Review Simplification of antiretroviral therapy: a necessary step in the public health response to HIV/AIDS in resource-limited settings

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1 Antiviral Therapy 2014; 19 Suppl 3:31 37 (doi: /IMP2898) Review Simplification of antiretroviral therapy: a necessary step in the public health response to HIV/AIDS in resource-limited settings Marco Vitoria 1 *, Nathan Ford 1, Meg Doherty 1, Charles Flexner 2 1 HIV Department, World Health Organization, Geneva, Switzerland 2 School of Medicine, Division of Clinical Pharmacology, Johns Hopkins University, Baltimore, MD, USA *Corresponding author vitoriam@who.int The global scale-up of antiretroviral therapy (ART) over the past decade represents one of the great public health and human rights achievements of recent times. Moving from an individualized treatment approach to a simplified and standardized public health approach has been critical to ART scale-up, simplifying both prescribing practices and supply chain management. In terms of the latter, the risk of stock-outs can be reduced and simplified prescribing practices support task shifting of care to nursing and other non-physician clinicians; this strategy is critical to increase access to ART care in settings where physicians are limited in number. In order to support such simplification, successive World Health Organization guidelines for ART in resource-limited settings have aimed to reduce the number of recommended options for first-line ART in such settings. Future drug and regimen choices for resource-limited settings will likely be guided by the same principles that have led to the recommendation of a single preferred regimen and will favour drugs that have the following characteristics: minimal risk of failure, efficacy and tolerability, robustness and forgiveness, no overlapping resistance in treatment sequencing, convenience, affordability, and compatibility with anti-tb and anti-hepatitis treatments. Introduction The global scale-up of antiretroviral therapy (ART) over the past decade represents one of the great public health and human rights achievements of recent times. When the World Health Organization (WHO) issued its first ART guidelines for resource-limited settings in 2002 [1] approximately 230,000 people were receiving HIV treatment, half of them in one country, namely Brazil. Ten years later, at the end of 2012, some 10 million people were receiving ART in low- and middle-income countries a 40-fold increase in just 10 years [2]. The provision of ART to people living with HIV (PLHIV) is first and foremost a life-saving intervention in HIV care. In Thailand, in the pre-art era, approximately 80% of patients presenting at clinics with AIDS-defining illnesses died within 2 years [3]; with ART even patients with advanced illness had an 80% chance of survival at 2 years [4]. To further reduce mortality programmes aim to start PLHIV on ART earlier to attain better long-term survival. A recent analysis of data from six treatment programmes in three provinces in South Africa concluded that adult patients starting ART have life expectancies around 80% of normal life expectancy, provided they start treatment before their CD4 + T-cell counts drop below 200 cells/mm 3 [5]. In addition to these clinical benefits, there is increasing evidence to support the preventive benefits of wide-scale ART coverage. Results from a large multi-country trial assessing the extent to which early initiation of ART reduces the risk of HIV transmission from HIV-positive individuals to their HIV-negative partners showed that if an HIV-infected person adheres to an effective ART regimen, the risk of transmitting the virus to their uninfected sexual partner can be reduced by as much as 96% [6]. Recent ecological evidence from a large population-based cohort in rural South Africa found that HIV incidence was significantly lower in areas with moderate to high ART coverage with more than 30% of PLHIV on ART, compared to areas of low coverage with fewer than 10% of PLHIV on ART; in this study, for every 10% increase in the number of people getting ART, the HIV incidence fell by 17% [7] International Medical Press (print) (online) 31

2 M Vitoria et al. The potential to extend lives and prevent new infections has provided renewed international commitment to expanding and sustaining ART coverage. In order to realize these benefits there is a need to ensure that ART is as simple as possible for patients, providers and programmes. This article summarizes work by the WHO and partners in recent years to arrive at a single, preferred option for ART to further support scale-up of treatment in resource-limited settings. Benefits of regimen simplification The widespread use of ART in low- and middle-income countries changed the perspective of HIV infection, from an acute life-threatening disease to a disease that can, with timely and effective treatment, be managed as a chronic condition. However, early regimens were complex, comprising 20 pills a day or more, and such a high pill burden can lead to poor adherence because of side effects and regimen complexity [8]. High adherence to ART is critical for treatment success and to avoid the development of drug resistance, and for these reasons both once-daily regimens [9] and fixed-dose combinations (FDCs) [10] have been associated with better adherence, including for patients considered at high risk of non-adherence [11]. Such simplification is a critical part of the transition of HIV management from acute care provided by clinicians to a chronic condition managed largely by nurses and other health-care providers. Moreover, the benefits of ART simplification extend well beyond improving adherence. For patients, the use of FDCs has been associated with improved general satisfaction and quality of life, ease of use and treatment convenience [12]. For providers and programmes, regimen simplification can improve task shifting such that routine care can be provided by health workers other than doctors, such as nurses, and dispensed by pharmacy assistants rather than pharmacists. This is critical to the expansion of ART services in resource-limited settings, where specialized staff are few, generally located in secondary and tertiary hospitals of urban centres, or once trained have moved into the private sector or to higher-income countries [13 15]. FDCs also support the simplification of supply chain management, lower health-care costs and there is some evidence that stock management may be facilitated and the occurrence of drug stock-outs may be reduced if national guidelines recommend one single fixed-dose for all patients initiating first-line therapy [16]. Towards a preferred fixed-dose combination for first-line ART Successive WHO guidelines for ART in resource-limited settings have aimed to reduce the number of recommended options for first-line ART in resource-limited settings and recent guideline revisions have reduced the number of recommended preferred options from eight in 2006 to one in 2013 (Table 1) [17 19]. Furthermore, with an aging epidemic, simplification of ART regimens should take into account the risk of drug interactions with additional co-medications that can compromise the antiretroviral (ARV) treatment tolerability and response. Moving from an individualized treatment approach to a simplified and standardized approach has been critical to ART scale-up, reducing the risk of dosing error and therefore supporting task shifting of ART prescribing to lesser-trained health-care workers, simplifying prescribing practices, programmatic planning and supply chain management. However, despite this most studies point in the same direction, favouring the use of FDCs. The assessment of evidence in the field of FDC benefits is a challenge as few studies have been designed explicitly to directly compare the same regimens as separate pills and fixed dose. Nevertheless, the results of a recent systematic review showed that the use of ARVs as FDCs appears to offer multiple advantages for patients and programmes, particularly with respect to treatment adherence [16]. The scale-up of ART over the past decade has been supported by the availability of a simple, affordable FDC comprising nevirapine (NVP), stavudine (d4t) and lamivudine (3TC). This simple regimen was the first generic FDC option to become available and critical to ensuring that ART could be provided to large numbers of patients as part of a public health approach. This public health approach includes the simplification and standardization of treatment so that it can be provided by a trained variety of different health professionals within the health service. However, while this combination represents the most affordable option in terms of cost per pill, there are complications that prevent it being recommended as a long-term preferred regimen for the majority of patients. The main limitations are that NVP can pharmacologically interact with several other drugs commonly used in HIV care, such as antihistamines, antifungals and rifampicin [20]; NVP-associated skin and hepatic toxicities result in a high rate of drug substitutions [21]. Most importantly, cumulative exposure to d4t has the potential to cause disfiguring, painful and life-threatening side effects, such as lipodystrophy, peripheral neuropathy and lactic acidosis [22,23]. For these reasons, there was a need to establish an alternative first-line FDC regimen. Considering current available drugs, the combination of tenofovir (TDF), 3TC and efavirenz (EFV) has been considered the preferred option; however, important uncertainties about safety in children and pregnancy, as well as cost, had until recently limited the potential for this regimen to be recommended as the preferred first-line option. In 2011, as part of the International Medical Press

3 Simplification of ART in resource-limited settings Table 1. Evolution of key clinical recommendations in the WHO guidelines for antiretroviral therapy over the past decade Guidelines topic When to start ART CD4 + T-cell counts CD4 + T-cell counts CD4 + T-cell counts CD4 + T-cell counts CD4 + T-cell counts 200 cells/mm cells/mm cells/mm cells/mm cells/mm 3. Immediate for WHO Immediate for WHO Immediate for WHO Immediate for WHO Immediate for WHO clinical stage 3 or 4. clinical stage 3 or 4. clinical stage 3 or 4. clinical stage 3 or 4, clinical stage 3 or 4, Consider if CD4 + T-cell active TB disease, active TB disease, counts between 200 chronic HBV disease chronic HBV disease and 350 cells/mm 3. (if need HBV treatment). (with severe liver CD4 + T-cell counts disease), HIV 350 cells/mm 3 for serodiscordant active TB disease. couples. CD4 + T-cell counts 350 cells/mm 3 as priority. Preferred first-line 8 Recommended options: 4 Recommended options: 8 Recommended options: 4 Recommended options: 1 Preferred option: ART AZT/3TC+NVP/EFV or d4t/azt+3tc+nvp/efv. TDF/ABC; AZT/d4T+ FDCs (AZT/TDF+ FDC (TDF+3TC/FTC ABC or PI. AZT preferred. NVP/EFV+3TC/FTC. 3TC/FTC+NVP/EFV). +EFV). AZT preferred. AZT or TDF preferred. AZT or TDF preferred. TDF preferred. d4t Dose reduction d4t Phase out. d4t Phase out. (addendum 2007). Preferred second-line Boosted PI (IDV/r, LPV/r, Boosted PI (IDV/r, LPV/r, Boosted PI (ATV/r, DRV/r, Boosted PI heat-stable Boosted PIs heat- ART SQV/r) or non-boosted SQV/r). FPV/r, LPV/r, SQV/r). FDC (ATV/r, LPV/r). stable FDC (ATV/r, PI (NFV). LPV/r). Third-line ART None. None. None. DRV/r, RAL, ETV (limited DRV/r, RAL, ETV availability and high (limited availability cost). and high cost). CD4 + T-cell testing Encouraged. Advisable. Yes. Yes. Yes (use of PoC). Phase-in approach. Need better access. Need better access. Viral load testing No. No. Yes. Yes. Yes (preferred for Not recommended. Encouraged. Tertiary centres. Phase-in approach. monitoring, use of Clinical monitoring only. Need simple assays. PoC, DBS). Adapted with permission from Lippincott Williams and Wilkins/Wolters Kluwer Health from [19]. ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; AZT, zidovudine; DBS, dried blood spots; DRV, darunavir; d4t, stavudine; EFV, efavirenz; FDC, fixed-dose combination; FTC, emtricitabine; IDV, indinavir; LPV, lopinavir; NFV, nelfinavir; NVP, nevirapine; PoC, point-of-care; PI, proterase inhibitor; r, ritonavir; RAL, raltegravir; SQV, saquinavir; TB, tuberculosis; TDF, tenofovir disoproxil fumarate; WHO, World Health Organization; 3TC, lamivudine. Treatment 2.0 strategy (Table 2) [24], the WHO commissioned a series of evidence reviews in order to address these concerns. These reviews focused on three main questions: the safety of TDF in children and adolescents, the safety of EFV in pregnancy and the pharmacological equivalence of 3TC and emtricitabine (FTC). Tenofovir safety in children and adolescents TDF is becoming one of the most commonly used ARVs in adolescents and adults because of its potency and favourable pharmacokinetic profile that allows it to be dosed once daily [25]. Up until 2010 TDF was not approved for use in adolescents and children, principally because of concerns about renal and bone long-term toxicity. However, in March 2010, the US Food and Drug Agency (US FDA) approved TDF for use in adolescents aged years and, in January 2012, this approval was extended to children aged 2 to less than 12 years [26]. Following this approval, a review of the evidence concluded that based on the available data, TDF is efficacious in children older than 2 years of age and in adolescents less than 18 years at current US FDA approved doses [27]. The review noted that while further studies are needed to confirm the optimal dose and investigate the side effects of TDF in combination with EFV in children, it was important for programme managers to balance the benefits of using TDF in children and adolescents such as the ability to harmonize with adult treatment, better sequencing of nucleoside/ nucleotide reverse transcriptase inhibitors in first- and second-line regimens and the convenience of a potential once-daily FDC against the risks of bone and renal toxicity, especially the impact of low bone mineral density on the long-term risk of fragility-related fractures. Furthermore, considering that TDF is active against both HIV and the HBV and is available as a Antiviral Therapy 19 Suppl 3 33

4 M Vitoria et al. Table 2. Treatment 2.0 principles and practice Principle Example Benefit Optimize drug regimens TDF-XTC-EFV as fixed-dose combination Better safety, improved efficacy, improved adherence [21,35] Provide point-of-care diagnostics Point-of-care CD4 + T-cell count Improved time eligibility assessment and reduced loss to care pre-art initiation [36] Reduce costs Treatment optimization Reduced costs associated with the use of generic drugs [37] Adapt delivery systems Decentralization Improved access and retention in care [38] Mobilize communities Community ART delivery Improved retention in care [39] ART, antiretroviral therapy; EFV, efavirenz; TDF, tenofovir disoproxil fumarate; XTC, emtricitabine or lamivudine. one-pill-once-daily regimen, the benefits of TDF currently outweigh the risks compared to alternatives. Efavirenz safety in pregnancy EFV has been recommended as the preferred option for a non-nucleoside reverse transcriptase inhibitor in optimized first-line ARV regimens. However, concerns persist about its safety in early pregnancy, resulting in more complex treatment algorithms for HIV-infected women who might become pregnant and in early pregnancy, and ongoing confusion regarding when to use EFV or NVP. The clinical consequences arising from this include unnecessary switching to alternative and more complex ARV regimens in pregnancy, more frequent regimen changes from EFV to NVP, increased complexity in the management of tuberculosis (TB) coinfection due to interactions between anti-tb drugs and NVP, increased risk of severe drug reactions in patients with a high CD4 + T-cell count at baseline and a potential increase in the number of pregnancies terminated due to a belief that EFV use in early pregnancy may be teratogenic. Programmatic consequences include difficulties in simplifying ART regimens for adults, including for pregnant women and those of reproductive age, and harmonizing them with regimens for prevention of mother-to-child HIV transmission programmes. This has resulted in higher costs and increased complexity of treatment guidelines, clinical management and drug procurement. A review of the available data and programmatic experience provides reassurance that exposure to EFV in early pregnancy has not resulted in increased birth defects or other significant toxicities. In addition, evidence suggests that EFV is clinically superior to NVP, as it provides better long-term viral suppression, has fewer adverse events and less risk of resistance [21,28]. Finally, the cost of EFV has decreased considerably, and it is now increasingly available as part of oncedaily FDCs (Table 3). Based on the available data, programme experience and a public health perspective, this interim guidance provides further support for the use of EFV as part of the WHO strategy to optimize and simplify first-line treatment, including among pregnant women and those of reproductive age [29]. 3TC and FTC: pharmacological equivalence 3TC and FTC are commonly used ARV drugs and the WHO Model List of Essential Medicines and various international guidelines have considered both drugs as clinically equivalent [18,30,31]. However, in vitro and in vivo studies suggest that the active intracellular form of FTC (FTC-triphosphate) has a longer half-life than the active intracellular form of 3TC (3TC-triphosphate), a potential advantage of FTC over 3TC. This question is important because despite some recent reductions, manufacturing costs generally remain higher for FTC, and FDCs containing 3TC are less expensive and more available than those containing FTC in low- and middle-income countries. Following an evidence review, it was concluded that the clinical efficacy and safety of FTC and 3TC are comparable [32]. The role of global guidance in supporting national level policy and practice These evidence-based reviews, together with programmatic considerations, illustrate the important role the WHO and partners can play in undertaking strategic reviews to inform member state governments with evidence-based recommendations to guide national policies. These reviews have enabled the WHO to recommended TDF+3TC+EFV or TDF+FTC+EFV as the preferred first-line regimen for adults, adolescents and older children, as well as for specific situations such as pregnancy, TB HIV and HBV HIV coinfections. It is anticipated that this simplification approach will lead to a variety of benefits, including improved patient adherence, reduced side effects and regimen substitutions, simplified prescribing enabling task shifting and decentralization, and market harmonization that could stimulate further price and cost reductions. Many countries that had previously prescribed a broad range of diverse ARV regimens for first lines International Medical Press

5 Simplification of ART in resource-limited settings Table 3. Summary of clinical and pharmacological characteristics of EFV and NVP Clinical characteristics EFV NVP Safety and tolerability CNS side effects, usually resolve after 2 4 weeks. Severe rash and hepatotoxicity, particularly in Ongoing concern but very low evidence for women with CD4 + T-cell counts >250 cells/mm 3. teratogenicity (neural tube defects) in humans Stevens Johnson syndrome. during early pregnancy. Not recommended in pregnant women with CD4 + T-cell counts >350 cells/mm 3. Drug interactions No significant interactions. NVP concentrations are reduced in the presence of rifampicin. Convenience Available as a once-daily, fixed-dose combination Twice-daily regimen (with AZT or TDF). (with TDF and 3TC or FTC). Requires lead-in dosing (that is, use of half-dose in the first 2 weeks of treatment). Efficacy Comparable efficacy in early clinical trials. Comparable efficacy in early clinical trials. More recent data suggest greater efficacy for EFV in TDF-containing regimens. Drug resistance (robustness) Higher risk of NNRTI resistance mutations with NVP. Cost (generic, annual, per patient) a Single drug USD44. USD29. Fixed-dose combination USD172 (TDF/3TC/EFV once-daily fixed-dose USD119 (AZT/3TC/NVP twice-daily fixed-dose combination). combination). a Single drug and fixed-dose combination costs based on generic drug costs by Médecins Sans Frontières. AZT, zidovudine; CNS, central nervous system; EFV, efavirenz; FTC, emtricitabine; NNRTI, non-nucleoside reverse transcriptase inhibitor; NVP, nevirapine; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine. have adopted or indicated a willingness to use single tablet first-line regimens. The future of drug optimization The latest guidelines for ART released by the WHO in June 2013 recommend that countries move towards policies of initiating treatment earlier in the course of HIV infection, at CD4 + T-cell counts 500 cells/mm 3. This new criterion is supported by the recent evidence of the significant impact of earlier ART on HIV transmission and also on the risk of death and disease progression. These guidelines also recommend an expanded range of scenarios for immediate initiation of ART, for example, for pregnant women, people in HIV serodiscordant relationships and children under 5 years of age [18]. While recognizing that the priority remains to treat those in greatest need, with a CD4 + T-cell count 350 cells/mm 3, the implications of these new recommendations are that some patients will be treated before they develop symptoms, and will also receive treatment for longer. This shift in the balance of risks implies that patients should be offered treatment that is as safe, has limited toxicities and is as simple to take as possible. For countries, in the immediate term, any shift towards earlier provision of ART should go hand in hand with a shift towards the preferred first-line regimen. Many countries are still prescribing regimens that are no longer recommended by the WHO, such as d4t, or recommending a broad range of ARVs [2]. The WHO and major implementation partners will work with countries to offer technical support for a rapid transition to a reduced formulary of preferred firstand second-line options. Looking further, several recent expert consultations have aimed to assess further potential for regimen simplification over the next 5 10 years. A meeting organized by Médicins Sans Frontières in September 2011 concluded that, in the short term, TDF+3TC+EFV or TDF+FTC+EFV would remain the preferred first-line option, considering its favourable profile in terms of simplicity, tolerability and safety, durability, universal applicability, affordability and heat stability [33]. This conclusion was confirmed at a subsequent expert meeting convened by the WHO in May 2012 [34], and served to inform the recommendation in the latest WHO guidance issued in June 2013 that countries should shift towards this preferred option [18]. In order to further simplify treatment over the medium term of the next 3 5 years, several critical research questions have been identified. These include the establishment of long-term safety of TDF-containing regimens in pregnancy and childhood, the long-term safety efficacy of integrase inhibitors and the development of appropriate paediatric formulations, optimal dosing and safety data for new agents for children. Capacity to measure viral load is projected to increase significantly in high burden countries over the next 3 5 years, and this can be expected to lead to an increased demand for second- and third-line regimens. Antiviral Therapy 19 Suppl 3 35

6 M Vitoria et al. Over the longer-term, the next 5 10 years and beyond, it is expected that current first and subsequent ART regimens can be further improved as new drugs and innovative strategies, like induction-maintenance therapy, long-acting formulations and anti-latency drugs, progress through the pipeline. Conclusions The scale-up of ART over the past decade has depended on a strategy of treatment simplification in order to maximize patient adherence and the delivery of ART at scale within a public health approach. 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