AIDS Support and Technical Assistance Resources ProjectAIDS Support and Technical Assistance Resources, Sector I, Task Ord...
INTRODUCTION                                                         less toxic treatment regimens, and an expanded role  ...
highlighted. Links to key resources for countries re-        have sex with men, and people who inject drugs.vising guideli...
ing 80 percent treatment coverage by 2015 would            second-line ART was shown to provide more clinicalrequire 49 pe...
to allow for switching to an alternative drug in             the revision process, par tial adoption of earlier ART    cas...
These steps are usually more time-intensive than              many countries in sub-Saharan Africa have beenthe others, be...
18 percent increase in the need for ART, while an          of Health decided to take an approach to guidelineincrease to ≤...
challenging. In January 2010, the Zambian MOH               In Zambia, the MOH was concerned about the sig-called an initi...
SUCCESSFUL STRATEGIES FOR                                  Guyana began using TDF-based first-line therapy                ...
burden resulting from expansion of their national ART           a summary of the successful strategies described thatprogr...
Planning with suppliers for increased ARV pro-             CD4 reagents occurred in early 2010. Despite revi-duction: On A...
changes to the WHO guidelines between 2006 and                ing the side effects that accompany the use of these2010 abo...
d4T-based first-line therapy for several years. However,   Zimbabwe already has a very high treatment gap:the WHO 2010 gui...
In 2008, the government began implementing a strat-          be transported to higher-level facilities for automatedegy of...
for results. To address this challenge, the MOH is          HBV endemicity (prevalence greater than eight per-building the...
in PLHIV remains a challenge. Smear-negative TB is           challenge for resource-limited settings, especially ascommon ...
mens be developed and implemented find it provides          that have helped the countries detailed in this brieflittle gu...
the standing guideline review committee will minimize    ment guidelines, but also to manage patient concernscosts and tim...
phlebotomy, microscopy, and administrative responsi-         where resources are limited….[and] to serve as anbilities sho...
AIDSTAR-One WHO's 2010 Recommendations for HIV Treatment: National Guideline Revision Challenges and Lessons Learned
AIDSTAR-One WHO's 2010 Recommendations for HIV Treatment: National Guideline Revision Challenges and Lessons Learned
AIDSTAR-One WHO's 2010 Recommendations for HIV Treatment: National Guideline Revision Challenges and Lessons Learned
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AIDSTAR-One WHO's 2010 Recommendations for HIV Treatment: National Guideline Revision Challenges and Lessons Learned


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In 2010, the World Health Organization released revised recommendations for adult and adolescent HIV treatment. This technical brief provides HIV policy makers and program managers with a point of reference as they adapt and implement revised national HIV treatment guidelines. Approaches that worked well, challenges and lessons learned from Sub-Saharan Africa, Latin America, and South-East Asia are highlighted. Links to key resources for countries revising guidelines and implementing revisions are also provided.

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AIDSTAR-One WHO's 2010 Recommendations for HIV Treatment: National Guideline Revision Challenges and Lessons Learned

  1. 1. WORLD HEALTH ORGANIZATION’S2010 RECOMMENDATIONS FOR HIVTREATMENT: NATIONALGUIDELINE REVISION CHALLENGESAND LESSONS LEARNEDTECHNICAL BRIEFFEBRUARY 2012This publication was produced for review by the United States Agency for International Development. It wasprepared by the AIDSTAR-One project.
  2. 2. AIDS Support and Technical Assistance Resources ProjectAIDS Support and Technical Assistance Resources, Sector I, Task Order 1 (AIDSTAR-One) is funded by the U.S.Agency for International Development under contract no. GHH-I-00–07–00059–00, funded January 31, 2008.AIDSTAR-One is implemented by John Snow, Inc., in collaboration with Broad Reach Healthcare, Encompass,LLC, International Center for Research on Women, MAP International, Mothers 2 Mothers, Social and ScientificSystems, Inc., University of Alabama at Birmingham, the White Ribbon Alliance for Safe Motherhood, and WorldEducation. The project provides technical assistance services to the Office of HIV/AIDS and USG country teamsin knowledge management, technical leadership, program sustainability, strategic planning, and program implemen-tation support.Acknowledgments:The authors would like to thank the following agencies for providing input and guidance in development of thistechnical brief: the U.S. Agency for International Development (USAID)/Washington, Clinton Health Access Initia-tive/South Africa, Supply Chain Management System in Tanzania and Guyana, USAID | DELIVER PROJECT in Nica-ragua, AIDSTAR-One in Honduras, Center for Infectious Disease Research in Zambia, and FHI/Cambodia. The au-thors would also like to thank Robert Ferris (USAID) and Tom Minior (USAID) of the U.S. President’s EmergencyPlan for AIDS Relief Treatment Technical Working Group.Recommended Citation:Rossi, Victoria, Bisola Ojikutu, and Lisa Hirschhorn. 2012. World Health Organization’s 2010 Recommendations forHIV Treatment: National Guideline Revision Challenges and Lessons Learned. Arlington, VA: USAID’s AIDS Supportand Technical Assistance Resources, AIDSTAR-One, Task Order 1.The author’s views expressed in this publication do not necessarily reflect the views of the United States Agency forInternational Development or the United States Government.AIDSTAR-OneJohn Snow, Inc.1616 Fort Myer Drive, 11th FloorArlington, VA 22209 USAPhone: 703-528-7474Fax: 703-528-7480E-mail: info@aidstar-one.comInternet:
  3. 3. INTRODUCTION less toxic treatment regimens, and an expanded role for laboratory monitoring, including both CD4 testingI n 2002, the World Health Organization (WHO) first published guidelines for a public health approach toscaling up antiretroviral therapy (ART) in resource-lim- and viral load (VL) monitoring (WHO 2010a). Although the scientific evidence in support of theseited settings. These guidelines were simplified in 2003 recommendations is compelling, national programsand revised in 2006. Throughout 2009, WHO engaged in resource-limited settings throughout the worldwith multiple stakeholders to update HIV treatment are encountering challenges with their adoption andguidelines, culminating in the dissemination of Rapid implementation. The aim of this technical brief is toAdvice: Antiretroviral Therapy for HIV Infection in Adults and provide policymakers and program managers with aAdolescents in late November 2009 (WHO 2009b). point of reference as they adapt and implement re-Table 1 lists eight key Rapid Advice recommendations. vised national treatment guidelines.The full revised guidelines, Antiretroviral Therapy for HIVInfection in Adults and Adolescents: Recommendations for Much of the information contained in this brief isa Public Health Approach (July 2010 version), expanded derived from grey literature and key informant inter-on Rapid Advice and were released in July 2010 views. Approaches that worked well, challenges, and(WHO 2010a). lessons learned from three regions of the world— sub-Saharan Africa (South Africa, Tanzania, Zambia,The key messages that emerged from these recom- Zimbabwe), Latin America (Guyana, Honduras, andmendations were earlier initiation of ART, the use of Nicaragua), and Southeast Asia (Cambodia)—are TABLE 1. WORLD HEALTH ORGANIZATION RAPID ADVICE KEY RECOMMENDATIONS Key Recommendations 1. Start antiretroviral therapy (ART) in all patients with HIV who have a CD4 count of less than 350 cells/mm3, irrespec- tive of clinical symptoms. 2. Start one of the following regimens in ART-naïve individuals eligible for treatment. • Zidovudine (AZT) + lamivudine (3TC) + efavirenz (EFV) • AZT + 3TC + nevirapine (NVP) • Tenofovir (TDF) + 3TC or emtricitabine (FTC) + EFV • TDF + 3TC or FTC + NVP 3. Start ART in all individuals living with HIV with active tuberculosis, irrespective of CD4 cell count. 4. Start ART in all individuals living with both HIV and hepatitis B virus who require treatment for their hepatitis B virus infection, irrespective of CD4 cell count or WHO clinical stage. 5. Start ART in all pregnant women with HIV and a CD4 count of less than 350 cells/mm3, irrespective of clinical symp- toms. 6. Where available, use viral load (VL) to confirm treatment failure. • Where routinely available, use VL every six months to detect viral replication. • A persistent VL above 5,000 copies/mL confirms treatment failure. • When VL is not available, use immunological criteria to confirm clinical failure. 7. A boosted protease inhibitor (bPI/r) plus two nucleoside analogues are recommended for second-line ART. • For second-line ART, atazanavir/ritonavir (ATV/r) and lopinavir/ritonavir (LPV/r) are preferred. 8. National programs should develop policies for third-line therapy that consider funding, sustainability, and equitable ac- cess to ART.Source: WHO 2009b W H O ’ S 2 010 R E C O M M E N D AT I O N S F O R H I V T R E AT M E N T: N AT I O N A L 1 GUIDELINE REVISION CHALLENGES AND LESSONS LEARNED
  4. 4. highlighted. Links to key resources for countries re- have sex with men, and people who inject drugs.vising guidelines and implementing revisions are also Latin America is primarily home to low-level andprovided. concentrated epidemics with a regional adult HIV prevalence of 0.5 percent. Men who have sex with men account for the largest share of HIV infectionsPROGRAM CONSIDERATIONS in Latin America, with epidemics also concentrated among sex workers and people who inject drugsSub-Saharan Africa is the region of the world most (UNAIDS and WHO 2009).heavily affected by the HIV epidemic, accounting forover 67 percent of all people living with HIV (PLHIV). In recent years, much progress has been made inAdult HIV prevalence in the region is five percent, scaling up access to HIV treatment worldwide, as thebut the epidemic varies significantly from country to global health community continues to work towardcountry. The nine countries of Southern Africa bear universal access (defined as providing treatment toa disproportionate share of the global HIV burden, at least 80 percent of patients in need). Table 2 pro-with each having an adult HIV prevalence greater vides HIV data for three key regions of the develop-than 10 percent. Heterosexual intercourse is the ing world, including estimated ART coverage. In 2009,driving force for the epidemic in the region (Joint an estimated 3.91 million people were receiving ARTUnited Nations Programme on HIV/AIDS [UNAIDS] in sub-Saharan Africa, a 33 percent increase fromand WHO 2009). the previous year. East, South, and Southeast Asia increased ART patients by approximately 29 percentAsia, home to 60 percent of the world’s population, in 2009 to 739,000. Latin America had an approxi-is second only to sub-Saharan Africa in terms of the mately 6 percent increase from 2008 with 425,000number of PLHIV. With the exception of Thailand, people receiving ART in 2009. However, much workevery country in Asia has an adult HIV prevalence of remains to be done to increase ART coverage to theless than one percent. The regional adult HIV preva- level of universal access from 2009 rates of 37 per-lence in South and Southeast Asia is 0.3 percent. cent in sub-Saharan Africa; 31 percent in East, South,Asia’s epidemic is largely concentrated in specific and Southeast Asia; and 51 percent in Latin Americapopulations: sex workers and their clients, men who (WHO 2010b). Global data indicate that “achiev- TABLE 2. REGIONAL HIV DATA Region Adult HIV People Receiving Estimated People in Estimated Prevalence Antiretroviral Need of Antiretroviral Antiretroviral (2009) Therapy Therapy (December Therapy Coverage (December 2009; Based on WHO (December 2009; 2009) 2010 Guidelines) Based on WHO 2010 Guidelines) Sub-Saharan 5.2% 3,911,000 10,600,000 37% Africa East, South, and <0.2% 739,000 2,400,000 31% Southeast Asia Latin America 0.6% 425,000 840,000 51%Sources: UNAIDS and WHO 2009; WHO 2010b2 A I D S TA R - O N E T E C H N I C A L B R I E F
  5. 5. ing 80 percent treatment coverage by 2015 would second-line ART was shown to provide more clinicalrequire 49 percent more person-years of treatment benefits (e.g., greater life expectancies) than accesswith eligibility at <350 [cells/mm3] but would reduce to TDF, but to be less economically efficient. Over-AIDS deaths by 22 percent and reduce the number all, the data suggest that an appropriate sequenceof new infections by 11 percent” (Stover, Bollinger, is implementation of earlier ART first, then d4Tand Avila 2010). substitution with an alternative nucleoside reverse transcriptase inhibitor (NRTI), followed by provision A recent study in South Africa used mathematical of second-line ART in settings where simultaneous modeling to predict resource requirements for full implementation of these recommendations is not implementation of the new WHO treatment guide- feasible (Walensky et al. 2010a, 2010b). lines during the first five years. The study’s findings estimated that approximately seven percent extra annual investments would be required, but predicted GUIDELINE REVISION a profound impact on HIV incidence leading to lower annual costs after seven years. The study concluded WHO recommends that countries work through that the “resulting cumulative net costs reach a a 12-step process for revision of their national break-even point after on average 16 years,” and that treatment guidelines, as described in Table 3. As of“apart from the benefits associated with many life- December 2009, 45 countries globally had already years saved, a modest frontloading appears to lead incorporated the new WHO recommendations on to net savings within a limited time horizon” (Hon- eligibility criteria and regimen choice for adults and telez et al. 2010, abstract). adolescents into their national treatment guidelines (WHO 2010b). Countries are advised to “explicitlyWHO has acknowledged that “immediate and full consider risks, benefits, and cost of new recommen-adoption of these recommendations may not be dations, as well as local values, preferences, resourcepractical, feasible or affordable” (WHO 2009a, 4). requirements and limitations” (WHO 2009a, 11). Ac-However, WHO advises that “country planning cording to WHO, the following four operational prin-should be directed towards the goal of their even- ciples should guide country decision making through-tual implementation” (WHO 2009a, 4). A study was out the guideline revision process (WHO 2009a):recently completed to provide data on the poten-tial impact of prioritizing certain recommendations 1. Strengthen health systems: Consider inter ven-over others (Walensky et al. 2010a). When the tions that will strengthen health guideline recommendations were consideredseparately, they found that five-year survival would 2. Implement in phases: It will not be possible tobe maximized by initiating ART at CD4 ≤350 cells/ implement every recommendation in ever y set-mm3 (87 percent survival) compared with adding ting, so a phased-in approach is recommended.second-line ART (66 percent) or substituting tenofo-vir (TDF) for stavudine (d4T; 66 percent). Therefore, 3. Understand the perspectives of PLHIV: Theimplementation of ART initiation at a CD4 count toxicity of d4T is of concern to the majority ofof ≤350 cells/mm3 alone was found to provide the PLHIV, and its continuing use may underminegreatest short- and long-term survival advantage confidence in ART. If d4T needs to be included inand to be highly cost-effective. Providing access to ongoing regimens, strategies should be devised W H O ’ S 2 010 R E C O M M E N D AT I O N S F O R H I V T R E AT M E N T: N AT I O N A L 3 GUIDELINE REVISION CHALLENGES AND LESSONS LEARNED
  6. 6. to allow for switching to an alternative drug in the revision process, par tial adoption of earlier ART cases of toxicity, with a plan to eventually discon- initiation, ensuring strong government leadership of tinue using this drug. the process, and forecasting and resource mobiliza- tion.4. Be forward looking: The WHO guidelines on ART in adults and adolescents will next be up- Streamline the revision process: After a countr y dated in 2012. Countries should strive to adopt begins reviewing its national treatment guidelines, new recommendations prior to this. much time can pass before officially approved, re- vised guidelines are ready to disseminate (e.g., steps TABLE 3. STEPS FOR GUIDELINE REVISION 1 to 12 in Table 3). Tanzania has taken a streamlined 1. Establish a guideline review group. approach to the guideline revision process by first 2. Decide on the composition of the guideline review completing a feasibility review and rapidly priori- group. tizing specific recommendations over others (e.g., 3. Establish clear terms of reference for the group. steps 1 to 7), and then quickly skipping to step 11 4. Manage conflicts of interest. for Ministry of Health (MOH) approval of the rec- 5. Prepare supporting materials to guide review ommendations to be adopted. group’s decision making. Circulate supporting mate- rials and 2009 Rapid Advice/2010 WHO recom- Working closely with par tner organizations, includ- mendations to review group prior to scheduling a review meeting. ing WHO, the U.S. President’s Emergency Plan for 6. Explicitly consider risks, benefits, and cost of new AIDS Relief (PEPFAR) agencies (e.g., the Centers recommendations, as well as local values, prefer- for Disease Control and Prevention and the U.S. ences, resource requirements, and limitations (e.g., Agency for International Development [USAID]), evidence assessment). and the Clinton Health Access Initiative, Tanza- 7. Draft final recommendations to be included in the nia’s National AIDS Control Programme (NACP) new guidelines. reviewed the risks, benefits, and costs of WHO’s 8. Set up and coordinate external, independent peer review of the new recommendations. new recommendations and assessed the feasibility 9. Finalize the new guidelines. of their implementation in the local context. This 10. Develop a detailed and budgeted plan for intro- group, led by NACP, agreed that it would not be duction of the new guidelines. economically feasible to implement all of the new 11. Facilitate health ministry review and approval. WHO recommendations across all patient popula- 12. Publish and disseminate the guidelines. tions simultaneously in Tanzania. Based on its feasi-Source: WHO 2009a bility analysis, which included robust cost estimates for antiretrovirals (ARVs) and laboratory supplies required to implement the new WHO guidelinesSUCCESSFUL STRATEGIES FOR over one year and five years, the group made rec-GUIDELINE REVISION ommendations to MOH policymakers for priority adoption of cer tain WHO recommendations, whileGuideline revision can be challenging. Several ap- leaving others for a later phase of implementa-proaches helped to expedite and improve the revi- tion. The NACP is currently awaiting feedback fromsion process in Tanzania, South Africa, Honduras, MOH policymakers on their recommendations,and Zambia. These strategies include streamlining before completing the more lengthy steps 8 to 10.4 A I D S TA R - O N E T E C H N I C A L B R I E F
  7. 7. These steps are usually more time-intensive than many countries in sub-Saharan Africa have beenthe others, because the guideline review group struggling for years to fund their national HIV treat-must draft revised guidelines, develop a budgeted ment programs under an initiation threshold of 200implementation plan, and allow time for peer re- cells/mm3. Table 4 provides a summary of changesview of the draft guidelines. Tanzania’s goal with this to the WHO guidelines between 2006 and 2010approach is to foster government commitment for about when to star t ART in various types of HIVrapid dissemination and to ensure the guideline re- patients.view group’s time is well spent on steps 8 to 10 byfirst securing high-level approval of the final recom- Although the benefit of earlier initiation to patientsmendations to be included in the revised guidelines. has been proven and accepted, the reality of in- creased patient loads in the context of severe bud-Partial adoption of earlier ART initiation: getary constraints presents challenges for countriesWHO’s 2010 guidelines recommend initiation of trying to adopt this new recommendation. Stud-ART in all patients with a CD4 count of ≤350 cells/ ies suggest that increasing the treatment eligibilitymm3, irrespective of clinical symptoms. However, criteria from ≤200 to ≤250 cells/mm3 results in an TABLE 4. SUMMARY OF CHANGES TO THE WORLD HEALTH ORGANIZATION’S RECOMMENDATIONS ON WHEN TO START ANTIRETROVIRAL THERAPY Target Population WHO 2006 Antiretroviral Therapy Guidelines WHO 2010 Antiretroviral Therapy Guidelines HIV-positive CD4 ≤200 cells/mm3 CD4 ≤350 cells/mm3 asymptomatic, antiretroviral (ARV)- naïve individuals HIV-positive WHO clinical stage II or III and CD4 ≤200 cells/mm3 WHO clinical stage II if CD4 ≤350 symptomatic, ARV- or cells/mm3 naïve individuals WHO clinical stage III if CD4 not available or or WHO clinical stage III or IV WHO clinical stage IV irrespective of CD4 irrespective of CD4 or Consider treatment for WHO clinical stage III or IV and CD4 200 to 350 cells/mm3 (but initiate before drops below 200 cells/mm3) HIV-positive pregnant, WHO clinical stage I or II and CD4 ≤200 cells/mm3 CD4 ≤350 cells/mm3, irrespective ARV-naïve women or of clinical symptoms WHO clinical stage III and CD4 ≤350 cells/mm3 or or WHO clinical stage III or IV, WHO clinical stage IV, irrespective of CD4 irrespective of CD4 HIV/tuberculosis co- Presence of active tuberculosis and CD4 ≤350 cells/ Presence of active tuberculosis, infection, ARV-naïve mm3 irrespective of CD4 individuals HIV/hepatitis B virus No specific recommendation Presence of chronic active co-infection, ARV-naïve hepatitis B virus, irrespective of individuals CD4Source: WHO 2010a W H O ’ S 2 010 R E C O M M E N D AT I O N S F O R H I V T R E AT M E N T: N AT I O N A L 5 GUIDELINE REVISION CHALLENGES AND LESSONS LEARNED
  8. 8. 18 percent increase in the need for ART, while an of Health decided to take an approach to guidelineincrease to ≤350 cells/mm3 results in a 53 percent revision that would allow for rapid implementationincrease in need globally. The results by country of WHO’s new recommendations and simultaneousvary from increases in the need for ART from 12 finalization of a new national HIV strategy. The Na-percent to 22 percent for the switch to ≤250 cells/ tional AIDS Programme moderated an active, multi-mm3, and 33 percent to 62 percent for the switch stakeholder process of assessing the feasibility ofto ≤350 cells/mm3 (Stover, Bollinger, and Avila the new WHO recommendations in the Honduran2010). Some countries have opted for par tial rather context. It was an open process of dialogue thatthan full adoption of WHO’s 2010 recommenda- included key international par tner organizationstions by initiating ART earlier in some but not all such as the Pan American Health Organization andsubpopulations of HIV patients. WHO, civil society, and PLHIV. Consensus on each recommendation was reached where possible.For example, South Africa has an HIV prevalenceof 17.8 percent and the largest HIV treatment pro- Building on advice gleaned from the feasibility re-gram in the world (UNAIDS 2009a). The country view process, the government of Honduras issuedwent through a feasibility review process prior to an official notification in December 2010 calling forrevision of its national treatment guidelines and mandatory and immediate implementation of thefound that full implementation of WHO’s recom- new CD4 threshold (e.g., initiation of patients onmendation to initiate ART in all patients with a ART when their CD4 count is ≤350 cells/mm3, rath-CD4 count of ≤350 cells/mm3 was not economical- er than ≤200 cells/mm3). Clinical coordinators fromly possible. It instead adopted a strategy of initiating each of the 34 ART sites countrywide were mem-only pregnant women and patients co-infected with bers of the ARV Therapy Working Group, whichtuberculosis (TB) who are ≤350 cells/mm3, while all had been providing technical input to the Nationalother HIV patients are initiated on ART only when AIDS Programme for close to 10 years. Throughtheir CD4 count falls below 200 cells/mm3 or they this forum, the clinical coordinators were advised ofdevelop stage IV disease. The South African govern- the implementation procedures for the governmentment considers this an intermediate step until ad- mandate, and these instructions were funneled backditional resources become available. to health care workers at each of the ART sites in Honduras. All of the remaining WHO recommen-Strong government leadership: Ensuring govern- dations have been subsequently adopted and arement leadership and commitment is key for a suc- being implemented in a similar fashion, althoughcessful guideline revision process. Honduras and dissemination of officially revised national treatmentZambia provide examples of strong government guidelines has not yet occurred.leadership to revise the national treatment guide-lines. Zambia has a significant HIV burden, with preva- lence of 13.5 percent (UNAIDS 2009b). SignificantHonduras was in the process of completing the HIV funding has flowed into the country over the2009 revisions to its national treatment guidelines last decade from various multilateral agencies, bi-and developing a new national HIV strategy at the lateral donors, nongovernmental organizations, andtime that WHO’s Rapid Advice and subsequent private foundations. However, building consensus2010 recommendations were released. The Ministry among this wide array of stakeholders can be6 A I D S TA R - O N E T E C H N I C A L B R I E F
  9. 9. challenging. In January 2010, the Zambian MOH In Zambia, the MOH was concerned about the sig-called an initial meeting to compare the new WHO nificantly increased costs expected to be incurredrecommendations with the current national treat- if the WHO recommendations were implemented,ment guidelines. The PEPFAR team; the National especially in view of an expected funding gap forAIDS Council and other relevant not-for-profit the national treatment program in the next feworganizations (e.g., the Centre for Infectious Dis- years. The Ministry of Health held meetings withease Research in Zambia; the Zambia HIV/AIDS key stakeholders to discuss the cost implications,Prevention, Care and Treatment Par tnership; John both human and financial, of the recommendedSnow, Inc.; and the Japanese International Coopera- guideline changes. The Supply Chain Managementtion Agency); private companies such as Konkola System project, funded by PEPFAR through USAID,Copper Mines; the University Teaching Hospital; the which provides logistics and supply chain manage-Zambian Defense Force; and other stakeholders ment suppor t to the MOH, was asked to providewere invited. Private practitioners were also invited cost estimates of each guideline change. These esti-but did not attend. At this initial meeting, the MOH mates suggested that an additional 70,000 patientsled a transparent and inclusive process by which require treatment immediately. The total additionalpar ticipants reviewed and discussed each of the re- costs calculated were estimated to reach betweenvised WHO recommendations. Each recommenda- U.S.$800,000 and $1,000,000 over the next fivetion was considered individually for its appropriate- years, including the anticipated costs of additionalness, feasibility, and acceptability within the Zambian drugs and laboratory testing.context. The Ministry of Health effectively builtconsensus among various stakeholders while at the The Ministry of Health forecasted that existing stockssame time clearly ar ticulating its vision and guiding would be sufficient to absorb the additional drug needsthe revision group to develop guidelines that were up to the end of 2010. However, beyond 2010 it wasconsistent with their local priorities. By December estimated that funding would fall short of the amount2010, Zambia had completed the revision process, necessary to purchase additional stocks, as manyand the MOH began dissemination of the updated budgets were being phased out or flat-lined in 2011.guidelines in 2011. However, the MOH remained committed to imple- menting the new CD4 initiation threshold and decidedForecasting and resource mobilization: Estimates to adopt this new recommendation. Using these costindicate that the standard zidovudine (AZT)-based reg- projections, the government of Zambia attempted toimen is 30 percent more expensive than the standard mobilize resources through the Global Fund to Fightd4T-based regimen, while the standard TDF-based regi- AIDS, Tuberculosis and Malaria (GFATM) grants and themen is 66 percent more expensive than the d4T-based national budgetary process. The government applied forregimens (Médecins Sans Frontières 2011b). WHO a GFATM Round 10 grant to support increased ARVexplicitly advises countries to consider the “cost of new procurement according to its quantifications, and therecommendations…resource requirements and limita- application was recently approved with an overall granttions” in step 6 of Table 3. Zambia has completed ro- budget of approximately U.S.$260 million (GFATM 2011).bust cost forecasting and quantification and successfullymobilized additional resources to cover the increased Table 5 provides a summary of the successful strategiesup-front costs associated with adoption of WHO’s described which various countries have utilized to man-2010 recommendations. age challenges with guideline revision. W H O ’ S 2 010 R E C O M M E N D AT I O N S F O R H I V T R E AT M E N T: N AT I O N A L 7 GUIDELINE REVISION CHALLENGES AND LESSONS LEARNED
  10. 10. TABLE 5. SUMMARY OF SUCCESSFUL IN-COUNTRY STRATEGIES TO MANAGE CHALLENGES WITH GUIDELINE REVISION Country Challenge Successful Strategy Tanzania Slow guideline revision process leading to Foster government commitment for rapid dissemination delayed implementation. and ensure efficient use of the guideline review group’s time by first securing high-level approval of the final recommendations to be included in the revised guidelines. South Increased patient loads from revised CD4 Initiate antiretroviral therapy in all pregnant women and Africa initiation threshold of ≤350 cells/mm3. patients co-infected with tuberculosis with CD4 ≤350 cells/ mm3. All other HIV patients initiate antiretroviral therapy when CD4 ≤200 cells/mm3 or stage IV disease develops. Honduras Concurrent development of a revised Issuance of a government mandate for antiretroviral therapy national HIV strategy and revised guidelines, initiation in patients with CD4 ≤350 cells/mm3 that was leading to delayed implementation of new funneled back to health care workers through clinical recommendations. coordinators from every antiretroviral therapy site, prior to official guideline revision. Zambia Building consensus among a large number Transparent and inclusive multi-stakeholder process of of HIV stakeholders while simultaneously guideline revision with strong leadership from the Ministry achieving the vision of the Ministry of Health. of Health. Increased up-front costs associated with new Robust cost forecasting and quantification to support a recommendations. successful Global Fund to Fight AIDS, Tuberculosis and Malaria Round 10 application for additional HIV funding. • Determining when to start ARTGUIDELINE IMPLEMENTATION • Determining what ART regimen to startOnce countries have completed the guideline revisionprocess as outlined in steps 1 to 12 in Table 3, they • Reducing the use of d4Tshould then move into the implementation phase. • Treating all PLHIV who have active TB with ARTWHO acknowledges that “immediate and full adop-tion of these recommendations may not be practical, • Introducing better laboratory monitoring.feasible or affordable” in every setting and recom-mends a phased-in implementation approach for As of December 2009, 33 countries globally hadsome countries (WHO 2009a, 4). Countries should already started implementing d4T phase-out plansfollow a step-by-step, budgeted implementation plan according to WHO’s 2010 recommendation (WHOthat is based on the findings from a review of the 2010b). Many other countries have begun implement-scientific evidence for each recommendation and a ing the recommendation of ART initiation in all HIVrobust situational assessment. WHO further recom- patients with ≤350 cells/mm3. Most countries were al-mends that the following points be considered imple- ready practicing early initiation of pregnant women onmentation priorities (WHO 2009a): ART, irrespective of clinical symptoms, prior to release of WHO’s 2010 recommendations. Successful imple-• Ensuring access to the most in need (e.g., CD4 mentation strategies for all of WHO’s 2010 recommen- count ≤200 cells/mm3, stage III or IV disease, and dations, related challenges, and lessons learned from pregnant women) various countries are discussed in the following sections.8 A I D S TA R - O N E T E C H N I C A L B R I E F
  11. 11. SUCCESSFUL STRATEGIES FOR Guyana began using TDF-based first-line therapy in 2006. All new patients initiating ART began TDF/GUIDELINE IMPLEMENTATION emtricitabine (FTC) in combination with a non-NRTI, specifically nevirapine (NVP) or efavirenz (EFV). Guid-Zambia, Guyana, and South Africa provide examples ance for the management of existing patients on d4T-of some successful approaches to addressing challeng- based therapy recommended an immediate switch toes presented by implementation of the 2010 WHO a TDF-based regimen in the absence of contraindica-recommendations. These approaches include rolling tions. However, some patients were concerned aboutout national training of trainers workshops, mentoring moving from the simple dosing of one pill with thesocial workers to address patient concerns, and imple- d4T-based fixed dose combinations to the more com-menting various task-shifting strategies. plicated dosing of two different pills in the new TDF- based regimens. The Ministry of Health addressed thisTrain Health Workers challenge by focusing on the role of the social work- ers and lay counselors at the ART centers. MinistryRoll-out of new treatment guidelines requires in- of Health staff advised social workers and counselorsservice training of current health workers to 1) deliver to use more effective counseling to increase ARThigh-quality services according to national protocols patients’ understanding of the benefits of the newand 2) manage patient concerns associated with regimen and the reasoning behind the switch. Patientschanges in drug regimens and dosing. Following final- were told that the new drugs reduced their risk ofization of revised HIV treatment guidelines in Zambia treatment failure and adverse side effects and there-at the end of 2010, the guideline revision committee fore increased the quality of care they received.developed an orientation package highlighting thechanges made from previous guidelines. A one- to Task Shiftingtwo-day training of trainers workshop was plannedwith partner organizations and the MOH, and is pres- WHO’s recommendation for a higher CD4 initiationently being rolled out. Each district has an identified threshold results in increased patient loads for healthtrainer/mentor who will be trained to lead the train- facilities that are already understaffed. The Ministrying workshop in their district for health care workers. of Health in Malawi completed a feasibility appraisalMentors are primarily medical officers. All 72 districts of the new WHO recommendations and found thatin Zambia will be targeted. The relevant district health the number of people eligible for ART under themanagement teams will be responsible for inviting key new CD4 cutoff of ≤350 cells/mm3 would increaseclinicians from each site to be trained. by 30 to 40 percent (230,000 to 355,500) and would require an additional 780 full-time-equivalent healthTraining will be repeated in high-density areas where workers by 2014 (Chirwa et al. 2009).needed, but all districts will receive a minimum of onetraining session. National coverage for training on the One potential solution is task shifting, a strategy thatnew guidelines will take an estimated two to three delegates specific tasks to less specialized health caremonths. The costs of this training will be split between workers to ease the workload on doctors and nursesthe cooperating partners, the sites, and the MOH. A and save patients’ time. Various task-shifting strategiesformal assessment of the implementation process is implemented in South Africa, Zambia, and Guyanaplanned after six to eight months. successfully eased the increased human resource W H O ’ S 2 010 R E C O M M E N D AT I O N S F O R H I V T R E AT M E N T: N AT I O N A L 9 GUIDELINE REVISION CHALLENGES AND LESSONS LEARNED
  12. 12. burden resulting from expansion of their national ART a summary of the successful strategies described thatprograms. various countries have utilized to manage challenges with guideline implementation.Since 2010, South Africa has conducted in-service train-ing of nurses to initiate ART, which had previously beenthe responsibility of doctors. A study examined thetotal cost and potential cost savings of the national ART IMPLEMENTATION CHALLENGESprogram in South Africa from 2010 to 2017 as a resultof various scenarios including task shifting and lower Countries are experiencing various implementationdrug prices. It found that task shifting alone would de- challenges associated with WHO’s 2010 recommen-crease total cost by 10 to 11 percent (Meyer-Rath et dations. Some of the key implementation challengesal. 2010). Zambia has launched a program similar to include supply chain management, d4T withdrawal,South Africa’s. The General Nursing Council offers a laboratory capacity, treatment for patients with TB, andyear-long nurse practitioner course that qualifies nurses second- and third-line prescribe ARVs and manage stable patients. It hasalso trained over 1,000 lay counselors to help with fil- Supply Chain Managementing, adherence counseling, and patient flow. At severalpilot sites, lay counselors have been trained to perform WHO’s 2010 recommendations have significant impli-vital sign assessments, including height, weight, blood cations for the supply chain, and successful implementa-pressure readings, and temperature charting. Guyana tion of the recommendations requires that countrieshas also successfully trained lay counselors to provide have strong supply chain management systems in place.HIV counseling in the larger clinics and thus alleviate National governments must effectively plan for pro-the bottleneck presented by long lines of patients wait- curement, storage, and distribution of all HIV commodi-ing for counseling sessions with nurses. Table 6 provides ties. TABLE 6. SUMMARY OF SUCCESSFUL IN-COUNTRY STRATEGIES TO MANAGE CHALLENGES WITH GUIDELINE IMPLEMENTATION Country Challenge Successful Strategy Zambia Need for in-service training of health care Rapid, national roll-out of one- to two-day training of workers nationwide on revised treatment trainers workshops for health care workers using district guidelines. trainers/mentors over a two- to three-month period. Shortage of human resources at antiretroviral Preservice training of nurse practitioners to initiate ART; therapy (ART) sites. introduction of lay counselors to assist with administrative duties, patient counseling, and vital sign assessments at ART sites. Guyana Patient concerns with tenofovir (TDF) Mentoring of social workers at ART sites to deliver more substitution and associated changes in drug effective patient counseling around the drug switch. dosing. Shortage of human resources at ART sites. Introduction of lay counselors to assist with patient counseling at ART sites. South Shortage of human resources at ART sites. In-service training of nurses to initiate ART. Africa10 A I D S TA R - O N E T E C H N I C A L B R I E F
  13. 13. Planning with suppliers for increased ARV pro- CD4 reagents occurred in early 2010. Despite revi-duction: On April 1, 2010, South Africa officially sion to the national guidelines, the change in initiationbegan implementation of new national HIV treat- criteria was not actually being implemented at the sitement guidelines and simultaneously launched a mas- level due to the unavailability of CD4 testing. Patientssive national scale-up campaign for HIV testing and were only being initiated on treatment based on clini-treatment, with a target of testing 15 million people cal symptoms the first year. However, the revised treatmentguidelines were disseminated only a few weeks prior Once the MOH resolved the issue of stocked-outto the April first implementation date. ARV suppli- CD4 reagents, another laboratory supply chain chal-ers did not receive any definitive notice or guidance lenge arose. Problems with the new VL testing equip-from the government on the expected surge in ARV ment that had been procured at the reference labora-needs resulting from the new guidelines and national tory resulted in the unavailability of VL tests. Therefore,testing campaign. These suppliers could not ramp up the expected surge in the number of patients eligibleARV production quickly enough to meet the national for ART when CD4 initiation criteria changed in 2009program’s implementation demands. was mitigated by a break in both CD4 and VL test- ing capacity due to supply chain problems. Now thatAs a result of this limited ARV production, TDF for these supply chain issues have been resolved andadult treatment was not available on the shelves at CD4 and VL testing is available in Nicaragua, the im-facilities until June/July 2010. Abacavir (ABC) solution pact of the new CD4 initiation criteria on ART patientfor pediatric treatment and NVP suspension for the loads can be accurately assessed throughout 2011.prevention of mother-to-child transmission programwere not available until August/September 2010. Overstock of old ARVs: When the 2006 revisedDespite dissemination of the new guidelines and ad- guidelines were formally endorsed and disseminatedvance training of health care workers, the new guide- to health facilities in Guyana, the MOH had a nationallines could not be fully implemented, and patients overstock of ARVs for the old, d4T-based first-linecould not get the newly recommended ARV drugs therapy. They were not comfortable allowing all theuntil several months after the government-mandated old ARVs to expire unused, so they delayed distribu-implementation date due to this lack of advance tion of the ARVs for the new TDF/FTC-based first-lineplanning with suppliers. therapy until more of the old ARVs had been con- sumed. This resulted in some confusion among healthEnsuring adequate stocks of laboratory reagents: care workers who had been trained to use the newIn 2009, the MOH in Nicaragua updated the national guidelines because the corresponding ARVs were notART guidelines; this included changing the CD4 cell available to them at the health facilities. To address thiscount threshold to ≤350 cells/mm3 as an indication challenge, ongoing updates were provided to the clini-to start treatment regardless of VL. (Exceptions are cians at the treatment sites about stock-on-hand ofmade for patients with a CD4 count >350 cells/mm3 the old ARVs and orders for new ARVs.if they have a VL >100,000 copies/mL—they arealso initiated on ART.) Surprisingly, the national HIV Stavudine (d4T) Withdrawalprogram did not experience a sudden increase in thenumber of patients eligible for ART. Following further WHO recommends phasing out d4T and replacinginvestigation, it was determined that stockouts of it with AZT or TDF. Table 7 provides a summary of W H O ’ S 2 010 R E C O M M E N D AT I O N S F O R H I V T R E AT M E N T: N AT I O N A L 11 GUIDELINE REVISION CHALLENGES AND LESSONS LEARNED
  14. 14. changes to the WHO guidelines between 2006 and ing the side effects that accompany the use of these2010 about which ARVs to start in various types of drugs should also be considered.HIV patients. As of 2009 in low- and middle-incomecountries (excluding countries in the Americas), 59.7 Increased up-front costs: Cambodia updated itspercent of first-line ART patients were on d4T-based national treatment guidelines in 2010 but found in-regimens, 32.1 percent on AZT-based regimens, and clusion of AZT or TDF in the first-line treatment to7.7 percent on TDF-based regimens (WHO 2010b). be cost prohibitive and decided against adopting thisIncreased up-front costs are a major challenge that recommendation. However, Zambia and Zimbabwecountries face as they withdraw d4T and substitute it are confronting the reality of these increased up-frontwith more patient-friendly yet more expensive first- costs.line drugs. With HIV funding levels already low, AIDSactivists have expressed concern that if these new, In 2007, Zambia switched to TDF-based first-linemore expensive regimens are adopted, many people therapy. The Ministry of Health issued stringent guide-may fail to access treatment in the long run. A fea- lines on which patients to switch and how to do so,sibility appraisal completed in Malawi estimated the including information on possible concerns such as aadditional costs (leaving all other costs unchanged) switch not being indicated, poor adherence, treatmentfor substitution of d4T with a TDF-based regimen to failure, renal dysfunction, and patient preference. Ifbe U.S.$100 million, and U.S.$50 million with an AZT- patients were stable, did not have side effects, and didbased regimen for the period up to 2014 (Chirwa et not wish to change drugs, they were kept on d4T. Thisal. 2009). When comparing the costs of TDF against resulted in a relatively gradual switch overall, as ap-AZT, the additional cost of monitoring and treat- proximately 40 percent of patients remained on the TABLE 7. SUMMARY OF CHANGES TO THE WORLD HEALTH ORGANIZATION’S RECOMMENDATIONS ON WHICH ANTIRETROVIRALS TO START Target Population WHO 2006 Antiretroviral Therapy WHO 2010 Antiretroviral Therapy Guidelines Guidelines HIV-positive, Zidovudine (AZT) or tenofovir (TDF) No change. antiretroviral (ARV)- + lamivudine (3TC) (or emtricitabine [FTC]) naïve adults and + efavirenz (EFV) or nevirapine (NVP) adolescents HIV-positive, ARV- AZT + 3TC + NVP • AZT preferred but TDF acceptable. naïve pregnant • EFV included as preferred non- women nucleoside reverse transcriptase inhibitor (non-NRTI) option (but do not initiate EFV during first trimester). • Benefits of NVP outweigh risks where CD4 count is 250 to 350 cells/mm3. HIV/tuberculosis co- AZT or TDF No change. infection + 3TC (or FTC) + EFV HIV/hepatitis B virus TDF Non-NRTI regimens that contain both TDF co-infection + 3TC (or FTC) + 3TC (or FTC) are required. + EFVSource: WHO 2010a12 A I D S TA R - O N E T E C H N I C A L B R I E F
  15. 15. d4T-based first-line therapy for several years. However, Zimbabwe already has a very high treatment gap:the WHO 2010 guidelines recommended a more around 226,000 people receive ART through the pub-aggressive transition, with rapid weaning of patients lic health system, while another 340,000 are eligibleoff d4T. After the Supply Chain Management System for ART but have failed to access it. Recent estimatesproject conducted a comprehensive cost analysis, it indicate that, under the new guidelines for earlierwas agreed that the process of transition from d4T- ART initiation, the treatment gap will increase, with atto TDF-based regimens should occur over a period least half a million people qualifying for treatment. Dr.of four years (up to the start of 2015), based on the Owen Mugurungi, National Coordinator of the MO-assumption that this would be the most appropriate HCW’s AIDS and TB Unit, has admitted that the newtime period over which to absorb the increased costs drug regimen is expensive but said in the long-termof the switch. To promote a smooth transition, health it would turn out much cheaper: “We may be ablecare workers and lay counselors received training on to put many people on ARVs now using the cheaperthe guidelines for switching patient regimens and ap- regimens, but five years from now we will be losing apropriate patient counseling. Targeted media messag- lot of money…treating people for side effects froming of patients and caregivers through printed litera- stavudine-based regimens” (PlusNews 2011).ture and radio was also conducted. Health care workers operating outside the na- tional guidelines: South Africa and Tanzania haveIn May 2010, Zimbabwe released updated treatment experienced a challenge when health care workers—guidelines that replaced d4T-based regimens with aware that TDF is a superior drug—switch patientsTDF-based regimens as first-line therapy, and also sug- who do not meet the national eligibility criteria. Asgested initiating ART in all HIV-positive adults with a of April 1, 2010, when implementation of the revisedCD4 count of ≤350 cells/mm3 and in all HIV-positive treatment guidelines officially began, all new patientspregnant women and infants regardless of their CD4 in South Africa were initiated on a TDF-based regimen.count or clinical stage. However, funding constraints Existing patients were kept on d4T if stable and werehave resulted in nearly a one-year delay in implemen- only switched to TDF if they experienced toxicities.tation of these new guidelines so far. The Permanent However, contrary to the national treatment guidelines,Secretary at the Ministry of Health and Child Welfare health care workers started switching their existing(MOHCW) sent a circular to implementing partners patients onto TDF because they knew it was a superiorexplaining that implementation of the new guidelines drug. This behavior became so widespread that it beganwould officially begin April 1, 2011. It explained that, to diminish stocks of TDF. It was feared that TDF sup-due to resource constraints, the new guidelines would plies might end up so diminished that patients wouldbe phased in over a three-year period. Because there experience a lapse in treatment or health care work-were still significant stocks of d4T, the MOHCW man- ers would have to switch patients back to d4T. Thedated that all new patients be initiated on d4T until Director General of Health addressed this concern bystocks were finished, while existing patients already sending out an official communication from his officeexperiencing side effects would be moved to TDF- ordering health care workers to follow the treatmentbased first-line therapy. The Ministry of Health and guidelines carefully by keeping stable patients on d4TChild Welfare further mandated that all HIV-positive and only initiating TDF in new patients.pregnant women eligible for ART be immediatelyplaced on the new TDF-based regimens (PlusNews In Tanzania, the 2005 national treatment guidelines in-2011). cluded both d4T and AZT as part of first-line therapy. W H O ’ S 2 010 R E C O M M E N D AT I O N S F O R H I V T R E AT M E N T: N AT I O N A L 13 GUIDELINE REVISION CHALLENGES AND LESSONS LEARNED
  16. 16. In 2008, the government began implementing a strat- be transported to higher-level facilities for automatedegy of gradually phasing out d4T over a three-year CD4 testing, but sample transport systems are of-period. In 2009, guidelines were officially updated to ten slow. Referral to higher-level facilities for a CD4recommend that all new patients get initiated on AZT count requires strong patient referral networks andas the preferred first-line therapy. Tanzania is currently introduces additional barriers for the patient, includingin the process of revising its national treatment guide- transportation costs and lost time at work or school,lines in response to WHO’s 2010 recommendations, which can result in high loss-to-follow-up rates.but has not yet adopted TDF as first-line treatment.However, similar to South Africa’s experiences, physi- Honduras adopted WHO’s recommendation of ini-cians are informed of TDF’s merits, and the national tiating ART in all patients with a CD4 count of ≤350program is finding that consumption rates of TDF cells/mm3 while simultaneously rolling out a new HIVhave increased from previous years. strategy that promotes expansion of first-line ART services to the primary care level. However, HondurasLaboratory Capacity is finding that access to flow cytometry for automated CD4 testing, especially at the primary care level andMany resource-limited countries struggle with weak among pregnant women in antenatal clinics, is a majorlaboratory capacity, characterized by under-trained implementation challenge. Most primary care clinicslaboratory personnel, broken or inadequate equip- are only able to conduct manual CD4 testing, whilement, and limited funding for laboratory reagents and higher-level facilities in Honduras have laboratorysupplies, which contributes to poor screening and facilities that offer automated CD4 testing. A weakmonitoring of HIV patients. In this context, countries patient referral system, poor patient tracking, andare encountering significant challenges as they move the cost of transport mean that patients referred toto implement WHO’s 2010 recommendations on higher-level facilities often receive delayed care or areCD4 testing for ART eligibility, increased VL testing, lost to follow-up.and hepatitis B virus (HBV) and TB screening. Viral load testing: WHO recommends that VL test-CD4 testing: WHO’s 2010 guidelines recommend ing be used as part of a targeted strategy to confirminitiation of ART in all patients with a CD4 count of treatment failure, but cautions that “any decision on≤350 cells/mm3, irrespective of clinical symptoms. His- implementing VL testing should not undermine im-torically, many resource-limited settings, especially in proved access to better ARVs, which should take pri-sub-Saharan Africa, have been using an ART initiation ority if resources are limited” (WHO 2009a, 17). Mostthreshold of 200 cells/mm3. Patients with a CD4 count countries, including Honduras, Cambodia, and Zambia,of ≤200 cells/mm3 will usually present at a health facil- are encountering challenges associated with imple-ity with more advanced disease (i.e., stage III or IV) mentation of this recommendation.than patients with a higher CD4 count. Clinical stagingcan often determine treatment eligibility in patients Honduras has adopted WHO’s recommendation towith advanced disease, but CD4 testing must be avail- expand the use of VL testing for monitoring of treat-able to effectively screen patients for ART eligibility ment failure, but access to the test is limited. Only oneat higher CD4 counts. Access to CD4 testing can be laboratory in the country has the capacity to carryespecially limited at lower levels of the health system, out VL testing. The system for transporting blood sam-due to lack of CD4 testing equipment and a shortage ples from ART sites to the central laboratory is veryof trained laboratory personnel. Blood samples can slow, with a turnaround time of four to eight months14 A I D S TA R - O N E T E C H N I C A L B R I E F
  17. 17. for results. To address this challenge, the MOH is HBV endemicity (prevalence greater than eight per-building the capacity of two additional sites to offer VL cent) and expanding ART programs (Hoffmann andtesting in the future. Thio 2007). However, most resource-limited settings are struggling with limited funding for procurement ofCambodia adopted the recommendation that a per- HBV testing supplies and with weak laboratory capac-sistent VL above 5,000 copies/mL confirms treatment ity for routine HBV screening.failure. The national HIV program has a target of mak-ing 10,000 VL tests available in 2012 and 30,000 tests The Western Pacific Region comprises 37 countries,available in subsequent years. It also has plans for each including Cambodia (WHO Regional Office for theART patient to receive an annual VL test after being Western Pacific 2005–2011). This region contains onlyon treatment for two years. However, the cost of VL 28 percent of the world population, yet it is home totesting remains a major challenge for Cambodia’s lim- over half of the global deaths caused by HBV (Cle-ited financial resources. ments et al. 2006). Although Cambodia has adopted almost all of WHO’s 2010 recommendations, it de-Viral load testing is available on a limited basis to pa- cided against adopting the recommendation to treattients in a few areas in Zambia, as determined by a all HIV/HBV co-infected patients with ART, due to thetesting algorithm that detects patients presumed to cost and limited availability of HBV serodiagnostic andbe failing treatment. It costs about U.S.$27 per sample virologic tests. However, Cambodia’s revised nationaland is covered almost exclusively by partner orga- treatment guidelines do include guidance on the usenizations. To avoid unnecessary testing and preserve of TDF/lamivudine (3TC) instead of d4T for treat-limited resources, only patients who are obviously ment of HIV patients who are already known to haveexperiencing clinical or immunological failure receive chronic HBV.VL testing. While the limitations of this algorithmic ap-proach were recognized during the guideline revision Although Zambia adopted this WHO recommenda-process, it was decided that the national program tion in its revised guidelines, weak laboratory capacity,should continue with this approach and address the higher costs for procurement of HBV testing sup-issues of prohibitive cost and limited VL laboratory plies, and increased ART patient loads are challeng-capacity again in one year. ing implementation. There are limited data on HBV prevalence in PLHIV in Zambia, but crude data basedHepatitis B virus screening: Hepatitis B virus is the on blood bank statistics suggest an estimate of anleading cause of chronic liver disease and liver-related additional 10,000 HIV patients who may need treat-death worldwide, with the majority of these cases ment (Mphahlele et al. 2002). Historically, ART sites inoccurring in areas of Africa and Asia where HBV Zambia have not routinely screened PLHIV for HBV,prevalence is high. Many of the countries affected by and the national program does not currently have theHBV are also affected by a high HIV burden, leading systems in place to conduct wide-scale HBV frequent HIV/HBV co-infection. The consequencesof co-infection include “increased liver-related morbid- Treatment for Patients with Tuberculosisity and mortality, increased HBV viral replication, im-mune reconstitution to HBV in the setting of ART, and Tuberculosis is a major cause of death for PLHIV,hepatotoxicity from ARVs” (Hoffmann and Thio 2007, hence WHO’s recommendation to initiate ART in all402). Laboratory capacity to screen for HBV in HIV patients with active TB. Though many countries havepatients is especially important in regions with high adopted this recommendation, diagnosing active TB W H O ’ S 2 010 R E C O M M E N D AT I O N S F O R H I V T R E AT M E N T: N AT I O N A L 15 GUIDELINE REVISION CHALLENGES AND LESSONS LEARNED
  18. 18. in PLHIV remains a challenge. Smear-negative TB is challenge for resource-limited settings, especially ascommon in co-infected patients, and limited labora- their national treatment programs grow older. Intory facilities hinder diagnosis by culture. In addition, 2009, the weighted median cost per person per yeardiagnosing extrapulmonary TB is complicated by lack for first-line therapy was U.S.$137 in low-incomeof access to histopathology and advanced imaging countries and U.S.$141 in lower-middle-incomein the developing world. As a result, fewer than half countries, compared to U.S.$853 and U.S.$1,378 forof TB cases in PLHIV are diagnosed before death second-line therapy (WHO 2010b). WHO’s 2010(Domousa et al. 1995; Lucas et. al 1993; Mohar et al. recommendations include lopinavir/ritonavir (LPV/r)1992). A new molecular TB test (GeneXpert MTB/RIF) and atazanavir/ritonavir (ATV/r) as the preferredendorsed by WHO simultaneously detects Mycobac- boosted protease inhibitors (bPIs) in second-lineterium tuberculosis and tests for rifampin resistance, therapy. Table 8 provides a summary of changesreducing the time required to diagnose drug-resistant to the WHO guidelines between 2006 and 2010TB from up to three months down to less than two regarding second-line therapy for various types ofhours. The test can also detect TB more easily among HIV patients. A generic heat-stable formulation ofpeople co-infected with HIV, in whom diagnosing TB is LPV/r is on the market already, and a generic heat-challenging. Médecins Sans Frontières is rolling out this stable fixed dose combination of ATV/r packagednew test in 16 countries in 2011 (Evans 2011; Méde- together with TDF/3TC is under development (WHOcins Sans Frontières 2011a). 2010a). Historically, LPV/r has been the predominant bPI available in resource-limited settings, with 92.7An additional decision point for countries about this percent of adult second-line patients using it in low-recommendation is when to start ART in co-infected and middle-income countries outside of the Americaspatients. Many concerns have been raised about treat- (WHO 2010b). However, some countries, includinging HIV and TB concurrently. Drug-drug interactions, Zambia, are beginning to consider use of ATV/rdrug side effects, and adherence within the setting because of its anticipated cost savings.of high pill burden are challenging to manage. Para-mount among these concerns is the development of In Zambia, LPV/r has been the recommended second-immune reconstitution inflammatory syndrome (IRIS). line bPI since 2005. However, Zambia has recognizedHowever, two recent randomized trials have shown the potential clinical importance and cost savings ofthat starting ART within four weeks of beginning TB ATV/r, which has a ceiling price of U.S.$355 per pa-treatment decreased the risk of death for patients tient per year, with further price reductions expectedco-infected with HIV (Abdool Karim et al. 2010; Hav- in the future, compared to LPV/r, with a ceiling pricelir et al. 2011). Zambia is initiating ART in all patients of U.S.$399 per year (Clinton Health Access Initiativewith active TB within two to four weeks after starting 2011). A gradual transition from LPV/r to ATV/r isTB treatment. Similarly, Cambodia’s revised guidelines planned in Zambia as soon as the drug has been reg-call for ART initiation in active TB patients within two istered and becomes available locally. To avoid confu-weeks of TB treatment. sion among care providers, the new guidelines briefly mention ATV/r but do not yet recommend the com-Second-Line Therapy bination as part of second-line therapy. Once available, guidelines will be updated so that ATV/r will be rec-The price of second-line therapy remains considerably ommended as an alternative to LPV/r, and appropriatehigher than first-line therapy, which presents a provider training will be scheduled.16 A I D S TA R - O N E T E C H N I C A L B R I E F
  19. 19. TABLE 8. SUMMARY OF CHANGES TO THE WORLD HEALTH ORGANIZATION’S RECOMMENDATIONS ON SECOND-LINE THERAPY Target Population WHO 2006 Antiretroviral Therapy WHO 2010 Antiretroviral Therapy Guidelines Guidelines HIV-positive adults Zidovudine (AZT) + didanosine (ddI) If stavudine (d4T) or AZT used in first-line: and adolescents or TDF + 3TC (or emtricitabine [FTC]) + Tenofovir (TDF) + abacavir (ABC) ATV/r or LPV/r or ddI + lamivudine (3TC) or TDF + 3TC ( ± AZT) If TDF used in first-line: plus AZT + 3TC + ATV/r or LPV/r Atazanavir/ritonavir (ATV/r) or fosamprenavir/ ritonavir (FPV/r) or indinavir/ritonavir (IDV/r) or Lopinavir/ritonavir (LPV/r) or saquinavir/ritonavir (SQV/r) HIV-positive ABC + ddI Same regimens recommended for adults and pregnant women or adolescents. TDF + ABC or ddI + 3TC or TDF + 3TC (± AZT) plus LPV/r or nelfinavir (NFV) or SQV/r HIV/tuberculosis ABC + ddI If rifabutin available: co-infection or Same regimens as recommended for adults TDF + ABC and adolescents. or If rifabutin not available: ddI + 3TC Same nucleoside reverse transcriptase or inhibitor (NRTI) backbones recommended TDF + 3TC (± AZT) for adults and adolescents, plus LPV/r or plus SQV/r with adjusted dose of RTV (i.e., LPV/r LPV/r or SQV/r with adjusted dose of ritonavir 400 mg/400 mg twice a day or SQV/r 400 (RTV) (i.e., LPV/r 400 mg/400 mg twice a day mg/400 mg twice a day). or SQV/r 400 mg/400 mg twice a day) HIV/hepatitis B 3TC- and/or TDF-containing regimens AZT + TDF + 3TC (or FTC) + (ATV/r or virus co-infection LPV/r)Source: WHO 2010aThird-Line Therapy adult patients were on first-line therapy, 2.4 percent on second-line therapy, and 0.01 percent were re-Third-line therapy is still widely considered to be cost- ported to be on third-line therapy. In the Americas,prohibitive in most resource-limited settings, and it is 84 percent of adults were on first-line therapy, 9.7not widely available in any of the countries reviewed percent on second-line therapy, and 6.3 percent onfor this brief. As of 2009 in low- and middle-income third-line therapy (WHO 2010b). Countries reviewingcountries outside of the Americas, 97.5 percent of WHO’s 2010 recommendation that third-line regi- W H O ’ S 2 010 R E C O M M E N D AT I O N S F O R H I V T R E AT M E N T: N AT I O N A L 17 GUIDELINE REVISION CHALLENGES AND LESSONS LEARNED
  20. 20. mens be developed and implemented find it provides that have helped the countries detailed in this brieflittle guidance on how to obtain these drugs or what successfully adopt and implement new use. For example, in Zambia third-line therapy isnot supplied through the national program, although Conduct a feasibility analysis: Each country shoulddraft preliminary guidelines have recently been devel- complete a feasibility analysis of the WHO recom-oped. In Honduras, third-line therapy is available on mendations, considering the risks, benefits, costs, locala very limited basis in the private sector, but the new values, preferences, resource requirements, and limita-national HIV strategy includes future plans for roll-out tions of each. Robust cost forecasting can clearly ar-to the public sector. ticulate the human and financial resources associated with their implementation in the local context.The national ART program in Zambia is now in itsseventh year and, as of February 2010, has already Include an appropriate mix of stakeholders: Na-identified over 300 patients who potentially require tional health leaders should invite an appropriate mixthird-line treatment. Third-line drugs are available of stakeholders to participate in the guideline revi-only to patients who can afford them; the national sion process. It should be a forum for collaborativeprogram does not supply these drugs. However, Zam- partnership between local and international agencies,bia has recently drafted preliminary guidelines on including representatives from the government; mul-third-line therapy that recommend raltegravir (RAL) tilateral, bilateral, and nongovernmental partner orga-and darunavir/ritonavir (DRV/r) with either TDF/FTC nizations; civil society; PLHIV groups; and the privateor AZT/3TC. Genotyping is required before any pa- sector. Technical expertise should be drawn from atients are considered for third-line regimens. Because mix of policymakers, program managers, implement-funding is not currently available, expanding access ers, clinical personnel, supply chain managers, andto third-line ART is on hold. However, the MOH has costing experts. Early in the revision process, effortsestablished a third-line advanced treatment center at should be made to foster a spirit of inclusion, trans-the University Teaching Hospital that has the techni- parency, and technical expertise and appropriate diagnostics to monitorpatients who are able to pay for third-line regimens. Strong government leadership: National healthUnder Honduras’ new HIV strategy, there are plans leaders should lead the revision committee to de-to offer third-line therapy at third- and fourth-level velop guidelines that will most effectively achieve theirhospitals in the public sector, although it is not avail- vision. Strong government leadership can dramaticallyable yet. As of early 2011, around 8,000 patients were reduce the timeline for guideline revision. In someactively on ART through the national program, and cases, implementation of key recommendations canapproximately 10 patients in the country were receiv- be mandated prior to dissemination of officially re-ing third-line therapy from abroad through a private vised guidelines.organization. Establish an annual guideline review process: InIn-country challenges with guideline implementation the ever-changing field of HIV treatment, it is likelyare summarized in Table 9. that recommendations will be updated or changed regularly. Establishing an annual guideline review pro-RECOMMENDATIONS cess would significantly streamline any revisions and ensure that new WHO recommendations are auto-Recognizing that the guideline process will vary in dif- matically incorporated into country guidelines. Havingferent contexts, there are a few common approaches a small, flexible core group of reviewers that acts as18 A I D S TA R - O N E T E C H N I C A L B R I E F
  21. 21. TABLE 9. SUMMARY OF IN-COUNTRY CHALLENGES WITH GUIDELINE IMPLEMENTATIONCountry Challenge DescriptionZambia Stavudine (d4T) Phased implementation of more patient-friendly regimens over a four-year withdrawal period as a result of increased up-front costs. Laboratory capacity Limited use of viral load (VL) for confirmation of treatment failure due to prohibitive cost and weak laboratory capacity. Laboratory capacity Limited implementation of recommendation for ART in all patients co-infected with HIV/hepatitis B virus (HBV) due to weak laboratory capacity, increased costs of HBV testing supplies, and increased antiretroviral therapy (ART) patient loads. ART for patients with Recommends starting ART in all active TB patients within two to four weeks tuberculosis (TB) after starting TB treatment to manage decision point about “when to start.” Second-line therapy High cost of second-line; plans for gradual transition from lopinavir/ritonavir (LPV/r) to atazanavir/ritonavir (ATV/r) due to expected cost savings. Third-line therapy Developed draft third-line guidelines that recommend raltegravir (RAL) and darunavir/ritonavir (DRV/r); established third-line advanced treatment center.Guyana Supply chain Delayed implementation of more patient-friendly regimens resulting from an management overstock of old antiretrovirals (ARVs).South Africa Supply chain Delayed implementation of more patient-friendly regimens resulting from lack of management advance planning with ARV suppliers. d4T withdrawal Health care workers switching patients to tenofovir (TDF) who do not meet eligibility criteria, adversely impacting national TDF stocks.Nicaragua Supply chain Delayed implementation of earlier ART initiation due to stockouts of CD4 management reagents and problems with VL testing equipment.Cambodia d4T withdrawal Exclusion of more patient-friendly regimens from revised guidelines due to prohibitive up-front costs. Laboratory capacity Plans for VL scale-up hampered by prohibitive cost. Laboratory capacity Exclusion of recommendation for ART in all patients co-infected with HIV/HBV from revised guidelines due to prohibitive cost and limited availability of HBV serodiagnostic and virologic tests. ART for TB patients Recommends starting ART in all active TB patients within two weeks of TB treatment to manage decision point around “when to start.”Zimbabwe d4T withdrawal Phased implementation of more patient-friendly regimens over a three-year period as a result of increased up-front costs.Tanzania d4T withdrawal Phased implementation of more patient-friendly regimens over a three-year period as a result of increased up-front costs; health care workers switching patients to TDF who do not meet eligibility criteria adversely impacting national TDF stocks.Honduras Laboratory capacity Delayed implementation of earlier ART initiation due to unavailability of CD4 testing at the primary care level. Laboratory capacity Limited use of VL for confirmation of treatment failure due to four- to eight- month turnaround time for VL test results. ART for TB patients Administer empirical TB treatment to suspected TB patients and monitor for clinical improvement to manage difficulty with accurate diagnosis of TB. Third-line therapy New HIV strategy includes plans to offer third-line therapy through the public sector at third- and fourth-level health centers. W H O ’ S 2 010 R E C O M M E N D AT I O N S F O R H I V T R E AT M E N T: N AT I O N A L 19 GUIDELINE REVISION CHALLENGES AND LESSONS LEARNED
  22. 22. the standing guideline review committee will minimize ment guidelines, but also to manage patient concernscosts and time associated with the guideline review associated with changes in drug regimens and dosing.process. Using email for informal correspondence Training workshops should be rolled out nationally im-and official memorandums from the MOH for formal mediately following government endorsement of re-communication will allow for more rapid adoption vised treatment guidelines. Clear guidance around theand dissemination of policy. methods and timeframe for withdrawal of d4T should be provided to health care workers. The rationale andEffective supply chain management: National gov- timeframe for phased implementation of specific rec-ernments should use robust cost forecasting and com- ommendations needs to be clearly explained in set-modity quantification to plan for procuring additional tings where such an approach is necessary. Standingdrugs, diagnostics, laboratory reagents, and supplies implementer meetings or a similar mechanism shouldassociated with the new WHO recommendations. be established for feedback, questions, and concernsStocks should be monitored carefully to ameliorate from the health care workers at the facilities to poli-the high risk of stockouts during the drug phase-in/ cymakers and program managers at the national level.phase-out period. Suppliers need to be informed in Plans for on-the-job mentoring of health care workersadvance of increased demand so they can adjust their during the early stages of the implementation phaseproduction plans accordingly. Stocks of old ARVs and should be made where possible.their potential for expiry should be considered beforedisseminating new ARVs. Educate patients and the community: Patients need counseling to increase their understanding ofDevelop realistic, budgeted implementation plans: the benefits associated with newer, more patient-As countries decide when and how to implement the friendly drug regimens. Patient concerns associatedWHO recommendations, they must carefully balance with changes in drug regimens, especially d4T with-expansion of ART and management of program costs. drawal and dosing schedules, should be addressed.A budgeted implementation plan that is time-bound Communication with patients and the community canand realistically considers the local context should be achieved through targeted media messaging usingbe developed and followed carefully. A phased-in ap- printed literature, public television, and radio broad-proach can be taken as necessary with certain recom- casts, as well as through existing community structures,mendations prioritized for immediate implementation such as patient support groups. Media campaignsand others delayed for roll-out later. Recent data should engage and include messages from traditionalsupport step-by-step implementation of a revised and religious leaders, civil society, and PLHIV, andCD4 initiation threshold first, then TDF substitution, should reach the broadest audience possible.followed by provision of second-line therapy in set-tings where simultaneous implementation of the rec- Manage limited human resources through taskommendations is not feasible (Walensky et al. 2010a, shifting: Implementation of WHO’s 2010 recommen-2010b). dations will result in increased patient loads for health facilities that are already under-staffed. Task shifting ofSupport health care workers through rapid, ART initiation from doctors to nurses can alleviatestandardized in-service training and mentoring: significant bottlenecks within the HIV service deliveryHealth care workers must be trained not only to system. Introduction of lay health care workers todeliver high-quality services according to new treat- assist with patient counseling, vital sign assessments,20 A I D S TA R - O N E T E C H N I C A L B R I E F
  23. 23. phlebotomy, microscopy, and administrative responsi- where resources are limited….[and] to serve as anbilities should be considered. advocacy tool to policy makers and to provide a ba- sis for difficult choices and decisions within MemberStrengthen laboratory systems: WHO’s 2010 States.”recommendations emphasize increased laboratoryscreening and monitoring of HIV patients. National Available at: need to strengthen the capacity of labo- for_adaptation.pdfratory systems to ensure adequate access to CD4testing to determine ART eligibility and access to VL Adapting WHO Normative HIV Guidelines for Na-testing to identify treatment failure. The capacity for tional Programmes (WHO 2011): This guide “de-accurate TB diagnosis and routine HBV screening of fines the principles of adaptation promoted by WHOHIV patients should be established. and outlines a generic framework for the process of adapting HIV guidelines for national programs. ItDevelop capacity to manage third-line therapy: does not provide full guidance on developing an op-As national treatment programs grow older, treat- erational plan, but does offer suggestions for strategicment failure becomes more widespread, and patients planning (or re-planning) for the national response towill increasingly require third-line therapy. National HIV.” It also includes country case studies in the annexgovernments should develop preliminary guidelines to offer guidance on how national programs mightfor third-line therapy and establish centers that have address some of the specific challenges being faced inthe technical expertise and appropriate diagnostics to the guideline adaptation and implementation process.monitor patients on third-line regimens. The adventof new medications, including rilpivirine and cobicistat; Available at: expanded use of other medications, including index.htmlRAL; and the likelihood of decreased future pricing forthird-line therapy precipitate the need for countries Crosswalk Analysis of Antiretroviral Therapy Cost-to have preliminary guidelines that will facilitate imple- ing Models and Their Policy Impact (AIDSTAR-Onementation of third-line therapy. 2010): Through PEPFAR and other initiatives, several different packages of modeling software have been developed to address different aspects of resourceRESOURCES allocation. This crosswalk analysis evaluates and compares nine commonly used ART costing models,This section lists key resources for countries working including model utility, data output, impact on policythrough the guideline revision and implementation decisions, and other pertinent information to informprocess. HIV policymakers and program managers.A Guide for Adaptation and Implementation: Available at: Principles and Recommendations (WHO ment/ART_costing_cross_walk2009): This guide was developed in late 2009 tocomplement Rapid Advice with the purpose of “assist- WHO Phase 1 Toolkit: Understanding the Reviseding Member States and program managers to choose WHO Recommendations and Supporting Theirand prioritize among the recommendations, especially Adaptation into National Guidelines (Elizabeth W H O ’ S 2 010 R E C O M M E N D AT I O N S F O R H I V T R E AT M E N T: N AT I O N A L 21 GUIDELINE REVISION CHALLENGES AND LESSONS LEARNED