 2004 to 2012 were included, with procurement of 33 formulations at a total value of USD 204 million. Use of dual and triple FDC formulations increased substantially over time, but with limited changes in price. Upon multivariate analysis, prices of originator formulations were found to be on average 72 % higher than generics (p < 0.001). A 10 % increase in procurement volume was associated with a 1 % decrease (p < 0.001) in both originator and generic prices. The entry of one additional manufacturer producing a formulation was associated with a decrease in prices of 2 % (p < 0.001) and 8 % (p < 0.001) for originator and generic formulations, respectively. The mean generic ARV price did not differ by country income level. Prices of originator ARVs were 48 % (p < 0.001) and 14 % (p < 0.001) higher in upper-middle income and lower-middle income countries compared to low income countries respectively, with the exception of South Africa, which had lower prices despite being an upper-middle income country. CONCLUSIONS: The donor funded pediatric ARV market as represented by the GPRM database is small, and lacks price competition. It is dominated by generic drugs due to the lower prices offered and the practicality of FDC formulations. This market requires continued donor support and the current initiatives to protect it are important to ensure market viability, especially if new formulations are to be introduced in the future.

Prices paid for adult and paediatric antiretroviral treatment by low- and middle-income countries in 2012: high, low or just right?

A viable market for antiretroviral drugs in low- and middle-income countries is key to the continued scale-up of antiretroviral treatment. We describe the price paid by low- and middle-income countries for 10 first- and 7 second-line adult and paediatric treatment regimens from 2003 to 2012, and compare the price of their finished formulations with the price of their active pharmaceutical ingredients in 2005, 2007, 2010 and 2012. Between 2003 and 2012 the median price of adult first-line treatment regimens per treatment-year decreased from USD499 to USD122, and that of second-line regimens from USD2,934 to USD497. In 2005 adult formulations were sold for a price 170% higher than the cost of their active pharmaceutical ingredients. This margin had decreased to 28% in 2012. Between 2004 and 2013, the price of paediatric treatment per treatment-year decreased from USD585 to USD147 for first-line and from USD763 to USD288 for second-line treatment. In 2005, paediatric treatment regimens were sold at a price 231% higher than the cost of their active pharmaceutical ingredients. This margin remained high and was 195% in 2012. The prices paid for antiretroviral drugs by low- and middle-income countries decreased between 2003 and 2012. Although the margins on their sale decreased, there is likely still space for price reduction, especially for the more recent World Health Organization recommended adult first-line regimens and for paediatric treatment.

Systematic review of the use of dried blood spots for monitoring HIV viral load and for early infant diagnosis.

BACKGROUND: Dried blood spots (DBS) have been used as alternative specimens to plasma to increase access to HIV viral load (VL) monitoring and early infant diagnosis (EID) in remote settings. We systematically reviewed evidence on the performance of DBS compared to plasma for VL monitoring and EID. METHODS AND FINDINGS: Thirteen peer reviewed HIV VL publications and five HIV EID papers were included. Depending on the technology and the viral load distribution in the study population, the percentage of DBS samples that are within 0.5 log of VL in plasma ranged from 52-100%. Because the input sample volume is much smaller in a blood spot, there is a risk of false negatives with DBS. Sensitivity of DBS VL was found to be 78-100% compared to plasma at VL below 1000 copies/ml, but this increased to 100% at a threshold of 5000 copies/ml. Unlike a plasma VL test which measures only cell free HIV RNA, a DBS VL also measures proviral DNA as well as cell-associated RNA, potentially leading to false positive results when using DBS. The systematic review showed that specificity was close to 100% at DBS VL above 5000 copies/ml, and this threshold would be the most reliable for predicting true virologic failure using DBS. For early infant diagnosis, DBS has a sensitivity of 100% compared to fresh whole blood or plasma in all studies. CONCLUSIONS: Although limited data are available for EID, DBS offer a highly sensitive and specific sampling strategy to make viral load monitoring and early infant diagnosis more accessible in remote settings. A standardized approach for sampling, storing, and processing DBS samples would be essential to allow successful implementation. TRIAL REGISTRATION: PROSPERO Registration #: CRD42013003621.

Predicted levels of HIV drug resistance: potential impact of expanding diagnosis, retention, and eligibility criteria for antiretroviral therapy initiation.

BACKGROUND: There is concern that the expansion of antiretroviral roll-out may impact future drug resistance levels and hence compromise the benefits of antiretroviral therapy (ART) at an individual and population level. We aimed to predict future drug resistance in South Africa and its long-term effects. METHODS: The previously validated HIV Synthesis model was calibrated to South Africa. Resistance was modeled at the level of single mutations, transmission potential, persistence, and effect on drug activity. RESULTS: We estimate 652 000 people (90% uncertainty range: 543 000-744 000) are living with nonnucleoside reverse transcriptase inhibitor (NNRTIs)-resistant virus in South Africa, 275 000 in majority virus [Non-nucleoside reverse transcriptase inhibitor resistant virus present in majority virus (NRMV)] with an unsuppressed viral load. If current diagnosis and retention in care and eligibility criteria are maintained, in 20 years' time HIV incidence is projected to have declined by 22% (95% confidence interval, CI -23 to -21%), and the number of people carrying NNRTI resistance to be 2.9-fold higher. If enhancements in diagnosis and retention in care occur, and ART is initiated at CD4 cell count less than 500  cells/µl, HIV incidence is projected to decline by 36% (95% CI: -37 to -36%) and the number of people with NNRTI resistance to be 4.1-fold higher than currently. Prevalence of people with viral load more than 500  copies/ml carrying NRMV is not projected to differ markedly according to future ART initiation policy, given the current level of diagnosis and retention are maintained. CONCLUSION: Prevalence of resistance is projected to increase substantially. However, introduction of policies to increase ART coverage is not expected to lead to appreciably higher prevalence of HIV-positive people with resistance and viral load more than 500  copies/ml. Concern over resistance should not stop expansion of treatment availability.

The role of mathematical modelling in the development of recommendations in the 2013 WHO consolidated antiretroviral therapy guidelines.

Despite the exponential growth in the literature on modelling and simulation studies of impact and cost-effectiveness in different aspects of healthcare, there is no clear consensus on the appropriate role of modelling in the development of recommendations in clinical guidelines. This is compounded both by the lack of a standardised approach to assess the quality of modelling, and lack of clarity on its positioning within the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) method for decision-making in the development of WHO guidelines, that considers both evidence from systematic reviews of randomized clinical trials (RTCs) or observational studies, together with stakeholder values and preferences, resource use, and feasibility issues. In the development of the 2013 WHO Consolidated Guidelines on the use of Antiretroviral drugs for treating and preventing HIV infection, a series of modelling projects were undertaken to inform the recommendations on eligibility criteria for ART initiation, and approaches to monitoring for treatment response. We report our experiences, challenges encountered, and several key considerations to guide the future use of modelling in the development of WHO guidelines. These are: (1) Transparency in the conduct and reporting of model inputs and results; (2) The need for agreed standards for critical appraisal and use of modelling data in healthcare policy making; (3) recognition that modelling of cost-effectiveness is only one component of decision-making in development of WHO recommendations and in priority-setting; (4) The need for closer interaction and an ongoing dialogue between modellers and model end-users or decision-makers; (5) the important role of WHO in convening and facilitating comparative assessment of multiple models; and (6) The need to optimize research and data collection to inform modelling studies.

Effectiveness and cost-effectiveness of potential responses to future high levels of transmitted HIV drug resistance in antiretroviral drug-naive populations beginning treatment: modelling study and economic analysis.

BACKGROUND: With continued roll-out of antiretroviral therapy (ART) in resource-limited settings, evidence is emerging of increasing levels of transmitted drug-resistant HIV. We aimed to compare the effectiveness and cost-effectiveness of different potential public health responses to substantial levels of transmitted drug resistance. METHODS: We created a model of HIV transmission, progression, and the effects of ART, which accounted for resistance generation, transmission, and disappearance of resistance from majority virus in the absence of drug pressure. We simulated 5000 ART programmatic scenarios with different prevalence levels of detectable resistance in people starting ART in 2017 (t0) who had not previously been exposed to antiretroviral drugs. We used the model to predict cost-effectiveness of various potential changes in policy triggered by different prevalence levels of resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) measured in the population starting ART. FINDINGS: Individual-level resistance testing before ART initiation was not generally a cost-effective option, irrespective of the cost-effectiveness threshold. At a cost-effectiveness threshold of US$500 per quality-adjusted life-year (QALY), no change in policy was cost effective (ie, no change in policy would involve paying less than $500 per QALY gained), irrespective of the prevalence of pretreatment NNRTI resistance, because of the increased cost of the policy alternatives. At thresholds of $1000 or higher, and with the prevalence of pretreatment NNRTI resistance greater than 10%, a policy to measure viral load 6 months after ART initiation became cost effective. The policy option to change the standard first-line treatment to a boosted protease inhibitor regimen became cost effective at a prevalence of NNRTI resistance higher than 15%, for cost-effectiveness thresholds greater than $2000. INTERPRETATION: Cost-effectiveness of potential policies to adopt in response to different levels of pretreatment HIV drug resistance depends on competing budgetary claims, reflected in the cost-effectiveness threshold. Results from our model will help inform WHO recommendations on monitoring of HIV drug resistance in people starting ART. FUNDING: WHO (with funds provided by the Bill & Melinda Gates Foundation), CHAIN (European Commission).

Investment in HIV/AIDS programs: does it help strengthen health systems in developing countries?

BACKGROUND: There is increasing debate about whether the scaled-up investment in HIV/AIDS programs is strengthening or weakening the fragile health systems of many developing countries. This article examines and assesses the evidence and proposes ways forward. DISCUSSION: Considerably increased resources have been brought into countries for HIV/AIDS programs by major Global Health Initiatives. Among the positive impacts are the increased awareness of and priority given to public health by governments. In addition, services to people living with HIV/AIDS have rapidly expanded. In many countries infrastructure and laboratories have been strengthened, and in some, primary health care services have been improved. The effect of AIDS on the health work force has been lessened by the provision of antiretroviral treatment to HIV-infected health care workers, by training, and, to an extent, by task-shifting. However, there are reports of concerns, too - among them, a temporal association between increasing AIDS funding and stagnant reproductive health funding, and accusations that scarce personnel are siphoned off from other health care services by offers of better-paying jobs in HIV/AIDS programs. Unfortunately, there is limited hard evidence of these health system impacts. Because service delivery for AIDS has not yet reached a level that could conceivably be considered "as close to Universal Access as possible," countries and development partners must maintain the momentum of investment in HIV/AIDS programs. At the same time, it should be recognized that global action for health is even more underfunded than is the response to the HIV epidemic. The real issue is therefore not whether to fund AIDS or health systems, but how to increase funding for both. SUMMARY: The evidence is mixed - mostly positive but some negative - as to the impact on health systems of the scaled-up responses to HIV/AIDS driven primarily by global health partnerships. Current scaled-up responses to HIV/AIDS must be maintained and strengthened. Instead of endless debate about the comparative advantages of vertical and horizontal approaches, partners should focus on the best ways for investments in response to HIV to also broadly strengthen the primary health care systems.

Use of antiretroviral therapy in resource-limited countries in 2006: distribution and uptake of first- and second-line regimens.

OBJECTIVE: To address the information gap on current use of antiretroviral drugs (ARTs) in developing countries. METHODS: The AIDS Medicines and Diagnostics Service of the World Health Organization (WHO) carried out a multi-country survey in early 2006. Questionnaires covered the use of first- and second-line regimens in adults and children, and the rates of switching from first-line to second-line regimen. Weighted percentages of use of ARTs across the cohort of adults and children were calculated and correlated with 2006 WHO guidelines. A second analysis compared demand for ARTs with rates of production of active pharmaceutical ingredients. RESULTS: Twenty-three countries (96%) returned the questionnaires, representing 53% of relevant patients in developing countries as of June 2006, and comprising 92% adults and 8% children receiving ARTs. Response rates were highest for questions regarding first-line use and lowest for those regarding pediatric regimens. The distribution of first-line: second-line use was 96%: 4% among adults and 99%: 1% among children. For adults, 95% of those receiving first-line treatment, but only 25% of those receiving second-line treatment, were on regimens consistent with those preferred by the WHO. Among first-line users, the most common regimen (61%) was stavudine+lamivudine+nevirapine. Among second-line users, abacavir+didanosine+lopinavir/ritonavir was the most common regimen (24%). Among children, compliance with WHO guidelines was high among the respondents, with zidovudine+lamivudine+nevirapine reported as the main option. Estimates of first-year switching rate were highly variable, ranging from 1% to 15%, with only ten responses. Comparison of supply and demand showed that the stated production capacity for active pharmaceutical ingredients is sufficient to meet current demands for ARTs. CONCLUSION: This survey has provided valuable information on the uptake of ARTs in developing countries and will help forecast future demand. Reporting for second-line and pediatric antiretroviral therapy should improve as national programs gain more experience. The current availability of active pharmaceutical ingredients appears to be sufficient to meet current demand. Further work is needed for an understanding of switching rates.

Examining the production costs of antiretroviral drugs.

OBJECTIVES: 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: 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 pricing and procurement of antiretroviral drugs: an observational study of data from the Global Fund.

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.

How human immunodeficiency virus voluntary testing can contribute to tuberculosis control.

Human immunodeficiency virus (HIV) is fueling the tuberculosis (TB) epidemic, particularly in sub-Saharan Africa. However, despite their close epidemiological links, the public health responses have largely been separate. WHO has set out a strategy to decrease the burden of HIV-related TB, comprising interventions against both TB and HIV. Voluntary counselling and testing (VCT) for HIV can link TB and HIV programme activities. The benefits of VCT for HIV to TB patients include referral for appropriate clinical care and support for those testing HIV-positive. Likewise, people attending a centre for VCT can benefit from TB screening: those found to be both HIV-positive and with active TB need referral for TB treatment; those without active TB should be offered TB preventive treatment with isoniazid. To explore how VCT for HIV can contribute to a more coherent response to TB, WHO is coordinating the ProTEST Initiative. The name "ProTEST" is derived from the Promotion of voluntary testing as an entry point for access to the core interventions of intensified TB case-finding and isoniazid preventive treatment. Other interventions may be added to provide finally a comprehensive range of HIV and TB prevention and care interventions. Under the ProTEST Initiative, pilot districts are establishing links between centres for VCT for HIV and TB prevention and care. This will pave the way for large-scale operationalization of the comprehensive range of interventions needed to control TB in settings with high HIV prevalence.