Modeling HIV/AIDS Drug Price Determinants in Brazil: Is Generic Competition a Myth?

Background

Brazil became the first developing country to guarantee free and universal access to HIV/AIDS treatment, with antiretroviral drugs (ARVs) being delivered to nearly 190,000 patients. The analysis of ARV price evolution and market dynamics in Brazil can help anticipate issues soon to afflict other developing countries, as the 2010 revision of the World Health Organization guidelines shifts demand towards more expensive treatments, and, at the same time, current evolution of international legislation and trade agreements on intellectual property rights may reduce availability of generic drugs for HIV care.

Methods and Findings

Our analyses are based on effective prices paid for ARV procurement in Brazil between 1996 and 2009. Data panel structure was exploited to gather ex-ante and ex-post information and address various sources of statistical bias. In-difference estimation offered in-depth information on ARV market characteristics which significantly influence prices. Although overall ARV prices follow a declining trend, changing characteristics in the generic segment help explain recent increase in generic ARV prices. Our results show that generic suppliers are more likely to respond to factors influencing demand size and market competition, while originator suppliers tend to set prices strategically to offset compulsory licensing threats and generic competition.

Significance

In order to guarantee the long term sustainability of access to antiretroviral treatment, our findings highlight the importance of preserving and stimulating generic market dynamics to sustain developing countries'' bargaining power in price negotiations undertaken with originator companies.     

Food Insecurity as a Barrier to Sustained Antiretroviral Therapy Adherence in Uganda

Background

Food insecurity is emerging as an important barrier to antiretroviral (ARV) adherence in sub-Saharan Africa and elsewhere, but little is known about the mechanisms through which food insecurity leads to ARV non-adherence and treatment interruptions.

Methodology

We conducted in-depth, open-ended interviews with 47 individuals (30 women, 17 men) living with HIV/AIDS recruited from AIDS treatment programs in Mbarara and Kampala, Uganda to understand how food insecurity interferes with ARV therapy regimens. Interviews were transcribed, coded for key themes, and analyzed using grounded theory.

Findings

Food insecurity was common and an important barrier to accessing medical care and ARV adherence. Five mechanisms emerged for how food insecurity can contribute to ARV non-adherence and treatment interruptions or to postponing ARV initiation: 1) ARVs increased appetite and led to intolerable hunger in the absence of food; 2) Side effects of ARVs were exacerbated in the absence of food; 3) Participants believed they should skip doses or not start on ARVs at all if they could not afford the added nutritional burden; 4) Competing demands between costs of food and medical expenses led people either to default from treatment, or to give up food and wages to get medications; 5) While working for food for long days in the fields, participants sometimes forgot medication doses. Despite these obstacles, many participants still reported high ARV adherence and exceptional motivation to continue therapy.

Conclusions

While reports from sub-Saharan Africa show excellent adherence to ARVs, concerns remain that these successes are not sustainable in the presence of widespread poverty and food insecurity. We provide further evidence on how food insecurity can compromise sustained ARV therapy in a resource-limited setting. Addressing food insecurity as part of emerging ARV treatment programs is critical for their long-term success.     

Care of HIV-infected patients in China

Compared with high infection areas of the world, the total HIV infection rate in China is relatively low. Nonetheless, because of China's vast territory and large population, the potential infection risk must be taken seriously. In the next few years, needle sharing among injection drug users will remain the most common route of transmission for the HIV/AIDS epidemic in China. Unprotected sex is gradually becoming a major route of transmission. China began to implement HAART in 1999 according to international standards. Prior to 2003, there were only about 150 HIV/AIDS patients were treated with HAART in some clinical trials and about 100 HIV/AIDS patients were treated by private sources. Results of those treatments are the scientific basis for development of the therapeutic strategies in China. In March of 2003, the Chinese government initiated China CARES program. In November of 2003, the Chinese Ministry of Health announced a national policy of free ARV treatment to all HIV+ Chinese citizens who were in poverty and required ARV therapy. There are total of 19,456 HIV/AIDS patients received free ARV drugs to date in 159 regions and 441 towns. Current challenges are how to follow-up and evaluate those patients in the clinical settings. The longer the therapy is postponed, the more side effects and the higher probability of drug resistance are going to occur. It remains unclear, therefore, when HAART regimen should be started in the HIV/AIDS population in China.     

Drug companies cut HIV drug prices in the developing world

The UN has reported that five multinational pharmaceutical companies would cut down HIV drug prices in the developing world. One of these drug companies is GlaxoWellcome, which has promised to reduce the price of zidovudine and lamivudine to US$2 in the poorest nations, a fifth of its price in the US. Although Peter Piot, director of the UN Program on HIV/AIDS, welcomed the companies' promises, he warned that price cuts alone will not curb the epidemic. He stated that this initiative is only one critical factor in what must become a much broader and more urgent effort to help people living with HIV/AIDS. Moreover, health and development agencies expressed concern that AIDS drugs will still be unaffordable for the vast majority of those in need in developing countries. In addition, poor countries lack the infrastructure to deliver these drugs safely and effectively. During the time of the UN announcement, US President Bill Clinton also signed an executive order allowing sub-Saharan Africa to adopt legal measures to obtain cheap HIV drugs. Meanwhile, South Africa's reaction to the offer to cut antiretroviral drug prices has been lukewarm.     

The (political) economics of antiretroviral treatment in developing countries

Despite unprecedented international mobilisation to support universal provision of highly active antiretroviral therapy (HAART), national governments continue to play the key role in determining access to treatment. Whereas some AIDS-affected countries have performed as well as or better than expected given their level of development, institutional characteristics and demographic challenges (e.g. Thailand and Brazil), others (notably South Africa) have not. This article argues that the 'economics' of antiretroviral drug delivery is at heart a political-economy of access to treatment. It depends on commitment on the part of national governments to negotiate with pharmaceutical companies over patented antiretroviral drug prices, on their policy towards compulsory licensing, and on the approach they adopt to delivering HAART. Civil society has an important role to play in encouraging governments to become, and remain, committed to taking action to ensure sustainable and widespread access to HAART.     

Cost Effectiveness of Daclatasvir/Asunaprevir Versus Peginterferon/Ribavirin and Protease Inhibitors for the Treatment of Hepatitis c Genotype 1b Na?ve Patients in Chile

Introduction

Daclatasvir and Asunaprevir (DCV/ASV) have recently been approved for the treatment of chronic hepatitis C virus infection. In association, they are more effective and safer than previous available treatments, but more expensive. It is unclear if paying for the additional costs is an efficient strategy considering limited resources.

Methods

A Markov model was built to estimate the expected costs in Chilean pesos (CL$) and converted to US dollars (US$) and benefits in quality adjusted life years (QALYs) in a hypothetic cohort of naive patients receiving DCV/ASV compared to protease inhibitors (PIs) and Peginterferon plus Ribavirin (PR). Efficacy was obtained from a mixed-treatment comparison study and costs were estimated from local sources. Utilities were obtained applying the EQ-5D survey to local patients and then valued with the Chilean tariff. A time horizon of 46 years and a discount rate of 3% for costs and outcomes was considered. The ICERs were estimated for a range of DCV/ASV prices. Deterministic and probabilistic sensitivity analyses were performed.

Results

PIs were extendedly dominated by DCV/ASV. The ICER of DCV/ASV compared to PR was US$ 16,635/QALY at a total treatment price of US$ 77,419; US$11,581 /QALY at a price of US$ 58,065; US$ 6,375/QALY at a price of US$ 38,710; and US$ 1,364 /QALY at a price of US$ 19,355. The probability of cost-effectiveness at a price of US$ 38,710 was 91.6% while there is a 21.43% probability that DCV/ASV dominates PR if the total treatment price was US$ 19,355. Although the results are sensitive to certain parameters, the ICER did not increase above the suggested threshold of 1 GDP per capita.

Conclusions

DCV/ASV can be considered cost-effective at any price of the range studied. These results provide decision makers useful information about the value of incorporating these drugs into the public Chilean healthcare system.     

Long-term costs and health impact of continued global fund support for antiretroviral therapy

Background

By the end of 2011 Global Fund investments will be supporting 3.5 million people on antiretroviral therapy (ART) in 104 low- and middle-income countries. We estimated the cost and health impact of continuing treatment for these patients through 2020.

Methods and Findings

Survival on first-line and second-line ART regimens is estimated based on annual retention rates reported by national AIDS programs. Costs per patient-year were calculated from country-reported ARV procurement prices, and expenditures on laboratory tests, health care utilization and end-of-life care from in-depth costing studies. Of the 3.5 million ART patients in 2011, 2.3 million will still need treatment in 2020. The annual cost of maintaining ART falls from $1.9 billion in 2011 to $1.7 billion in 2020, as a result of a declining number of surviving patients partially offset by increasing costs as more patients migrate to second-line therapy. The Global Fund is expected to continue being a major contributor to meeting this financial need, alongside other international funders and domestic resources. Costs would be $150 million less in 2020 with an annual 5% decline in first-line ARV prices and $150–370 million less with a 5%–12% annual decline in second-line prices, but $200 million higher in 2020 with phase out of stavudine (d4T), or $200 million higher with increased migration to second-line regimens expected if all countries routinely adopted viral load monitoring. Deaths postponed by ART correspond to 830,000 life-years saved in 2011, increasing to around 2.3 million life-years every year between 2015 and 2020.

Conclusions

Annual patient-level direct costs of supporting a patient cohort remain fairly stable over 2011–2020, if current antiretroviral prices and delivery costs are maintained. Second-line antiretroviral prices are a major cost driver, underscoring the importance of investing in treatment quality to improve retention on first-line regimens.     

Efflux transporters- and cytochrome P-450-mediated interactions between drugs of abuse and antiretrovirals

Multidrug regimens and corresponding drug interactions cause many adverse reactions and treatment failures. Drug efflux transporters: P-gp, MRP, BCRP in conjunction with metabolizing enzymes (CYPs) are major factors in such interactions. Most effective combination antiretrovirals (ARV) therapy includes a PI or a NNRTI or two NRTI. Coadministration of such ARV may induce efflux transporters and/or CYP3A4 resulting in sub-therapeutic blood levels and therapeutic failure due to reduced absorption and/or increased metabolism. A similar prognosis is true for ARV-compounds and drugs of abuse combinations. Morphine and nicotine enhance CYP3A4 and MDR1 expression in vitro. A 2.5 fold rise of cortisol metabolite was evident in smokers relative to nonsmokers. Altered functions of efflux transporters and CYPs in response to ARV and drugs of abuse may result in altered drug absorption and metabolism. Appropriate in vitro models can be employed to predict such interactions. Influence of genetic polymorphism, SNP and inter-individual variation in drug response has been discussed. Complexity underlying the relationship between efflux transporters and CYP makes it difficult to predict the outcome of HAART as such, particularly when HIV patients taking drugs of abuse do not adhere to HAART regimens. HIV(+) pregnant women on HAART medications, indulging in drugs of abuse, may develop higher viral load due to such interactions and lead to increase in mother to child transmission of HIV. A multidisciplinary approach with clear understanding of mechanism of interactions may allow proper selection of regimens so that desired therapeutic outcome of HAART can be reached without any side effects.     

Effect of generic drug competition on the price of prescription drugs in Ontario.

OBJECTIVE: To analyse the potential effect of generic drug competition on prices in Ontario to assess the costs and benefits associated with Bill C-22 (An Act to amend the Patent Act). DESIGN: Comparison of the cost of the least and most expensive versions of all products sold by more than one manufacturer in 1991. The number of brand-name and generic drug companies marketing each of the products was recorded. RESULTS: Of 1599 products 437 (27.3%) were made by more than one company. Almost half (44.6%) of the 437 were sold by two companies. The more companies that sold a drug the greater the difference in price between the least and most expensive versions. Similarly, as the proportion of generic drug companies in competition increased, the greater the price difference. When competition was between generic drug companies only, the price spread was smaller than when it was between brand-name drug companies only. CONCLUSIONS: Generic drug competition can result in savings to the Ontario Drug Benefit Plan. A more in-depth analysis of the potential savings is necessary to fully assess the costs and benefits associated with Bill C-22.     

Designing equitable antiretroviral allocation strategies in resource-constrained countries

Background

Recently, a global commitment has been made to expand access to antiretrovirals (ARVs) in the developing world. However, in many resource-constrained countries the number of individuals infected with HIV in need of treatment will far exceed the supply of ARVs, and only a limited number of health-care facilities (HCFs) will be available for ARV distribution. Deciding how to allocate the limited supply of ARVs among HCFs will be extremely difficult. Resource allocation decisions can be made on the basis of many epidemiological, ethical, or preferential treatment priority criteria.

Methods and Findings

Here we use operations research techniques, and we show how to determine the optimal strategy for allocating ARVs among HCFs in order to satisfy the equitable criterion that each individual infected with HIV has an equal chance of receiving ARVs. We present a novel spatial mathematical model that includes heterogeneity in treatment accessibility. We show how to use our theoretical framework, in conjunction with an equity objective function, to determine an optimal equitable allocation strategy (OEAS) for ARVs in resource-constrained regions. Our equity objective function enables us to apply the egalitarian principle of equity with respect to access to health care. We use data from the detailed ARV rollout plan designed by the government of South Africa to determine an OEAS for the province of KwaZulu–Natal. We determine the OEAS for KwaZulu–Natal, and we then compare this OEAS with two other ARV allocation strategies: (i) allocating ARVs only to Durban (the largest urban city in KwaZulu–Natal province) and (ii) allocating ARVs equally to all available HCFs. In addition, we compare the OEAS to the current allocation plan of the South African government (which is based upon allocating ARVs to 17 HCFs). We show that our OEAS significantly improves equity in treatment accessibility in comparison with these three ARV allocation strategies. We also quantify how the size of the catchment region surrounding each HCF, and the number of HCFs utilized for ARV distribution, alters the OEAS and the probability of achieving equity in treatment accessibility. We calculate that in order to achieve the greatest degree of treatment equity for individuals with HIV in KwaZulu–Natal, the ARVs should be allocated to 54 HCFs and each HCF should serve a catchment region of 40 to 60 km.

Conclusion

Our OEAS would substantially improve equality in treatment accessibility in comparison with other allocation strategies. Furthermore, our OEAS is extremely different from the currently planned strategy. We suggest that our novel methodology be used to design optimal ARV allocation strategies for resource-constrained countries.     

Understanding the Impact of Hazardous and Harmful Use of Alcohol and/or Other Drugs on ARV Adherence and Disease Progression

The objective of this study was to understand the impact of hazardous and harmful use of alcohol and/or other drugs on ARV adherence and disease progression among HIV patients. A cross-sectional study design was used. A total of 1503 patients attending HIV clinics in Cape Town, South Africa were screened for problematic substance use. A sub-sample of 607 patients (303 patients who screened positive for problematic substance use and 304 who did not) participated in this study. Hazardous or harmful alcohol use and problematic drug use predicted missing and stopping ARVs which, in turn, was associated with a decrease in CD4 counts and more rapid HIV-disease progression and poorer health outcomes in people living with HIV/AIDS (PLWHA). The findings of this study underscore the need for an integrated approach to managing substance-use disorders in PLWHA.     

The Financial Burden of Morbidity in HIV-Infected Adults on Antiretroviral Therapy in C?te d'Ivoire

Background

Large HIV care programs frequently subsidize antiretroviral (ARV) drugs and CD4 tests, but patients must often pay for other health-related drugs and services. We estimated the financial burden of health care for households with HIV-infected adults taking antiretroviral therapy (ART) in Côte d''Ivoire.

Methodology/Principal Findings

We conducted a cross-sectional survey. After obtaining informed consent, we interviewed HIV-infected adults taking ART who had consecutively attended one of 18 HIV care facilities in Abidjan. We collected information on socioeconomic and medical characteristics. The main economic indicators were household capacity-to-pay (overall expenses minus food expenses), and health care expenditures. The primary outcome was the percentage of households confronted with catastrophic health expenditures (health expenditures were defined as catastrophic if they were greater than or equal to 40% of the capacity-to-pay). We recruited 1,190 adults. Median CD4 count was 187/mm³, median time on ART was 14 months, and 72% of subjects were women. Mean household capacity-to-pay was $213.7/month, mean health expenditures were $24.3/month, and 12.3% of households faced catastrophic health expenditures. Of the health expenditures, 75.3% were for the study subject (ARV drugs and CD4 tests, 24.6%; morbidity events diagnosis and treatment, 50.1%; transportation to HIV care centres, 25.3%) and 24.7% were for other household members. When we stratified by most recent CD4 count, morbidity events related expenses were significantly lower when subjects had higher CD4 counts.

Conclusions/Significance

Many households in Côte d''Ivoire face catastrophic health expenditures that are not attributable to ARV drugs or routine follow-up tests. Innovative schemes should be developed to help HIV-infected patients on ART face the cost of morbidity events.     

Analysis of HIV Early Infant Diagnosis Data to Estimate Rates of Perinatal HIV Transmission in Zambia

Background

Mother-to-child transmission of HIV (MTCT) remains the most prevalent source of pediatric HIV infection. Most PMTCT (prevention of mother-to-child transmission of HIV) programs have concentrated monitoring and evaluation efforts on process rather than on outcome indicators. In this paper, we review service data from 28,320 children born to HIV-positive mothers to estimate MTCT rates.

Method

This study analyzed DNA PCR results and PMTCT data from perinatally exposed children zero to 12 months of age from five Zambian provinces between September 2007 and July 2010.

Results

The majority of children (58.6%) had a PCR test conducted between age six weeks and six months. Exclusive breastfeeding (56.8%) was the most frequent feeding method. An estimated 45.9% of mothers were below 30 years old and 93.3% had disclosed their HIV status. In terms of ARV regimen for PMTCT, 32.7% received AZT+single dose NVP (sdNVP), 30.9% received highly active antiretroviral treatment (HAART), 19.6% received sdNVP only and 12.9% received no ARVs. Transmission rates at six weeks when ARVs were received by both mother and baby, mother only, baby only, and none were 5.8%, 10.5%, 15.8% and 21.8% respectively. Transmission rates at six weeks where mother received HAART, AZT+sd NVP, sdNVP, and no intervention were 4.2%, 6.8%, 8.7% and 20.1% respectively. Based on adjusted analysis including ARV exposures and non ARV-related parameters, lower rates of positive PCR results were associated with 1) both mother and infant receiving prophylaxis, 2) children never breastfed and 3) mother being 30 years old or greater.Overall between September 2007 and July 2010, 12.2% of PCR results were HIV positive. Between September 2007 and January 2009, then between February 2009 and July 2010, proportions of positive PCR results were 15.1% and 11% respectively, a significant difference.

Conclusion

The use of ARV drugs reduces vertical transmission of HIV in a program setting. Non-chemoprophylactic factors also play a significant role in HIV transmission. The overall change in the proportions of positive PCR results over time is more likely an indication of better PMTCT implementation. Determination of the outcomes of PMTCT in program settings is feasible but requires accurate documentation and analysis.     

Patients' costs and cost-effectiveness of tuberculosis treatment in DOTS and non-DOTS facilities in Rio de Janeiro, Brazil

Background

Costs of tuberculosis diagnosis and treatment may represent a significant burden for the poor and for the health system in resource-poor countries.

Objectives

The aim of this study was to analyze patients'' costs of tuberculosis care and to estimate the incremental cost-effectiveness ratio (ICER) of the directly observed treatment (DOT) strategy per completed treatment in Rio de Janeiro, Brazil.

Methods

We interviewed 218 adult patients with bacteriologically confirmed pulmonary tuberculosis. Information on direct (out-of-pocket expenses) and indirect (hours lost) costs, loss in income and costs with extra help were gathered through a questionnaire. Healthcare system additional costs due to supervision of pill-intake were calculated considering staff salaries. Effectiveness was measured by treatment completion rate. The ICER of DOT compared to self-administered therapy (SAT) was calculated.

Principal Findings

DOT increased costs during the treatment phase, while SAT increased costs in the pre-diagnostic phase, for both the patient and the health system. Treatment completion rates were 71% in SAT facilities and 79% in DOT facilities. Costs per completed treatment were US$ 194 for patients and U$ 189 for the health system in SAT facilities, compared to US$ 336 and US$ 726 in DOT facilities. The ICER was US$ 6,616 per completed DOT treatment compared to SAT.

Conclusions

Costs incurred by TB patients are high in Rio de Janeiro, especially for those under DOT. The DOT strategy doubles patients'' costs and increases by fourfold the health system costs per completed treatment. The additional costs for DOT may be one of the contributing factors to the completion rates below the targeted 85% recommended by WHO.     

Projected Lifetime Healthcare Costs Associated with HIV Infection

Objective

Estimates of healthcare costs associated with HIV infection would provide valuable insight for evaluating the cost-effectiveness of possible prevention interventions. We evaluate the additional lifetime healthcare cost incurred due to living with HIV.

Methods

We used a stochastic computer simulation model to project the distribution of lifetime outcomes and costs of men-who-have-sex-with-men (MSM) infected with HIV in 2013 aged 30, over 10,000 simulations. We assumed a resource-rich setting with no loss to follow-up, and that standards and costs of healthcare management remain as now.

Results

Based on a median (interquartile range) life expectancy of 71.5 (45.0–81.5) years for MSM in such a setting, the estimated mean lifetime cost of treating one person was £360,800 ($567,000 or €480,000). With 3.5% discounting, it was £185,200 ($291,000 or €246,000). The largest proportion (68%) of these costs was attributed to antiretroviral drugs. If patented drugs are replaced by generic versions (at 20% cost of patented prices), estimated mean lifetime costs reduced to £179,000 ($281,000 or €238,000) and £101,200 ($158,900 or €134,600) discounted.

Conclusions

If 3,000 MSM had been infected in 2013, then future lifetime costs relating to HIV care is likely to be in excess of £1 billion. It is imperative for investment into prevention programmes to be continued or scaled-up in settings with good access to HIV care services. Costs would be reduced considerably with use of generic antiretroviral drugs.     

Brazilian alcohol: Food versus fuel?

The creation of the ProAlcool (National Alcohol Programme) late in 1975 for the production of fuel alcohol has raised varied criticisms as to the possible consequences for food production in Brazil. This food ‘problem’ in Brazil is embedded in its socio-economic and political system. Agricultural production has kept ahead of population growth, but the main beneficiaries have been commodity export crops; the issue can be identified as ‘commodity export crop production versus crop production for the domestic market’ rather than ‘food versus fuel’. The possible effects of the ProAlcool on food production have been exaggerated and the real implications largely overlooked. The sugar and alcohol sector is today among Brazil's largest industries and, with all its faults, the ProAlcool remains the world's most successful biomass energy programme and as such its importance extends beyond Brazil's national boundaries. Biomass has been demonstrated by a Third World country to be a viable alternative or complement to oil on a national scale. Despite the current (1986) low oil prices an interministerial commission has recently recommended that the ProAlcool programme should be maintained.     

Laser‐enhanced drug delivery of antiretroviral drugs into human immunodeficiency virus‐1 infected TZMbl cells

The introduction of highly active antiretroviral therapy (HAART) has significantly increased life expectancy and improved management of the human immunodeficiency virus‐1 (HIV‐1) disease globally. This well‐established treatment regime has shown to reduce viral capacity to undetectable limits when using traditional clinical assays. The establishment of viral reservoirs during the early stages of infection are the major contributors to failure of the current regimens to eradicate HIV‐1 infection since the reservoirs are not affected by antiretroviral drugs (ARVs). Therefore, advanced modification of the present treatment and investigation of novel antiretroviral drug delivery system are needed. The aim of this study was to use femtosecond (fs) laser pulses to deliver ARVs into HIV‐1 infected TZMbl cells. Different ARVs were translocated into TZMbl cells using fs pulsed laser (800 nm) with optimum power of 4 μW and 10 ms laser to cell exposure time. Changes in cellular processes were evaluated using cellular morphology, viability, cytotoxicity and luciferase activity assays. Cells treated with the laser in the presence of ARVs showed a significant reduction in viral infectivity, cell viability and an increase in cytotoxicity. This study demonstrated that fs laser pulses were highly effective in delivering ARVs into HIV‐1 infected TZMbl cells, causing a significant reduction in HIV‐1 infection.