Rational use of antiretroviral therapy in low-income and middle-income countries: optimizing regimen sequencing and switching
Elliott, Julian Ha,b; Lynen, Lutc; Calmy, Alexandrad,e; De Luca, Andreaf; Shafer, Robert Wg; Zolfo, Mariac; Clotet, Bonaventurah,i; Huffam, Sarahj,a; Boucher, Charles ABk,l; Cooper, David Aa; Schapiro, Jonathan Mm
aNational Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney
bMacfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Australia
cHIV/STD Unit, Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
dHIV Unit, Geneva University Hospital, Switzerland
eMédecins sans Frontières, MSF Campaign for Access to Essential Medicines, Geneva, Switzerland
fInstitute of Clinical Infectious Diseases, Catholic University, Rome, Italy
gDivision of Infectious Diseases, Department of Medicine, Stanford University, Stanford, California, USA
hHospital Universitari Germans Trias I Pujol, Spain
iirsiCaixa Foundation, Barcelona, Spain
jNational Center for HIV/AIDS, Dermatology and STDs, Ministry of Health, Phnom Penh, Cambodia
kDepartment of Virology, Erasmus MC, University Medical Center, Rotterdam
lDepartment of Medical Microbiology, University Medical Center, Utrecht, The Netherlands
mNational Hemophlia Center, Sheba Medical Center, Ramat Gan, Israel.
Received 28 March, 2008
Revised 6 May, 2008
Accepted 10 May, 2008
Correspondence to Julian H. Elliott, Macfarlane Burnet Institute for Medical Research and Public Health, GPO Box 2284, Melbourne, VIC 3001, Australia. E-mail: firstname.lastname@example.org
During the 4 years to the end of 2007, the number of people in low-income and middle-income countries (LMICs) receiving antiretroviral therapy (ART) increased from 400 000 to 3 million [1,2]. Although early mortality  and retention in care  remain significant challenges, the majority of reports from LMICs have shown encouraging immunological, virological and survival outcomes [5–12]. Reported rates of switching to second-line ART regimens have been lower than expected [13–15], in part due to actual rates of treatment success, but mainly because of limited access to both virological monitoring  and second-line drugs . Clinicians have also been reluctant to switch therapy  due to regimen cost, complexity, inconvenience and lack of subsequent treatment options. As cohorts mature and expand and access to virological monitoring and second-line regimens increase, however, rates of diagnosed treatment failure and switch to second-line regimens will increase . As the cost of second-line regimens are currently three to 20 times more expensive than that of first-line regimens , these increases will challenge the cost-effectiveness [19,20] and sustainability  of HIV-treatment programmes.
An effective response to the challenges of HIV treatment failure in LMICs must include reductions in the cost of second-line agents , but changes to commercial regulations, particularly in India, suggest the scale of price reductions seen with first-line agents are unlikely to occur with second-line agents. Strategies to maximize the effectiveness of first-line and second-line regimens and optimize the timing of regimen switching are required to fully utilize the survival benefit of available treatment options, maintain programme cost-effectiveness and enable achievement of universal access to HIV treatment. A comprehensive strategy must be evidence based and focused on the rational long-term use of ART at a population level. The objective of this review is to support the development of these strategies by providing an overview of available evidence with an emphasis on regimen sequencing and switching.
How can we prolong effective use of first-line antiretroviral therapy?
Drug resistance prior to initiation of combination antiretroviral therapy
Primary (transmitted) resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) increases the risk of NNRTI-based regimen failure , whereas the equivalent relationship remains to be defined for ritonavir-boosted protease inhibitor-based regimens. Although the use of mono-therapy and bi-therapy has been uncommon in LMICs, previous experience of sub-optimal ART is a significant contributor to virological failure in some settings [24,25]. The use of nevirapine monotherapy for the prevention of perinatal transmission is more common and is associated with development of resistance to NNRTIs  and reduced virological response to subsequent nevirapine-based therapy . Virological responses can be improved by delaying therapy after delivery . Alternatively, resistance can be limited with the use of alternative or additional  antiretroviral agents.
Recent analyses suggest primary NNRTI resistance is unlikely to have a significant population-level impact on the effective use of first-line NNRTI regimens in most LMICs in the near future [30,31]. Nevertheless, adequately resourced HIV drug resistance surveillance programmes  have the potential to inform treatment strategies and determine the utility of drug resistance testing for treatment of naive patients.
Timing of treatment initiation
The timing of initiation of ART has important implications for optimizing clinical benefit of first-line regimens. Low CD4 cell count at the time of initiation of ART is common in LMICs [3,5–11] due to constraints on HIV testing and treatment and limited access to CD4 cell counting to guide treatment initiation. This results in increased mortality [33,34], virological failure  and drug resistance , whereas use of ART is associated with reduced mortality even at high CD4 cell counts . These relationships favour initiation of therapy when the CD4 cell count falls below 350 cells/μl or earlier, but this strategy depends on early diagnosis and referral and the ability of health systems to manage larger cohorts. Given treatment interruption is not currently recommended [37–40], this strategy would also lead to longer duration of drug exposure, with attendant costs and risks of virological failure, drug resistance and subsequent clinical progression in settings with limited treatment options . The long-term risks and benefits of alternative initiation strategies in LMICs remain unknown, but data from treatment interruption studies suggest earlier treatment initiation may be associated with similar or greater reduction in clinical events compared with the use of this strategy in high-income countries [38,42].
Selection of first-line regimen
First-line antiretroviral regimens are highly effective in suppressing viral replication. Clinical studies of two nucleoside reverse transcriptase inhibitors (NRTIs) combined with either a NNRTI or a boosted protease inhibitor published since 2003 demonstrate a probability of virological success (HIV RNA <50 copies/ml at 48 weeks) between 59 and 83% by intent-to-treat analysis [43–53]. Efavirenz and nevirapine are both potent agents from the NNRTI class, but in a randomized comparison, equivalence could not be demonstrated , and some observational data suggest superior virological outcomes with efavirenz [54–57]. Moreover, mutations associated with reduced activity of etravirine, such as Y181C, are more commonly selected in patients failing nevirapine than in those failing efavirenz . Randomized studies of efavirenz versus a boosted protease inhibitor, lopinavir/ritonavir, have shown better virological suppression in the efavirenz arm, but greater CD4 cell count increase in the lopinavir/ritonavir arm . Ritonavir-boosted protease inhibitors have a high genetic barrier to resistance and are associated with fewer resistance mutations at the time of virological failure compared with NNRTI-based regimens [52,59]. Boosted protease inhibitors are an option when NNRTIs are contra-indicated: infection with HIV-2, intolerance of both nevirapine and efavirenz and in pregnant women requiring treatment for tuberculosis during first trimester. These advantages are, however, counterbalanced by their toxicity, drug interactions, greater potential for sub-optimal adherence , storage requirements of some agents and, despite recent price reductions, continuing high cost. A combination of two NRTIs and a NNRTI therefore continues to be recommended by WHO as standard first-line treatment . These assessments may need to be revisited if further price reductions or formulation changes occur.
NRTIs are used in combinations due to increased potency and genetic barrier to resistance. Randomized comparative studies have shown significantly greater virological response with tenofovir + emtricitabine as compared to zidovudine + lamivudine  and equivalence of virological response when abacavir + lamivudine was compared to zidovudine + lamivudine  and stavudine + lamivudine was compared to tenofovir + lamivudine . In all these studies, the NRTI backbones were combined with efavirenz. Comparative data on NRTI combinations administered with nevirapine or boosted protease inhibitor are limited.
The selection of an NRTI agent for use in combination with lamivudine/emtricitabine and a NNRTI is driven primarily by cost and toxicity in most LMICs. Despite its significant long-term toxicity, stavudine remains more widely used than zidovudine  owing to its lower cost and limited short-term toxicity . Some studies suggest that the risk of zidovudine-associated anaemia can be reduced by starting with a stavudine-containing regimen and routinely substituting stavudine with zidovudine after 6 months of therapy [63,64]. Tenofovir is associated with less toxicity in randomized trials than are thymidine analogues [46,49] and emerging data from populations in LMICs with lower body weight are reassuring . Although there are concerns regarding the prevalence of renal disease in Africa  and the feasibility of renal monitoring in many LMICs, the main barrier to more widespread use of tenofovir in first-line regimens is cost: currently a median three-fold increase in total regimen cost in LMICs compared to current first-line regimens .
An alternative to two class regimens is a nucleoside-only regimen. Randomized studies in high-income countries have shown that triple NRTI regimens lacking a thymidine analogue fail rapidly [67,68] and zidovudine + abacavir + lamivudine is inferior to standard regimens. Combining tenofovir and zidovudine has potential benefit due to antagonistic resistance pathways. A pilot randomized study comparing zidovudine + lamivudine + efavirenz and abacavir + lamivudine + zidovudine + tenofovir showed equivalent virological suppression  and in a large randomized trial ongoing in Uganda and Zimbabwe, the use of zidovudine + lamivudine + tenofovir was associated with HIV RNA more than 1000 copies/ml in 24% at 48 weeks , which is comparable to outcomes seen with the use of dual class initial regimens. Within the latter trial, a randomized comparison has shown superior virological suppression, but borderline increase in new WHO stage 3/4 events or death when zidovudine + lamivudine was combined with nevirapine compared to combination with abacavir . The mechanism for this finding is not clear and further comparative studies are warranted.
Agents from two new classes have been trialled in treatment-naive subjects. When compared with efavirenz in subjects with pretreatment CD4 cell count above 100 cells/μl, the integrase inhibitor raltegravir demonstrated comparable activity and less toxicity in combination with tenofovir and lamivudine . The potential role of this drug class in LMICs within second-line or even first-line therapy is significant and will be shaped by cost and accrual of additional efficacy, toxicity and drug interaction data. Maraviroc, a CCR-5 antagonist, showed similar, but slightly inferior efficacy when compared with efavirenz . The restriction of efficacy of this agent to patients with R5-tropic only virus and the need for pretreatment tropism assays suggests the role of this class will be limited in most LMICs. Early reports suggested subtype C viruses rarely utilize CXCR-4, but more recent reports from Zimbabwe  and South Africa  have shown substantial use of this co-receptor. From the NNRTI class, rilpivirine is an investigational agent with potent in-vitro antiretroviral activity and high genetic barrier to resistance . Its low dosage, lack of potential interactions and the possibility of daily dosing suggest this agent may play an important role in LMICs.
Adherence to antiretroviral therapy
Adherence to ART is a major determinant of the longevity of first-line regimens . A recent meta-analysis of adherence to ART in Africa and North America found a pooled estimate of adherence of 77% [95% confidence interval (CI) 68–85] for African studies compared to 55% (95% CI 49–62) for North American studies . The African data were largely drawn from small cohorts (median n = 100) and additional data from large treatment programmes are needed. Understanding the determinants of adherence behaviour across populations and over time remains critical to ensuring the success of first-line therapy, yet relevant data are currently extremely limited . The main barriers to ART adherence in LMICs identified to date are financial constraints, transportation or disruption to supply, forgetting or disrupted routine, fear of disclosure and lack of understanding of treatment benefits. Despite the widespread implementation of adherence support programmes in LMICs, a recent meta-analysis of randomized trials of adherence interventions did not identify any studies conducted in these settings .
Programme and structural factors are also likely to be important determinates of treatment outcomes, although these relationships remain poorly documented. Important factors may include the quality of drug production and distribution, the quality of clinical management, accessibility of ART centres , treatment preparedness and community support , and stigma and discrimination in healthcare settings and in broader society.
How can we accurately detect first-line failure and optimize switch to second-line therapy?
Monitoring and switch strategies
The rational use of ART in LMICs is critically dependent on the accurate detection of treatment failure and optimizing the timing of switch to alternative regimens. Monitoring and switch strategies aim to balance the risks of HIV drug resistance and compromised efficacy of second-line therapy, immunological and clinical progression and inappropriate early switching, taking into account variable factors such as the monitoring tools that are available, the risks and benefits of alternative regimens and current and future drug availability. Three broad approaches can be described.
Table 1 shows available data regarding the performance characteristics of current WHO clinico-immunological definition of treatment failure  for detection of virological failure [83–85]. Although these data are limited, they suggest these criteria detect approximately a quarter of patients with virological failure and that the majority of patients fulfilling these criteria are not failing virologically. Some studies suggest a CD4 cell count increase of less than 50 cells/μl by month 6 of therapy may more rapidly identify individuals with potential virological failure than current criteria, although significant inaccuracy remains due to discordant immunological and virological responses to initial ART [86–89]. One study suggested use of CD4 cell count decrease of more than 30% between months 12 and 24 was associated with an improved positive predictive value of 54%, but similar sensitivity  and cross-sectional studies have identified some improvements in sensitivity, but positive predictive values have generally remained below 25% [84,85,91,92].
Targeted HIV viral load testing
HIV viral load testing can be restricted to patients with an increased risk of virological failure using a high-sensitivity/low-specificity clinico-immunological algorithm [84,86,87,90]. For example, CD4 cell count decrease or increase of less than 10–20% or 150–200 cells/μl over 6–12 months is 70–80% sensitive for virological failure [84,86,90]. Alternatively, HIV viral load testing can be targeted to patients fulfilling current clinico-immunological algorithms [93,94], preventing inappropriate early switching and minimizing testing volumes, but with low sensitivity for virological failure. No prospective studies of targeted testing strategies have been reported.
Universal HIV viral load testing
Data from high-income countries suggest that more frequent HIV RNA viral load monitoring improves virological outcomes  and universal testing every 3–4 months has been the standard of care in high-income countries for many years [40,96,97]. Data largely from African cohorts, however, have shown no evidence that access to HIV viral load reduces mortality during early ART  and a recently published mathematical model suggested little survival benefit from addition of CD4 or viral load monitoring to clinical monitoring . A randomized trial of different monitoring strategies conducted in Uganda found in an adjusted analysis over a median 3 years of follow-up that adding CD4 cell counting to clinical monitoring was associated with a reduced risk of new AIDS-defining event or death, but no morbidity or mortality benefit was seen with the further addition of HIV viral load monitoring . Other randomized trials of treatment monitoring are ongoing in Thailand  and Uganda and Zimbabwe .
The advantages of universal testing are high sensitivity and specificity for treatment failure and collection of robust individual patient outcome data. Although feasibility is currently limited in many settings , this is likely to improve as technologies evolve . Inexpensive qualitative or semi-quantitative assays detecting loss of viral suppression are an urgent need . The cost-effectiveness of viral load testing will be dependent on morbidity, survival and resistance benefits, reduction of inappropriate switching, costs associated with increased use of second-line regimens and costs of viral load testing itself. One study suggested universal HIV viral load testing was cost-effective in South Africa , whereas another model suggested poor cost-effectiveness . Additional data are needed to support cost-effective analyses in a range of settings. No comparisons of universal and targeted testing strategies have been performed, and their relative cost benefits are unknown.
HIV viral load testing has also been used as an indicator of ART adherence [15,103]. Under this strategy, individuals with virological failure receive an adherence intervention and continue without regimen change if viral re-suppression occurs. Viral re-suppression of up to 70% has been documented , but the durability of virological suppression and rate of accumulation of NRTI resistance is not known. Longer term prospective studies with assessment of viral suppression and drug resistance are needed.
HIV viral load test frequency and switch threshold
Two key questions for HIV viral load testing strategies are the frequency of virological monitoring required to minimize clinical, immunological and virological progression and accumulation of drug resistance mutations and the appropriate viral load threshold for regimen switching.
A number of cohort studies of patients receiving predominantly unboosted protease inhibitor-based therapy in high-income countries have shown that immunological progression is unlikely if the HIV viral load is below 10–20 000 copies/ml [105–108] or suppressed approximately 1.5 log copies/ml or more below pretherapy baseline [107,109]. Moreover, the risk of disease progression or death has been shown to be lower if the HIV viral load is below 10–20 000 copies/ml [109–112]. Unfortunately, the only randomized trial to examine this question, which randomized patients to immediate versus delayed switch, did not recruit fully and was not able to demonstrate noninferiority .
In contrast, it is clear that resistance mutants accumulate even at low concentrations of plasma HIV RNA  and cohort studies of patients taking unchanged failing predominantly unboosted protease inhibitor-based regimens have largely shown that the rate of accumulation of drug resistance mutations is independent of HIV viral load [115–119], although one study found a higher rate of resistance accumulation for patients with moderate HIV viraemia (3–4 log copies/ml) or higher HIV viral load slope . Overall, the observed rates of drug resistance mutation accumulation was 39–77% of patients over a median 6–14 months [115,116,118–121] with an incidence of new resistance-associated mutations of 0.93  and 1.96  over 6 months and 1.61 mutations per year .
These data may not, however, be generalizable to patients taking NNRTI-based regimens in LMICs, despite the use of similar NRTI backbones to the cohorts described above. In an analysis of patients with triple class failure and stable viral load published by the PLATO collaboration multivariate linear regression demonstrated a negative CD4 cell count slope with use of NNRTI-based therapy (−23.0 cells/μl per year; 95% CI −35.0 to −11.0) compared with a positive slope with protease inhibitor-based therapy (+18.0 cells/μl per year; 95% CI +7.0 to +28.0) . Furthermore, NNRTI resistance may be more closely associated with increased mortality [58,122] and may have less impact on viral fitness [123,124] when compared with protease inhibitor resistance. Indeed, the ART-LINC collaboration reported that patients taking protease inhibitor-sparing regimens (mostly NNRTI based) were less likely to experience a positive immunological response in the setting of persistent HIV viraemia during early ART . Other studies from LMICs suggest rapid accumulation of drug resistance mutations following virological failure of NNRTI-based therapy  and an association between resistance mutations and subsequent immunological failure . Whether HIV viral load is associated with accumulation of resistance mutations in these settings remains unclear [125,126].
In the absence of more extensive data, the optimal frequency of viral load testing cannot be determined. Although this frequency may be dependent on factors such as time on therapy, duration of prior viral suppression and adherence, it is likely that in general the optimal frequency lies somewhere between 3 and 12 monthly. Similarly, in the absence of more definitive data, current WHO guidelines have provisionally suggested a HIV RNA level of 10 000 copies/ml  as a threshold for first-line regimen switching in LMICs.
Drug resistance genotyping
Resistance testing at time of treatment failure results in improved short-term virological response in treatment-experienced patients [127,128] and is cost-effective in high-income countries when based on HIV viral genotyping [129–131]. Expert advice increases its benefit , although free, open-interpretation systems may reduce the need for expert advice for many patients [132,133]. Cost-effectiveness is likely to be different in LMICs and related to the treatment, monitoring and switch strategies employed. A substantial proportion of patients with virological failure of first-line therapy lack resistance mutations [134–138], suggesting that resistance testing may reduce costs by triaging patients to adherence support rather than to second-line therapy. Although resistance testing is currently expensive (US$50–300 per test), this cost could be lowered by use of technologies targeting commonly selected mutations in order to demonstrate that failure is caused by resistance and not only by nonadherence .
Monitoring and switch strategies are heavily influenced by the agents employed in first-line and second-line regimens. Even with current treatment regimens, however, scarcity of data limits the development of rational strategies. It can be assumed that mutations associated with resistance to NNRTIs and lamivudine/emtricitabine will be rapidly selected in patients failing therapy. The key question is, therefore, which monitoring and switch strategies most cost-effectively minimize inappropriate early switching, medium-term and long-term immunological and clinical progression and the development of reverse transcriptase cross-resistance (engendered by mutations such as thymidine analogue mutations (TAMs), K65R, Q151M and T69 insertions and mutations associated with impaired efficacy of second-generation NNRTIs). The heterogeneity of LMICs makes a single answer unlikely. Setting-specific approaches are necessary and dependent on robust data from diverse settings.
Which second-line regimen should be used?
The efficacy of second-line regimens will be a function of the first-line regimen used, the duration of viral replication in the presence of these drugs and the range of drugs available to construct a second-line regimen. Subtype polymorphism at drug-related resistance positions may influence the selection of resistance, although this has not been found to be a major factor in treatment outcomes to date [140,141].
There is currently limited evidence to guide the selection of second-line regimens in LMICs after failure of first-line NNRTI-based therapy . Clinical data suggest continued benefit from NRTI despite the presence of confirmed resistance [143,144], possibly due to reduced fitness of mutated virus . NRTIs should therefore be continued as a component of second-line therapy even in the setting of resistance if other potent combination regimens are not available. Ritonavir-boosted protease inhibitors have shown impressive results when used in treatment-experienced patients in high-income countries [146,147]. High plasma concentrations and a broad genetic barrier to resistance appear to reduce the need for support from other fully active drugs in the regimen. Based on these characteristics and the tolerability, simplicity, costs and availability of certain fixed-dose combinations, WHO guidelines for a public health approach currently recommend a boosted protease inhibitor with two NRTIs.
Choice of nucleoside reverse transcriptase inhibitors
The choice of NRTIs used within a second-line regimen depends on those used in the first-line regimen (Fig. 1). Failure of zidovudine-containing or stavudine-containing first-line regimens select for TAMs, commonly along one of two pathways: TAM 1 (M41L, L210W and T215Y) or TAM 2 (D67N, K70R, T215F and K219Q/E). Stavudine combined with drugs with a low genetic barrier has been associated with a higher probability of type 1 TAMs [148,149]. Accumulation of two or more TAM 1 mutations has been most tightly correlated with broad NRTI resistance and inability to construct a potent second-line NRTI backbone [149,150]. Combinations with lamivudine or emtricitabine that select for the M184V mutation or high genetic barrier triple NRTI combinations such as zidovudine + lamivudine/emtricitabine + tenofovir may reduce or delay TAM selection . Nevertheless, multiple TAMs and broad NRTI resistance will ultimately develop with all thymidine analogue containing regimens if viral replication continues unchecked [70,152].
The K65R HIV-1 reverse transcriptase mutation is a multidrug resistance mutation associated most commonly with tenofovir, but also with didanosine, abacavir and rarely stavudine [153,154]. The prevalence of this mutation among viruses from subtype B-infected individuals receiving frequent virological monitoring has remained below 5% in clinical trials with tenofovir . TAMs and the L74V mutation occur rarely in the presence of K65R  and in one recent study of patients with K65R followed over 18 months, no patient developed additional multinucleoside resistance (Q151M or T69 insertions) . In-vitro data suggest that the combination of the K65R and M184V mutations, as seen at time of failure of tenofovir + lamivudine/emtricitabine, is associated with reduced viral replication capacity, although clinical correlates of this parameter are lacking . Susceptibility to zidovudine is increased in the presence of K65R and/or M184V , and selection of resistance will require multiple zidovudine mutations if these mutations are maintained. This supports the use of zidovudine following failure of tenofovir + lamividine/emtricitabine. Although laboratory data on stavudine are less clear, some clinical data suggest it has similar attributes. This provides support for the use of a thymidine analogue following tenofovir failure. One caveat is that preliminary in-vitro data suggest K65R may be selected more commonly in subtype C than B  and a higher frequency of K65R has been observed in subtype C patients failing didanosine-based or stavudine-based therapies .
Based on the above data, first-line regimens containing zidovudine and lamivudine/emtricitabine may therefore be associated with greater residual efficacy of NRTIs in second-line regimens than stavudine-containing regimens and tenofovir is likely to be an effective second-line agent in this situation, depending on the prevalence of broad NRTI resistance and K65R. Alternatively, there are some resistance data to support a sequencing strategy that employs tenofovir followed by a thymidine analogue. Lamivudine/emtricitabine provides a useful option for a second-line NRTI, as some degree of efficacy can be assured regardless of the availability of resistance testing and cost and toxicity are minimal. Continuation of both thymidine analogue and tenofovir may increase the probability of regimen efficacy in the absence of resistance testing and may reduce the incidence of additional mutations. Didanosine and abacavir are alternatives to tenofovir, but the toxicity of the former and cost of the latter do not compare favourably. In addition, the M184 mutation increases tenofovir susceptibility but increases resistance to abacavir and, to a lesser degree, resistance to didanosine.
Choice of boosted protease inhibitor
Ritonavir-boosted protease inhibitors have shown good utility in drug-experienced patients [161,162] and use in early salvage therapy from high-income countries shows favourable efficacy for many of these agents . Comparative data are complicated by the use of different doses, study populations and outcome measures . Head-to-head comparisons of boosted protease inhibitors for second-line treatment in LMICs are not available. Early data from cohorts without universal access to HIV viral load testing have shown good short-term outcomes, suggesting that the boosted protease inhibitor component is providing the majority of treatment efficacy [13,25]. The choice of protease inhibitor is mainly dictated by cost and logistic requirements and to date lopinavir/ritonavir is the only boosted protease inhibitor that does not require refrigeration. Once ritonavir in booster dose becomes available in heat-stable formulation, other convenient combinations will be feasible in LMICs. For example, atazanavir/ritonavir has been shown to be noninferior to lopinavir/ritonavir in this setting, has a more favourable lipid profile, and is dosed once daily . Darunavir/ritonavir has shown improved efficacy and similar tolerability in treatment-experienced patients when compared with control protease inhibitor/ritonavir  or lopinavir/ritonavir . WHO has prioritized lopinavir/ritonavir and atazanavir/ritonavir as the main protease inhibitors to be used in the setting of a second-line regimen in LMICs .
Monotherapy with a boosted protease inhibitor is an alternative approach to treatment of patients with failure of initial NNRTI-based therapy. This approach is theoretically attractive for LMICs, as efficacy is independent of cross-resistance to first-line agents, NRTI toxicity is eliminated, and drug costs are minimized. Data available to date, however, suggest moderately reduced efficacy of this strategy compared with standard protease inhibitor/ritonavir-based therapy [166–168], and non-B subtype virus has been associated with lopinavir/ritonavir monotherapy failure . Similarly, the use of dual boosted protease inhibitors alone is a strategy that would be free of concerns regarding cross-resistance to first-line agents. A number of small studies have examined this approach with encouraging pharmacokinetic and early clinical results, but significant toxicity [170–172]. Available data do not, therefore, support the use of a protease inhibitor only strategy for second-line regimens at this time.
Dose reduction is another strategy that holds potential for cost minimization in LMICs. Dose ranging studies and post-licensing clinical studies have shown adequate virological responses for doses lower than those currently licensed for indinavir/ritonavir [173,174], lopinavir/ritonavir  and atazanavir . Although this strategy can reduce toxicity as well as cost, greater levels of adherence may be required and the risks of treatment failure and resistance need to be evaluated carefully in adequately powered safety and efficacy trials.
Interruption of treatment at fixed or CD4-guided intervals has been investigated in a number of studies reviewed elsewhere . Although some studies in which therapy was reinitiated at relatively high CD4 cell counts suggested a role for treatment interruption [42,178], the Trivacan and DART studies showed increased severe morbidity in patients undergoing CD4-guided treatment interruptions and the SMART study demonstrated that CD4-guided treatment interruption was associated with an increase in mortality, opportunistic disease and major cardiovascular, renal or hepatic disease [37–39]. Therefore, this approach cannot be recommended at this time and additional clinical endpoint studies are unlikely.
Recent studies have shown the promise of integrase inhibitors [179,180] and CCR5 antagonists [181–183] and new nucleoside  and nonnucleoside  reverse transcriptase inhibitors to dramatically improve the management of treatment-experienced patients in high-income countries. Although there is unlikely to be a need for large-scale access to ‘third-line’ treatment regimens in LMICs for many years , these data suggest the possibility of constructing effective second-line therapy from two classes not used in first-line therapy, reducing the impact of delayed diagnosis of first-line failure and NRTI and NNRTI cross-resistance. Adequately powered efficacy trials of this strategy in nonsubtype B infected patients in LMICs are a priority.
The beginning of global ART scale-up characterized by the ‘3 by 5’ target has transitioned to a post-emergency phase defined by the goal of universal access [2,187]. Larger treatment goals and longer horizons have led to an increased focus on programme sustainability, which is challenged by the prospect of significant increases in direct drug expenditure as larger proportions of patients switch to second-line agents. Although reduction in the price of protease inhibitors in low-income and middle-income countries [22,188] is an essential step toward programme sustainability, these price reductions are likely to be insufficient.
A comprehensive approach to the long-term use of ART is needed to maximize therapeutic effectiveness and minimize costs over the long term. The aims of a comprehensive strategy should be explicit and address short-term treatment outcomes, accumulation and transmission of drug resistance, long-term morbidity and mortality and programme costs. Much is already known (Table 2), but many important evidence gaps exist and require urgent investigation (Table 3). As our knowledge improves, new drugs become available and monitoring and drug costs continue to fall, strategies for the use of ART in LMICs will continue to evolve. The challenge is profound, but so are the benefits of sound investment in rational and comprehensive strategies.
We thank Eva Vervecken for assistance with preparation and formatting of the manuscript.
Role of authors: J.H.E. and J.M.S. conceived the outline of the manuscript, contributed expertise in HIV treatment, drug resistance and use of ART in low-income and middle-income countries and contributed to the drafting of the manuscript. L.L., A.C., A.deL., R.W.S., M.Z., B.C., S.H., C.A.B.B. and D.A.C. contributed expertise in HIV treatment, drug resistance and use of ART in low-income and middle-income countries and contributed to the drafting of the manuscript.
J.H.E., L.L., A.C., M.Z., S.H. have no conflicts of interest. A.deL. has been paid as member of advisory boards or received speaker's honoraria from Gilead, Abbott, GlaxoSmithKline, Bristol-Myers Squibb, Boehringer Ingelheim and Siemens. R.W.S., in the last 2 years, has received research grant support from Abbott Laboratories, Bristol Myers Squibb, Celera, Gilead Sciences, GlaxoSmithKline, and Hoffman LaRoche and been paid for consulting/advisory board membership for Bristol Myers Squibb, Boehringer Ingelheim, Celera, Merck Pharmaceuticals, Siemens and Tibotec. B.C. has been paid for participation in advisory boards or received speakers honoraria from GlaxoSmithKline, Bristol Myers Squibb, Gilead, Abbott, Boehringer Ingelheim, Bayer Healthcare Diagnostics, Janssen, Merck, Pfizer, Roche and Siemens. C.A.B.B. has received research grants or served as a speaker or consultant for GlaxoSmithKline, Bristol-Myers Squibb, Abbott, Boehringer Ingelheim, Roche, Merck and Tibotec. D.A.C. has received advisory and consultancy fees, honoraria, and grant support from GlaxoSmithKline, Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, Abbott, Boehringer Ingelheim, Johnson & Johnson and Gilead Sciences. J.M.S. has served as a consultant, advisor or speaker for Abbott, Ambrilia, Siemens, BMS, Boehringer Ingelheim, Virology Education, Merck, Virco, Roche, Pfizer, Gilead Sciences, Tibotec, GSK and Monogram Biosciences and received research support from GSK, Monogram Biosciences, Roche and Tibotec.
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