Securing the supply of benzathine benzylpenicillin: a global perspective on risks and mitigation strategies to prevent future shortages.

Benzathine benzylpenicillin is a globally indispensable medicine. As a long-lasting injectable penicillin, it serves as the primary treatment for syphilis, group A streptococcal infections, rheumatic fever and rheumatic heart disease. A competitive market and low profit margins, compounded by limited visibility of demand, have resulted in a decreased number of active pharmaceutical ingredient (API) manufacturers. By 2016, only three Chinese API manufacturers remained, continuing to supply to the global market today. Recurring global shortages, a consequence of supply and demand imbalances, indicate underlying market risks. Therefore, the need for mitigation strategies is imperative.

Access to Treatment for Hepatitis B Virus Infection - Worldwide, 2016.

Worldwide, an estimated 257 million persons are living with chronic hepatitis B virus (HBV) infection (1). To achieve the World Health Organization (WHO) goals for elimination of HBV infection worldwide by 2030, defined by WHO as 90% reduction in incidence and 65% reduction in mortality, access to treatment will be crucial. WHO estimated the care cascade* for HBV infection, globally and by WHO Region. The patent and licensing status of entecavir and tenofovir, two WHO-recommended medicines for HBV treatment, were examined using the Medicines Patent Pool MedsPaL† database. The international price of tenofovir was estimated using WHO's global price reporting mechanism (GPRM), and for entecavir from a published study (2). In 2016, among the estimated 257 million persons infected with HBV worldwide, approximately 27 million (10.5%) were aware of their infection, an estimated 4.5 million (16.7%) of whom were on treatment. In 2017, all low- and middle-income countries (LMICs) could legally procure generic entecavir, and all but two LMICs could legally procure generic tenofovir. The median price of WHO-prequalified generic tenofovir on the international market fell from $208 per year in 2004 to $32 per year in 2016. In 2015, the lowest reported price of entecavir was $427 per year of treatment (2). Increased availability of generic antivirals effective in treating chronic HBV infection has likely improved access to treatment. Taking advantage of reductions in price of antivirals active against HBV infection could further increase access to treatment. Regular analysis of the hepatitis B treatment care cascade can assist in monitoring progress toward HBV elimination goals.

Projected Uptake of New Antiretroviral (ARV) Medicines in Adults in Low- and Middle-Income Countries: A Forecast Analysis 2015-2025.

With anti-retroviral treatment (ART) scale-up set to continue over the next few years it is of key importance that manufacturers and planners in low- and middle-income countries (LMICs) hardest hit by the HIV/AIDS pandemic are able to anticipate and respond to future changes to treatment regimens, generics pipeline and demand, in order to secure continued access to all ARV medicines required. We did a forecast analysis, using secondary WHO and UNAIDS data sources, to estimate the number of people living with HIV (PLHIV) and the market share and demand for a range of new and existing ARV drugs in LMICs up to 2025. UNAIDS estimates 24.7 million person-years of ART in 2020 and 28.5 million person-years of ART in 2025 (24.3 million on first-line treatment, 3.5 million on second-line treatment, and 0.6 million on third-line treatment). Our analysis showed that TAF and DTG will be major players in the ART regimen by 2025, with 8 million and 15 million patients using these ARVs respectively. However, as safety and efficacy of dolutegravir (DTG) and tenofovir alafenamide (TAF) during pregnancy and among TB/HIV co-infected patients using rifampicin is still under debate, and ART scale-up is predicted to increase considerably, there also remains a clear need for continuous supplies of existing ARVs including TDF and EFV, which 16 million and 10 million patients-respectively-are predicted to be using in 2025. It will be important to ensure that the existing capacities of generics manufacturers, which are geared towards ARVs of higher doses (such as TDF 300mg and EFV 600mg), will not be adversely impacted due to the introduction of lower dose ARVs such as TAF 25mg and DTG 50mg. With increased access to viral load testing, more patients would be using protease inhibitors containing regimens in second-line, with 1 million patients on LPV/r and 2.3 million on ATV/r by 2025. However, it will remain important to continue monitoring the evolution of ARV market in LMICs to guarantee the availability of these medicines.

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.

Forecast of demand for antiretroviral drugs in low and middle-income countries: 2007-2008.

BACKGROUND: Middle and low-income countries have scaled up HIV treatment in the past 5 years. To maintain this effort, information regarding the amounts and types of drugs is needed. Shortages or overstock of active pharmaceutical ingredients make the scale-up efforts more difficult and costly. To inform global planning and implementation, we estimate the volume of current and future demand for active pharmaceutical ingredients for first and second-line antiretroviral drugs. METHODS: Using regression analysis and documented assumptions, we estimated the number of individuals receiving antiretroviral drugs to 2008. The volume of active pharmaceutical ingredients was calculated using two methods: a normative approach modelling implementation of country-specific guidelines, and an empirical model projecting current trends in drug use estimated by a survey of country HIV programmes. RESULTS: The number of patients treated was estimated to reach 3.38 million by the end of 2008, of which 94.6% would be on first-line and 5.4% on second-line treatment. The largest estimated absolute demand volumes for 2008 were for nevirapine, lamivudine, and zidovudine using either approach; the largest proportional increases in 2007-2008, were observed for emtricitabine, tenofovir, indinavir, and nelfinavir. The gap between normative and empirical estimates was greatest (most positive) for tenofovir, zidovudine, didanosine, and smallest (most negative) for saquinavir and nelfinavir. CONCLUSION: A comparison of the results from the normative and empirical demand quantities suggests that more tenofovir, zidovudine and didanosine would be required if national treatment guidelines were fully implemented, whereas the countries seem to be using more saquinavir and nelfinavir than would be required by their current guidelines.