A fundamental component of working towards the goal of providing, by 2010, universal access to antiretroviral treatment for patients with acquired immunodeficiency syndrome (AIDS) is an increased and secured production of antiretroviral drugs (ARTs) in order to meet the increased demand from lower- and middle-income countries. To inform the manufacturers' planning of production of ARTs, a forecast of demand for the drugs has been developed for which data on current usage of ARTs is required, as discussed by Galarraga et al. in this Supplement . In addition, the World Health Organization (WHO) has recently updated its guidelines for the use of antiretroviral therapy (ART) in patients with human immunodeficiency virus (HIV) in countries with limited resources . A reliable description of the current pharmaceutical market could help policy makers, national program managers, and other stakeholders working on HIV/AIDS-related issues to improve their planning and implementation of ART programs. Ideally, this information should be based on a standardized methodology for gathering data on the actual use of ARTs at country level.
To address this gap in available data, the AIDS Medicines and Diagnostics Service (AMDS) of the WHO carried out a survey to assess the distribution and composition of ART regimens used in resource-limited countries.
Questionnaires were sent via the WHO country offices to the national AIDS programs in 24 resource-limited countries in March 2006, to assess the current distribution and uptake of ART treatment regimens. The countries were chosen on the basis of the availability of procurement information in the Global Price Reporting Mechanism established by AMDS . For the past several years, national AIDS programs have been increasingly involved in data collection and reporting on the HIV/AIDS epidemic, supported by regional workshops and training carried out by the WHO and the United Nations Programme on HIV/AIDS (UNAIDS) with respect to specific tools and methodologies. These include patient-level data gathered through sentinel surveillance and case reporting .
The forms provided included: questions covering the proportions of adult patients on first- and second-line regimens; the recommended regimens in the country and the current proportions of patients under each regimen; expected cumulative percentage rates of switching from first-line to second-line treatment in the near future; the proportion of children among all people treated with ART; other questions relating to the choice of treatment protocol and the revision of national treatment guidelines. The questions on the use of pediatric formulations requested respondents to specify the treatment protocols used (including first-line and second-line), and the proportion of children receiving each regimen. Respondents were asked to respond to quantitative questions in terms of percentages.
The completed questionnaires were collected by the WHO country offices and forwarded to the WHO AMDS in Geneva.
The numbers of patients receiving treatment, including adults and children, for each of the 23 respondent countries was taken from the UNAIDS/WHO ‘3 by 5’ report on the global AIDS epidemic for June 2006 . These figures were collated with the questionnaire data to calculate the percentages corresponding to the areas covered in the questionnaire for the entire cohort of patients across the 23 countries.
The calculated percentages of patients receiving specific first-line and second-line regimens were then compared with the 2006 WHO guidelines for a public health approach to the use of ART for HIV infection in countries with limited resources . On the basis of these guidelines, the many possible ART combinations were categorized for the analysis as follows: ‘preferred approach’ and ‘alternative approach’ for both first-line and second-line regimens, and ‘not considered or not recommended in 2006 WHO guidelines’ for either first-line or second-line approaches. These guidelines recommend the use of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and one non nucleoside reverse transcriptase inhibitor (NNRTI) for the preferred first-line approach and the use of two not previously used NRTIs and one boosted protease inhibitor for the preferred second-line approach. In the case of first-line regimens, the alternative approach was defined as the use of a triple-nucleoside regimen. In the case of second-line regimens, the alternative approach included the maintenance of one NRTI (eg, lamivudine) that was previously used within the first-line regimen, along with a new NRTI and one protease inhibitor (boosted or unboosted). ART regimens that did not match these definitions but which were listed by the countries in this survey were included in the ‘not considered or not recommended’ category. The percentage of patients in the 23 countries was sorted according to these categories to analyze the relative uptake of the different regimens and to compare that uptake relative to the WHO recommendations.
The results obtained were then used to carry out an analysis of demand and supply of active pharmaceutical ingredients (APIs) in order to compare the quantity in tons of APIs needed to treat the estimated worldwide total of patients receiving ART treatment in developing countries, as of June 2006, against data on the available production capacity for APIs previously collected by the AMDS . For this analysis, the percentage of patients using each single ART from the 23 countries was calculated, and then extrapolated for the total estimated number of patients receiving ARTs in resource-limited countries, taking into account an estimated 5% loss during the manufacturing process.
Of the 24 questionnaires sent, 23 (96%) were returned. According to the June 2006 report, an estimated total of 851 000 patients were receiving ART treatment in these 23 countries, representing 53.2% of the total number of patients in resource-limited countries as of June 2006. The 23 respondent countries were: Burkina Faso, Burundi, Cambodia, Cameroon, Côte d'Ivoire, Ethiopia, Guatemala, Haiti, India, Kenya, Lesotho, Malawi, Mozambique, Namibia, Nigeria, Russian Federation, Rwanda, Swaziland, Tanzania, Thailand, Uganda, Zambia, and Zimbabwe. The percentages reported in the questionnaire showed that 92% of the patients receiving ART regimens in the 23 countries were adults and 8% were children.
Adult use of antiretroviral therapy
Use of first-line regimens
The vast majority of adults (96%) were reported to be receiving first-line regimens. Reporting compliance was very high for this group, with information on the specific regimens used available for 97% of this set of patients. The programs reported that 95% of all adults receiving first-line regimens were using regimens consistent with the preferred first-line approach including: stavudine (d4T)+lamivudine (3TC)+nevirapine (NVP) (61%), zidovudine (ZDV)+3TC+NVP (16%), ZDV+3TC+efavirenz (EFV) (9%), and d4T+3TC+EFV (8%) (Figure 1). Fewer than 1% of this group were reported to be taking either alternative first-line regimens, including the triple nucleoside combinations of ZDV+3TC+abacavir (ABC) and d4T+3TC+ABC, or taking regimens not considered or not recommended by WHO. Reassuringly, only one country reported any patients receiving a first-line regimen containing d4T+didanosine (ddI), a regimen which is explicitly not recommended by WHO because of overlapping toxicities between these two NRTI drugs.
Use of second-line regimens
Reporting of second-line regimens was less consistent than that for first-line regimens, with greater diversity among regimens, lower rates of adherence to WHO recommendations, and lower reporting rates.
Among the study cohort, 4% of adults were reported to be receiving second-line regimens, with information on specific regimens used only reported for 76%. Despite the under-reporting, 61% of the entire group were reported to be receiving regimens consistent with the preferred and alternative second-line approaches recommended by WHO in the 2006 guidelines. However, only 25% were following the preferred approach, including: ABC+ddI+lopinavir/ritonavir (LPV/r) (24%) and tenofovir (TDF)+ddI+LPV/r (1%) (Figure 1). Regimens consistent with the alternative second-line approach were followed by 36%; these included: ddI+3TC+LPV/r (19%), ddI+3TC+indinavir/ritonavir (IDV/r) (9%), ZDV+ddI+LPV/r (4%), TDF+ddI+NFV (1%), ZDV+ddI+NFV (1%), and ABC+ddI+NFV (1%). Other second-line regimens consistent with the WHO alternative second-line approach were listed by less than 1% in this cohort; these included: TDF+3TC+LPV/r, ABC+ddI+IDV/r, ddI+3TC+saquinavir/ritonavir (SQVr), TDF+ddI+IDV/r, and ABC+ZDV+NFV. In contrast, 4% were reported to be receiving regimens that are considered within the WHO first-line approaches, and 12% were receiving regimens that were not considered or not recommended in the 2006 guidelines (Figure 2).
To help develop projections of future use of second-line regimens, questionnaire respondents were asked to estimate, from the cohort that started receiving first-line treatment during 2006, the cumulative percentage of patients who would move to second-line regimens for each of the next 5 years.
There was great variation between the estimates reported by countries and reporting compliance was low, with only 10 of the 23 countries reporting. First-year switching rate estimates ranged from 1% to 15%, with more than seven of the ten countries estimating rates less than or equal to 3% (Figure 3). Estimates of 5-year switching rate ranged from 5% to 40%, with seven countries providing estimates less than or equal to 20%.
Pediatric use of antiretroviral drugs
Reporting rates were low for pediatric patients, with information available for only 50% of the 23-country patient cohort. Of the entire pediatric cohort, 49% were reported to be receiving one of the preferred first-line regimens according to the 2006 WHO guidelines, with ZDV+3TC+NVP being the most widely used (30%) (Figure 4).
Comparison of demand and capacity for manufacturing active pharmaceutical ingredients
On the basis of a previous survey carried out by AMDS of the production capacity of 11 companies producing APIs used in the formulation of ART medicines, the results of the 23-country survey were used to compare the quantity of API needed to treat all the estimated 1.65 million patients receiving ART in lower- and middle-income countries with these reported capacity figures. A production loss of 5%, which is typical during the manufacturing process, was taken into account. In the case of stavudine, on the basis of discussions with companies and available procurement data, uptake was assumed to be 60% for the 30 mg formulations and 40% for the 40 mg formulations. Estimates of production capacity were available for 12 of the 13 different APIs used in the ARTs that were included in the survey, with the exception of tenofovir (Table 1).
This comprehensive survey, covering more than 50% of the estimated adults and children receiving ART in lower- and middle-income countries, showed that adherence to 2006 WHO guidelines for first-line regimens is very high. A number of factors, including the availability of generic versions of the drugs, and of fixed-dose combinations, are likely to explain the distribution of uptake seen in this survey. The high compliance rate is a positive development, as this will help advance the broader public health goals behind the development of these guidelines, including the standardization of treatment in resource-limited settings, facilitating adherence, and encouraging the rational prescribing of ARTs.
In contrast, understanding the uptake of second-line regimens is complex. The definition of second-line regimens is dependent on what has been used previously as a first-line regimen. Without knowing the treatment history of a given patient or cohort of patients, it is difficult to know if a regimen incorporating two NRTIs and a boosted protease inhibitor should be classified as a preferred second-line regimen (ie, the two NRTI drugs have not previously been used) or as an alternative second-line regimen (ie, a previously used NRTI is still included). This is further complicated by the challenges associated with understanding the distinction between a change in regimen because of treatment failure (‘switching’ from first- to second-line) and a change because of toxicity (‘substitution’ – remaining on a first-line regimen). For example, several regimens that were reported as second-line by countries were classified as follows: (1) within the range of first-line options according to WHO guidelines (eg, ABC+3TC+ZDV); (2) not considered or not recommended by the WHO guidelines, although some of these are used elsewhere as second-line options (eg, SQV+LPV/r).
Price is also likely to affect the ability of national programs to adhere to WHO guidelines, particularly regarding the use of second-line drugs. The survey confirms that the uptake of tenofovir, which has been more expensive and less available than drugs such as lamivudine or zidovudine, remains low, although this situation is changing as manufacturers and other stakeholders work to expand access. A fuller exploration of price comparisons was beyond the scope of this study, although data on prices are currently readily available through several sources, including the Global Price Reporting Mechanism (http://www.who.int/hiv/amds/price/en/index.html) established by the WHO. The reasons for low reporting rates for second-line regimens are less clear, but these could be related to the much larger set of options and increased complexity of second-line regimens. For example, survey respondents listed only 15 different regimens for the questions concerning uptake of first-line treatments, but 27 regimens for those concerning second-line treatments. Rapidly evolving changes in treatment guidelines and recommendations, particularly for second-line regimens, may also make it more difficult for program managers to answer questions relating to the use of this set of ARTs. However, reporting should continue to improve as programs become more proficient in measurement.
For the pediatric cohort, although most pediatric treatment programs are fairly new and there was only a 50% response rate, the available data showed that national programs had a high rate of adherence to the 2006 WHO guidelines. Expansion of HIV/AIDS programs to include treatment for pediatric age groups has been hampered for a number of reasons, including the limited drug formulary (ie, drugs approved for use in children), lack of affordable pediatric formulations of ARTs , and lack of appropriate fixed-dose combination formulations. There is great hope that this will improve in light of a tool being produced by the WHO to assist national programs, which includes generic weight-based dosing recommendations, and the work being carried out by ART advisory committees, which has resulted in agreements on safe dosing for existing and new ART products. The recent successful negotiations by the Clinton Foundation to decrease prices for pediatric ARTs, and their plans to expand access to these through collaboration with UNITAID , should also greatly improve access to pediatric formulations.
The demand–supply comparison showed that stated production capacity for the 12 APIs is largely sufficient to meet the current consumption of the population receiving ART in lower- and middle-income countries. Additional analysis by Galarraga et al.  addresses this question in relation to future demand.
Forecasting future demand for ARTs, particularly for those used in second-line regimens, is likely to continue to require regular updates on the use of ARTs in resource-limited countries. Data for rates of switching continue to rely mostly on estimates, as widespread scale-up and initiation of ART has started only recently, and there are limited data available concerning switching from HIV/AIDS programs in many low- and middle-income countries. However, switching rates do appear to be highly variable in high-income countries with closely monitored programs .
A Medical Research Council study currently in progress  should provide more information that will be relevant to ART usage in resource-limited countries. It will also be important to reinforce the capacity for program monitoring and collection of data on ART use as programs in countries with limited resources continue to scale up their programs, and to collect and compile these data at a global level.
We are grateful to the senior staff of the Ministries of Health, national AIDS programs and other key informants in the participating countries, including the WHO HIV officers and National Programme Officers, who completed or reviewed the questionnaires, the WHO regional advisers and other regional WHO staff, and the staff of the HIV Department in Geneva for their assistance and feedback in completing the survey.
Sponsorship: This work was supported by the World Health Organization, Geneva, Switzerland.
Conflicts of interest: None reported.
Disclaimer: The production of this special Supplement was supported by the World Bank, the Joint United Nations Programme on HIV/AIDS and the World Health Organization. The findings, interpretations and conclusions presented in this paper do not necessarily reflect the views of these institutions or their constituent agencies or governments.
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