Objective: This article reviews the antiretroviral therapy (ART) initiation criteria from national treatment guidelines for 70 countries and determines the extent of consistency with the current World Health Organization (WHO) recommendations.
Methods: Published ART guidelines were collected from the Internet, databases, and WHO staff. ART eligibility criteria for asymptomatic people, pregnant women, people with HIV-associated tuberculosis, serodiscordant couples, injecting drug users, men who have sex with men, and sex workers were abstracted from them. Multiple regression analysis was used to determine the relation between ART eligibility criteria, ART coverage, and various population characteristics and policy interventions.
Results: Of the 70 countries, 42 (60%) follow WHO’s ART guidelines for asymptomatic people and 31 (44%) for pregnant women, recommending ART at CD4 count of ≤350 cells/mm3. Twenty-three (33%) countries recommend ART for people with HIV-associated tuberculosis irrespective of CD4 count. Nineteen countries are also recommending or considering earlier ART above CD4 count ≤350 cell/mm3 for asymptomatic people, pregnant women, and/or serodiscordant couples. Multiple linear regression analysis shows that HIV prevalence, year of publication of guidelines, and HIV expenditure are significantly associated with published ART eligibility criteria. On average, the ART coverage is similar irrespective of published guidelines being consistent with the WHO recommendation (P < 0.53).
Conclusions: Published guidelines from a significant number of countries are not following WHO recommendations. Although published guidelines may not reflect practice, it is important to adapt recommendations and services quickly to reflect the emerging science on the health and prevention benefits of earlier access to ART.
*Department of HIV/AIDS, World Health Organization, Geneva, Switzerland
†Stop TB Department, World Health Organization, Geneva, Switzerland
‡Division for Global HIV/AIDS, Centers for Disease Control and Prevention, Atlanta, GA
§HIV Treatment and Care, World Health Organization, Brazzaville, Congo.
Presented at XIX International AIDS Conference, July 25, 2012, Washington, DC, and at Second Annual HIV Treatment as Prevention Workshop, April 23, 2012, Vancouver.
The opinions and statements in this article are those of the authors and do not represent the official policy, endorsement or views of the World Health Organization.
The authors have no conflicts of interest to declare.
Development of conceptual framework: R.G., A.S., and C.S.; Data abstraction: S.G., C.S., and A.S.; Data and statistical analysis: S.G.; Contribution of reagents/materials: C.S., A.D., M.D., F.L., and E.R.; Drafting and writing the paper: S.G., R.G., A.S., C.S., R.B., D.S., L.B., and G.H.; Review of the final version: R.G., A.S., G.H., R.B., D.S., A.D., M.D., E.R., F.L., and L.B.
Correspondence to: Somya Gupta, MA, Antiretroviral Treatment and HIV Care, Department of HIV/AIDS, Building D, 1st Floor, Room 1005, World Health Organization, Avenue Appia 20, CH-1211, Geneva, Switzerland (e-mail: email@example.com).
Received August 06, 2012
Accepted October 04, 2012
Thirty years after the first case was reported, HIV still remains a significant public health problem.1 Globally, an estimated 34 million people are living with HIV, including the 2.2 million people who acquired HIV infection in 2011.2 Antiretroviral therapy (ART) not only reduces AIDS-related morbidity and mortality but also reduces the risk of transmission by suppressing the viral load in people living with HIV.3–5 There is considerable scientific evidence supporting the use of early ART in treatment and prevention of HIV and tuberculosis (TB).6–8 In 2010, using the guideline review process,9 the World Health Organization (WHO) updated its guidelines on ART for HIV infection in adults and adolescents, recommending earlier initiation of ART.10 All HIV-positive asymptomatic people, including pregnant women, are recommended ART at CD4 count of ≤350 cells/mm3. People with HIV and TB are eligible for ART irrespective of CD4 count. In April 2012, WHO released “Guidance on HIV Testing and Counselling including Antiretroviral Therapy for Treatment and Prevention in Serodiscordant Couples” that strongly recommends ART for HIV-positive partners with CD4 count ≥350 cells/mm3 in serodiscordant couples to reduce HIV transmission to uninfected partners.11 The 2012 “Programmatic Update on Use of Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infection in Adults” proposes Option B+ in addition to Option B, wherein a single, universal regimen is provided to all HIV-positive pregnant women for life.12 Option B+ simplifies prevention of mother-to-child transmission requirements by recommending a less-complicated regimen and avoiding the risk of stopping and starting antiretroviral drugs; it also addresses the significant prevention benefits against sexual transmission in serodiscordant couples.
Achieving universal access to ART (defined as providing ART to at least 80% of people needing it) by 2015 lies at the core of the Joint United Nations Programme on HIV/AIDS (UNAIDS) Global Strategy 2011–2015.13 Access to ART (for people eligible at CD4 count ≤350 cells/mm3) increased to 8 million people in 2011 in low- and middle-income countries. However, treatment gains have not kept pace with the needs, and only 54% of the 15 million people eligible for ART were on it in 2011. For every person placed on treatment, 2 others are newly infected.2 ART coverage was even lower for key affected populations. This lack of coverage is reflected in the estimated 1.7 million HIV-related deaths in the year 2011.2
The national ART guidelines are vital guides for program design and management of people living with HIV. Successful dissemination and application of these guidelines are instrumental in accelerating ART scale-up and improving treatment outcomes. This article reviews the ART initiation criteria for key populations in published national guidelines to determine the extent of consistency with the current WHO guidelines. It also looks at the determinants of ART initiation criteria and ART coverage. The review helps identify gaps between the current published national guidelines and WHO recommendations and provides a foundation for the acceleration of the adoption of early ART in national HIV policies.
We searched the databases of WHO,14 AIDSTAR-One,15 and Geneva Foundation for Medical Education and Research,16 Web sites of the national HIV/AIDS control programs and contacted officials in WHO regional offices and ministries of health for published national HIV treatment guidelines of the 194 WHO member states. Adult ART guidelines from 70 countries (with 92% of people living with HIV) were collected till April 2012. We reviewed recommendations on ART eligibility criteria for asymptomatic people, pregnant women, people coinfected with HIV and TB, serodiscordant couples, injecting drug users (IDUs), men who have sex with men (MSM), and sex workers. These recommendations were compared with the WHO recommendations from “2010 Guidelines on Antiretroviral Therapy for HIV Infection in Adults and Adolescents”10 and “2012 Guidance on HIV Testing and Counselling including Antiretroviral Therapy for Treatment and Prevention in Serodiscordant Couples.”11
Using a scatter plot, we determined the correlation between average income in 2010 and (a) ART coverage as measured by 2010 WHO definition and (b) current ART eligibility criteria for asymptomatic people. Using ART coverage as a proxy for status of implementation of guidelines, we also undertook a multivariate regression analysis to determine the relation of coverage rates with population characteristics and policy interventions. This approach is similar to the analysis conducted by Wilsdon et al.17 We further developed their methodology to examine associations between above-mentioned factors and the current ART eligibility criteria. The regression equations are described below:
ART eligibility is defined as the current eligibility criteria for asymptomatic people obtained from the national guidelines and ART eligibility10 is the eligibility criteria for asymptomatic people in 2010. They take the value 1 for CD4 count ≤350 cells/mm3 and above and 0 otherwise. Region is a dummy variable taking the value 1 for sub-Saharan African countries and 0 for others. Year stands for year of publication of the national guidelines. Data for per capita income (in nominal US $) for 2010 and HIV prevalence (in population aged 15–49) for 2009 were obtained from World Bank; data for 2010 ART coverage rates (at CD4 count ≤350 cells/mm3) and HIV expenditure (as a proportion of gross domestic product) were taken from UNAIDS. We used Microsoft Excel 2011 for the statistical analysis.
We reviewed adult HIV treatment guidelines from 70 countries, dating from 2004 to March 2012 (Table 1). Of the 70 countries, 28 are from Africa, 21 from North and South America, 15 from Asia-Pacific region, and 6 from Europe and represent approximately 92% of the estimated number of people living with HIV.
Recommendations Regarding ART Initiation for Asymptomatic People
Of the 70 countries reviewed, 42 (60%) are similar with the 2010 WHO ART guidelines and recommend ART at CD4 count of ≤350 cells/mm3 for asymptomatic people. They include Guinea, France, Italy, and Uruguay, which also consider ART for asymptomatic people with CD4 counts between 350 cells/mm3 and 500 cells/mm3. Fourteen countries updated their guidelines to recommend ART at CD4 count ≤350 cells/mm3 before 2010 (Fig. 1). Other countries are not consistent with WHO recommendations. Five (7%) of the 70 countries recommend ART at CD4 count ≤250 cells/mm3; 19 (27%) countries recommend ART at CD4 count ≤200 cells/mm3, 5 of which also recommend considering ART at CD4 count of ≤350 cells/mm3. Three (4%) countries (Algeria, Argentina, and Bolivia) recommend ART at CD4 count ≤500 cells/mm3. Bolivia and Italy additionally consider ART at CD4 count ≥500 cells/mm3 if good adherence can be maintained. In 2012, the United States recommended ART for all people living with HIV irrespective of CD4 count.
Recommendations Regarding ART Initiation for People With HIV and TB
Of the 70 countries, 23 (33%) countries are consistent with WHO recommendation for ART irrespective of CD4 count for people coinfected with HIV and TB. In 24 (34%) countries, ART is recommended only for a CD4 count of ≤350 cells/mm3. These include (a) Zambia that additionally recommends ART at CD4 count ≥350 cells/mm3 for people with HIV, TB, and other WHO clinical stage III or IV illnesses; (b) Myanmar and Ethiopia, where ART is recommended irrespective of CD4 cell count only for people living with HIV and extrapulmonary or disseminated TB; (c) South Africa, where ART irrespective of CD4 cell count for HIV-positive people with drug-resistant TB is an additional recommendation. One country (Comoros) recommends ART for people with HIV and TB at CD4 count ≤200 cells/mm3. The remaining 22 (31%) of 70 countries do not mention ART eligibility criteria for people with HIV-associated TB and can be presumed to not be providing ART to all using active TB as a criterion.
Recommendations Regarding ART Initiation for Pregnant Women
A total of 31 countries (44%) are consistent with WHO ART guidelines and recommend ART at CD4 count ≤350 cells/mm3, of which France also considers ART for pregnant women with CD4 count ≤500 cells/mm3. Of the 70 countries, 10 (14%) countries have adopted Option B+ and recommend life-long ART irrespective of CD4 count. Thailand recommends ART irrespective of CD4 count in pregnant women but those with pretreatment CD4 count ≥350 cells/mm3 stop ART after delivery. Argentina considers ART at CD4 count ≥500 cells/mm3. ART at CD4 count ≤250 cells/mm3 is recommended by 5 (7%) countries, including Vietnam that additionally recommends ART at CD4 count ≤350 cells/mm3 for pregnant women with WHO stage 3 illnesses. Eleven (16%) countries recommend ART at CD4 count ≤200 cells/mm3 including (a) Cape Verde that also considers ART at CD4 count ≤350 cells/mm3 and (b) Myanmar that additionally recommends ART at CD4 count ≤350 cells/mm3 in pregnant women with WHO stage 3 illnesses. The remaining 11 (16%) countries do not have specific ART initiation guidelines for pregnant women.
Recommendations Regarding ART Initiation for Serodiscordant Couples
There are 13 countries with recommendations on use of ART in serodiscordant couples (Fig. 2). Britain, Thailand, and Nigeria recommend initiating ART at CD4 count ≥350 cells/mm3 and are consistent with WHO couples HIV testing and counseling guidelines; Mexico recommends ART for HIV-positive partners in serodiscordant couples with CD4 count between 350 cells/mm3 and 500 cells/mm3. The United States, Algeria, Canada, Italy, Venezuela, Uruguay, and Zambia recommend initiating ART irrespective of CD4 count for serodiscordant couples. Argentina and France recommend ART for HIV-positive partner at CD4 count ≥500 cells/mm3.
Although Burundi does not mention guidelines for serdiscordant couples, ART irrespective of CD4 count is recommended for HIV-positive partners of HIV-negative pregnant women. Malawi recommends initiating life-long ART irrespective of CD4 count in HIV-positive pregnant and breastfeeding women, one of the rationale being that it will prevent HIV transmission in serodiscordant couples.
Recommendations Regarding ART Initiation for IDUs, MSM, and Sex Workers
Although WHO recognizes their vulnerability and need for access to services, WHO uses immunological criteria and does not make specific recommendations regarding ART eligibility for specific at-risk populations. None of the countries reviewed have specific recommendations regarding ART for commercial sex workers, IDUs, and MSM. Guyana, Myanmar, and Vietnam recommend ART for IDUs at CD4 count levels recommended for other people living with HIV.
ART Eligibility Criteria in the WHO/UNAIDS Priority Countries
In the 28 priority countries [Brazil, Botswana, Cambodia, Cameroon, Caribbean (from the 2005 regional guidelines), China, Democratic Republic of Congo, Ethiopia, India, Indonesia, Ivory Coast, Kenya, Lesotho, Malawi, Mozambique, Myanmar, Namibia, Nigeria, Russia, Rwanda, South Africa, Swaziland, Tanzania, Thailand, Uganda, Ukraine, Zambia, and Zimbabwe] with an estimated 85% burden of HIV/TB, 16 (57%) countries recommend ART at CD4 count ≤350 cells/mm3 for asymptomatic people living with HIV. Three (11%) countries (Botswana, Mozambique, and Uganda) recommend ART at CD4 count ≤250 cells/mm3. The remaining 9 (32%) countries recommend ART for HIV-positive asymptomatic people at CD4 count ≤200 cells/mm3, of which Russia and Ukraine also consider ART at CD4 count ≤350 cells/mm3. For people living with HIV and TB, 13 (46%) countries recommend ART initiation irrespective of CD4 count; 10 (36%) countries recommend ART at CD4 count ≤350 cells/mm3. The remaining 5 (18%) countries do not have guidelines for this target population. In the 22 countries (Angola, Botswana, Burundi, Cameroon, Chad, Ivory Coast, Democratic Republic of the Congo, Ethiopia, Ghana, India, Kenya, Lesotho, Malawi, Mozambique, Namibia, Nigeria, South Africa, Swaziland, Uganda, Tanzania, Zambia, and Zimbabwe) with the highest estimated numbers of pregnant women living with HIV, 14 (64%) countries are consistent with WHO guidelines and recommend ART at CD4 count ≤350 cells/mm3. ART eligibility criteria are ≤250 CD4 cells/mm3 in Botswana and ≤200 CD4 cells/mm3 in 3 countries (Cameroon, Ethiopia, and Ivory Coast). Malawi recommends ART irrespective of CD4 count for pregnant women for life.
ART Eligibility Criteria and Coverage of ART
In the 66 countries with coverage data, an estimated 48% of the people eligible for ART at CD4 count ≤350 cells/mm3 were receiving it in 2010. Three countries with generalized epidemic (Botswana, Namibia, and Rwanda) and 7 countries with concentrated or low-level epidemic (Britain, Cambodia, Chile, Cuba, Guyana, Nicaragua, and Spain) have achieved universal access to ART. Coverage was below 50% in 30 (43%) countries in 2010. The published ART eligibility criteria and ART coverage across countries are positively but weakly correlated to income levels (Fig. 3). The degree of dispersion in coverage levels is substantially higher among lower income countries. Although some of them have achieved universal access targets, coverage rates in 2010 were extremely low in others. Similarly, the current ART eligibility criteria differs more among the low- and middle-income countries; all high-income countries are recommending ART for asymptomatic people at CD4 count ≤350 cells/mm3 or earlier.
The multiple regression analysis (Table 2) shows that, even though higher income countries seem more likely to be consistent with WHO guidelines or even recommend earlier ART, the effect of per capita income is not statistically significant (P < 0.53). ART eligibility criterion is significantly associated with HIV prevalence, HIV expenditure, and year of publication of guidelines. The probability of consistency with WHO recommendation is higher in countries with low HIV prevalence and greater HIV expenditure. On the other hand, results from regression of Equation (2) show that ART coverage is significantly associated with per capita income and HIV expenditure but not other factors (Table 2). In 2010, the average ART coverage was higher in countries recommending ART at CD4 count ≤350 cells/mm3 or earlier, but it was statistically indifferent from coverage rates in countries below the WHO recommendation.
In the 30 years since the start of HIV pandemic, over 30 million people have died,1,18,19 with TB being the leading cause of death despite being preventable and curable.20 ART has considerable potential to save lives and prevent HIV and TB.3–7 WHO’s 2010 ART guidelines reflect the evidence that starting ART at CD4 count ≤350 cells/mm3 is cost-effective, improves health outcomes, and reduces HIV and TB transmission.21,22 Emerging evidence from observational studies4,23 and the HIV Prevention Trials Network 052 randomized-controlled trial (which showed a 96% reduction in HIV transmission in serodiscordant couples initiating ART at CD4 counts between 350 and 550 cells/mm3)7 led WHO to also recommend ART at CD4 count ≥350 cells/mm3 for serodiscordant couples. Our review found that guidelines in many countries are consistent with the WHO recommendations on ART initiation for asymptomatic people, pregnant women, and people coinfected with HIV and TB. Policy adaptation is a dynamic process, and although the WHO couples HIV testing and counselling guidelines and programmatic update on prevention of mother-to-child transmission were released in 2012, some countries were already recommending Option B+ for pregnant women and ART for serodiscordant couples.
Our review shows that 60% of the national guidelines are consistent with the WHO recommendations for treatment eligibility for asymptomatic people. However, some countries have opted for earlier treatment in general population after weighing evidence from large observational studies from America, Europe, and Australia, which have demonstrated the benefits of early ART at CD4 count ≥350 cells/mm3. The results from ART cohort collaboration (ART-CC), collaboration of North American cohort studies (NA-ACCORD), and HIV Cohorts Analyzed Using Structural Approaches to Longitudinal data (HIV-CAUSAL collaboration) suggest that initiating ART at CD4 counts between 350 and 500 cells/mm3 is associated with lower risk of AIDS-defining illnesses.24–26 Additional national policy shifts to earlier access to ART are in progress and reflect the recent results from the HIV Prevention Trials Network 052 randomized clinical trial in developing country settings. It found that starting ART at CD4 count ≤550 cells/mm3 was significantly associated with fewer adverse clinical events when compared with those who started later.7 In contrast, many low-income countries in high-burden areas have yet to change their published eligibility criteria from CD4 cell counts of ≤200 cells/mm3 or ≤250 cells/mm3.
WHO is a member state organization, and its recommendations represent the outcome of the policy feedback loop whereby inputs from national programs are used to formulate global recommendations. National policies, while reflecting WHO and other guidelines, have also been influenced by the emerging scientific evidence and recommend early ART for preventing HIV morbidity, mortality, and transmission. As part of its routine normative role, WHO will systematically review the evidence on when to start ART for the guidelines update in 2013. Although the prevention and economic benefits of starting ART at a CD4 count ≤350 cells/mm3 are well established, program managers have to also take into account programmatic and operational considerations that may either limit expansion or push them to invest more heavily in their ART expansion efforts to realize greater health and prevention benefits. Our statistical analysis also establishes the significant association of ART eligibility criteria with HIV prevalence and HIV expenditure. There is a large variation in the published ART recommendation among poorer countries and all the countries below the WHO recommendation are in low-income bracket. Findings in this analysis can be used to help benchmark the current pace of policy adaptation and help guide the revision and dissemination of national ART recommendations to keep pace with the available science.
Despite the existence of clear national policy, there are often significant gaps in the implementation of these guidelines. Even though substantial progress has been made in providing ART to people living with HIV over the last decade, the estimated global coverage in the countries analyzed was still less than 50% in 2010. Statistically, the 2010 coverage levels are significantly associated with per capita income and HIV expenditure. Even though the correlation between ART coverage and per capita income is positive, many low-income countries have been able to approach levels of coverage of countries with higher income levels. The barriers preventing the poorer countries from achieving universal access targets are lack of awareness about HIV status, weak health systems, and social marginalization of people living with HIV.27 Further research is required to monitor and evaluate the extent of implementation of the guidelines and determine the barriers to ART scale-up in individual countries.
Our policy review has several limitations. Our analysis is restricted to the latest available guidelines from 70 countries. In addition, these guidelines maybe outdated or in the process of being updated especially after recent release of new WHO recommendations for pregnant women and serodiscordant couples. For example, South Africa, Democratic Republic of Congo, Myanmar and Botswana recently revised their published guidelines to ≤350 cells/mm3 for asymptomatic people living with HIV. Concentration solely on the published or drafted national guidelines for this review is a further limitation, as written policies may not reflect program implementation or practice. China, for instance, has announced plans to implement a countrywide “ART Treatment as Prevention Strategy” wherein ART will be provided to 30,000 discordant couples irrespective of CD4 count.28 Our statistical models use an imperfect proxy variable for guideline implementation and do not capture the correlation between ART coverage and variables like political commitment and prices of ART.
Over the past decade, several important developments in the field of HIV have emerged. Countries have considerably improved the scope of their HIV programs by revising their guidelines to keep abreast with the latest scientific evidence, internationally accepted WHO guidelines, and their ongoing experience in HIV care and treatment. However, slow implementation of these guidelines still poses a key challenge. Our study provides some insights regarding the structural determinants of policy change including the role of per capita income and HIV prevalence. In addition to reviewing the recent evidence and revising its own guidelines, WHO needs to continue working closely with the member states, assisting them in revision and adaption of the guidelines to the local context. ART is a powerful tool for treatment and prevention of HIV and progressive policy and programmatic actions to provide early ART to all eligible people are required to curb the growth of the HIV epidemic.
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
antiretroviral therapy; CD4; heterosexual transmission; opportunistic infections; prevention of sexual transmission; tuberculosis