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: email@example.com
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.
1. Progress on global access to HIV antiretroviral therapy: a report on “3 by 5” and beyond
Geneva: World Health Organization; 2006.
2. Towards universal access: scaling up priority HIV/AIDS interventions in the health sector: progress report.
Geneva: WHO, UNAIDS, UNICEF; 2008.
3. Braitstein P, Brinkhof MW, Dabis F, Schechter M, Boulle A, Miotti P, et al
. Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries. Lancet 2006; 367:817–824.
4. Rosen S, Fox MP, Gill CJ. Patient retention in antiretroviral therapy programs in sub-Saharan Africa: a systematic review. PLoS Med 2007; 4:e298.
5. Weidle PJ, Malamba S, Mwebaze R, Sozi C, Rukundo G, Downing R, et al
. Assessment of a pilot antiretroviral drug therapy programme in Uganda: patients' response, survival, and drug resistance. Lancet 2002; 360:34–40.
6. Ferradini L, Jeannin A, Pinoges L, Izopet J, Odhiambo D, Mankhambo L, et al
. Scaling up of highly active antiretroviral therapy in a rural district of Malawi: an effectiveness assessment. Lancet 2006; 367:1335–1342.
7. Laurent C, Diakhate N, Gueye NF, Toure MA, Sow PS, Faye MA, et al
. The Senegalese government's highly active antiretroviral therapy initiative: an 18-month follow-up study. AIDS 2002; 16:1363–1370.
8. Tassie JM, Szumilin E, Calmy A, Goemaere E. Highly active antiretroviral therapy in resource-poor settings: the experience of Medecins Sans Frontieres. AIDS 2003; 17:1995–1997.
9. Coetzee D, Hildebrand K, Boulle A, Maartens G, Louis F, Labatala V, et al
. Outcomes after two years of providing antiretroviral treatment in Khayelitsha, South Africa. AIDS 2004; 18:887–895.
10. Seyler C, Anglaret X, Dakoury-Dogbo N, Messou E, Toure S, Danel C, et al
. Medium-term survival, morbidity and immunovirological evolution in HIV-infected adults receiving antiretroviral therapy, Abidjan, Cote d'Ivoire. Antivir Ther 2003; 8:385–393.
11. Kumarasamy N, Solomon S, Chaguturu SK, Mahajan AP, Flanigan TP, Balakrishnan P, Mayer KH. The safety, tolerability and effectiveness of generic antiretroviral drug regimens for HIV-infected patients in south India. AIDS 2003; 17:2267–2269.
12. Ivers LC, Kendrick D, Doucette K. Efficacy of antiretroviral therapy programs in resource-poor settings: a meta-analysis of the published literature. Clin Infect Dis 2005; 41:217–224.
13. Pujades M, Calmy A, O'Brien D, Humblet P, Group MHAw. Outcomes of adults receiving second-line ART in M,decins Sans Frontières-supported projects in resources-limited countries. Proceedings of the 14th Conference on Retroviruses and Opportunistic Infections
; 25–28 February 2007; Los Angeles.
14. Renaud-Thery F, Nguimfack BD, Vitoria M, Lee E, Graaff P, Samb B, Perriens J. Use of antiretroviral therapy in resource-limited countries in 2006: distribution and uptake of first- and second-line regimens. AIDS 2007; 21(Suppl 4):S89–S95.
15. Orrell C, Harling G, Lawn SD, Kaplan R, McNally M, Bekker LG, Wood R. Conservation of first-line antiretroviral treatment regimen where therapeutic options are limited. Antivir Ther 2007; 12:83–88.
16. Consultation on technical and operational recommendations for scale-up of laboratory services and monitoring HIV antiretroviral therapy in resource-limited settings
. Geneva: World Health Organization; 2006.
17. Galarraga O, O'Brien ME, Gutierrez JP, Renaud-Thery F, Nguimfack BD, Beusenberg M, et al
. Forecast of demand for antiretroviral drugs in low and middle-income countries: 2007–2008. AIDS 2007; 21(Suppl 4):S97–S103.
19. Freedberg KA, Kumarasamy N, Losina E, Cecelia AJ, Scott CA, Divi N, et al
. Clinical impact and cost-effectiveness of antiretroviral therapy in India: starting criteria and second-line therapy. AIDS 2007; 21(Suppl 4):S117–S128.
20. Over M, Revenga A, Masaki E, Peerapatanapokin W, Gold J, Tangcharoensathien V, Thanprasertsuk S. The economics of effective AIDS treatment in Thailand. AIDS 2007; 21(Suppl 4):S105–S116.
21. Greco DB, Simao M. Brazilian policy of universal access to AIDS treatment: sustainability challenges and perspectives. AIDS 2007; 21(Suppl 4):S37–S45.
22. Ford N, Wilson D, Costa CG, Lotrowska M, Kijtiwatchakul K. Sustaining access to antiretroviral therapy in the less-developed world: lessons from Brazil and Thailand. AIDS 2007; 21(Suppl 4):S21–S29.
23. Kuritzkes DR, Lalama C, Ribaudo H, Marcial M, Meyer W, Shikuma CM, et al. Baseline resistance to NNRTI as a predictor of virological failure in treatment-naïve subject receiving efavirenz-based regimens in ACTG A5095. Proceedings of the 14th Conference on Retroviruses and Opportunistic Infections
; 25–28 February 2007; Los Angeles.
24. Pujades M, Calmy A, O'Brien D, Humblet P, MSF HIV/AIDS working group. Outcomes of adults receiving second-line ART in Medecins Sans Frontieres-supported projects in resources-limited countries. Proceedings of the 14th Conference on Retroviruses and Opportunistic Infections
; 25–28 February 2007; Los Angeles.
25. Ferradini L, Segeral O, Nouhin J, Leakhena S, Vara O, Dulioust A, et al. Efficacy of Kaletra-based second-line ART in Cambodia. Proceedings of the 14th Conference on Retroviruses and Opportunistic Infections
; 25–28 February 2007; Los Angeles.
26. Flys T, Nissley DV, Claasen CW, Jones D, Shi C, Guay LA, et al
. Sensitive drug-resistance assays reveal long-term persistence of HIV-1 variants with the K103N nevirapine (NVP) resistance mutation in some women and infants after the administration of single-dose NVP: HIVNET 012. J Infect Dis 2005; 192:24–29.
27. Jourdain G, Ngo-Giang-Huong N, Le Coeur S, Bowonwatanuwong C, Kantipong P, Leechanachai P, et al
. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med 2004; 351:229–240.
28. Lockman S, Shapiro RL, Smeaton LM, Wester C, Thior I, Stevens L, et al
. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N Engl J Med 2007; 356:135–147.
29. Chi BH, Sinkala M, Mbewe F, Cantrell RA, Kruse G, Chintu N, et al
. Single-dose tenofovir and emtricitabine for reduction of viral resistance to nonnucleoside reverse transcriptase inhibitor drugs in women given intrapartum nevirapine for perinatal HIV prevention: an open-label randomised trial. Lancet 2007; 370:1698–1705.
30. Vardavas R, Blower S. The emergence of HIV transmitted resistance in Botswana: “when will the WHO detection threshold be exceeded?”. PLoS ONE 2007; 2:e152.
31. Walensky RP, Weinstein MC, Yazdanpanah Y, Losina E, Mercincavage LM, Toure S, et al
. HIV drug resistance surveillance for prioritizing treatment in resource-limited settings. AIDS 2007; 21:973–982.
33. Egger M, May M, Chene G, Phillips AN, Ledergerber B, Dabis F, et al
. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002; 360:119–129.
34. Hogg RS, Yip B, Chan KJ, Wood E, Craib KJ, O'Shaughnessy MV, Montaner JS. Rates of disease progression by baseline CD4 cell count and viral load after initiating triple-drug therapy. JAMA 2001; 286:2568–2577.
35. Deeks SG. Determinants of virological response to antiretroviral therapy: implications for long-term strategies. Clin Infect Dis 2000; 30(Suppl 2):S177–S184.
36. Uy J, Armon C, Buchacz K, Brooks J, and the HOPS Investigators. Initiation of HAART at CD4 cell counts over 350 cells/mm3 is associated with a lower prevalence of antiretroviral resistance mutations at virologic failure. Proceedings of the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention;
22–25 July 2007; Sydney.
37. El Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, et al
. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006; 355:2283–2296.
38. Danel C, Moh R, Minga A, Anzian A, Ba-Gomis O, Kanga C, et al
. CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial. Lancet 2006; 367:1981–1989.
39. DART Trial Team. Fixed duration interruptions are inferior to continuous treatment in African adults starting therapy with CD4 cell counts <200 cells/microl. AIDS
40. US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents
. Washington: US Department of Health and Human Services; 2008.
41. Phillips A, Lepri A, Lampe F, Johnson M, Sabin C. When should antiretroviral therapy be started for HIV infection? Interpreting the evidence from observational studies. AIDS 2003; 17:1863–1869.
42. Ananworanich J, Gayet-Ageron A, Le Braz M, Prasithsirikul W, Chetchotisakd P, Kiertiburanakul S, et al
. CD4-guided scheduled treatment interruptions compared with continuous therapy for patients infected with HIV-1: results of the Staccato randomised trial. Lancet 2006; 368:459–465.
43. van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B, et al
. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 2004; 363:1253–1263.
44. Gulick RM, Ribaudo HJ, Shikuma CM, Lustgarten S, Squires KE, Meyer WA III, et al
. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 2004; 350:1850–1861.
45. Saag MS, Cahn P, Raffi F, Wolff M, Pearce D, Molina JM, et al
. Efficacy and safety of emtricitabine vs stavudine in combination therapy in antiretroviral-naive patients: a randomized trial. JAMA 2004; 292:180–189.
46. Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JM, Miller MD, et al
. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004; 292:191–201.
47. Eron J Jr, Yeni P, Gathe J Jr, Estrada V, DeJesus E, Staszewski S, et al
. The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised noninferiority trial. Lancet 2006; 368:476–482.
48. Johnson MA, Gathe JC Jr, Podzamczer D, Molina JM, Naylor CT, Chiu YL, et al
. A once-daily lopinavir/ritonavir-based regimen provides noninferior antiviral activity compared with a twice-daily regimen. J Acquir Immune Defic Syndr 2006; 43:153–160.
49. Gallant JE, DeJesus E, Arribas JR, Pozniak AL, Gazzard B, Campo RE, et al
. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 2006; 354:251–260.
50. DeJesus E, Herrera G, Teofilo E, Gerstoft J, Buendia CB, Brand JD, et al
. Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis 2004; 39:1038–1046.
51. DeJesus E, McCarty D, Farthing CF, Shortino DD, Grinsztejn B, Thomas DA, et al
. Once-daily versus twice-daily lamivudine, in combination with zidovudine and efavirenz, for the treatment of antiretroviral-naive adults with HIV infection: a randomized equivalence trial. Clin Infect Dis 2004; 39:411–418.
52. Bartlett JA, Johnson J, Herrera G, Sosa N, Rodriguez A, Liao Q, et al
. Long-term results of initial therapy with abacavir and lamivudine combined with efavirenz, amprenavir/ritonavir, or stavudine. J Acquir Immune Defic Syndr 2006; 43:284–292.
53. Moyle GJ, DeJesus E, Cahn P, Castillo SA, Zhao H, Gordon DN, et al
. Abacavir once or twice daily combined with once-daily lamivudine and efavirenz for the treatment of antiretroviral-naive HIV-infected adults: results of the Ziagen Once Daily in Antiretroviral Combination Study. J Acquir Immune Defic Syndr 2005; 38:417–425.
54. Matthews GV, Sabin CA, Mandalia S, Lampe F, Phillips AN, Nelson MR, et al
. Virological suppression at 6 months is related to choice of initial regimen in antiretroviral-naive patients: a cohort study. AIDS 2002; 16:53–61.
55. Phillips AN, Pradier C, Lazzarin A, Clotet B, Goebel FD, Hermans P, et al
. Viral load outcome of nonnucleoside reverse transcriptase inhibitor regimens for 2203 mainly antiretroviral-experienced patients. AIDS 2001; 15:2385–2395.
56. Kamya MR, Mayanja-Kizza H, Kambugu A, Bakeera-Kitaka S, Semitala F, Mwebaze-Songa P, et al
. Predictors of long-term viral failure among Ugandan children and adults treated with antiretroviral therapy. J Acquir Immune Defic Syndr 2007; 46:187–193.
57. Bannister WP, Ruiz L, Cozzi-Lepri A, Mocroft A, Kirk O, Staszewski S, et al
. Comparison of genotypic resistance profiles and virological response between patients starting nevirapine and efavirenz in EuroSIDA. AIDS 2008; 22:367–376.
58. MacArthur RD, Novak RM, Peng G, Chen L, Xiang Y, Hullsiek KH, et al
. A comparison of three highly active antiretroviral treatment strategies consisting of nonnucleoside reverse transcriptase inhibitors, protease inhibitors, or both in the presence of nucleoside reverse transcriptase inhibitors as initial therapy (CPCRA 058 FIRST Study): a long-term randomised trial. Lancet 2006; 368:2125–2135.
59. Riddler SA, Haubrich R, DiRienzo AG, Peeples L, Powderly WG, Klingman KL, et al
. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 2008; 358:2095–2106.
60. Sow PS, Otieno LF, Bissagnene E, Kityo C, Bennink R, Clevenbergh P, et al
. Implementation of an antiretroviral access program for HIV-1-infected individuals in resource-limited settings: clinical results from 4 African countries. J Acquir Immune Defic Syndr 2007; 44:262–267.
61. Antiretroviral therapy for HIV infection in adults and adolescents in resource-limited settings: towards universal access. Recommendations for a public health approach.
Geneva: World Health Organization; 2006.
62. WHO. Global price reporting mechanism (GPRM).
Geneva: WHO; 2007.
63. Huffam SE, Srasuebkul P, Zhou J, Calmy A, Saphonn V, Kaldor JM, Ditangco R. Prior antiretroviral therapy experience protects against zidovudine-related anaemia. HIV Med 2007; 8:465–471.
64. Toeung PD, Pouv S, Chel S, Huffam S, Khol V, Bun V, et al. Routine switch after 6 months from d4t to AZT containing antiretroviral therapy, at an outpatient HIV clinic in Phnom Penh, Cambodia. Proceedings of the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
; 22–25 July 2007; Sydney.
65. Gayet-Ageron A, Ananworanich J, Jupimai T, Chetchotisakd P, Prasithsirikul W, Ubolyam S, et al
. No change in calculated creatinine clearance after tenofovir initiation among Thai patients. J Antimicrob Chemother 2007; 59:1034–1037.
66. Peters P, Moore D, Mermin J, Brooks J, Downing R, Were W, et al. Renal function improves among Ugandans on NNRTI-based HAART: 24-Month follow-up from the home-based AIDS care program in rural Uganda. Proceedings of the 14th Conference on Retrovirsuses and Opportunistic Infections
; 25–28 February 2007; Los Angeles.
67. Landman R, Descamps D, Peytavin G, Trylesinski A, Katlama C, Girard PM, et al
. Early virologic failure and rescue therapy of tenofovir, abacavir, and lamivudine for initial treatment of HIV-1 infection: TONUS study. HIV Clin Trials 2005; 6:291–301.
68. Khanlou H, Yeh V, Guyer B, Farthing C. Early virologic failure in a pilot study evaluating the efficacy of therapy containing once-daily abacavir, lamivudine, and tenofovir DF in treatment-naive HIV-infected patients. AIDS Patient Care STDS 2005; 19:135–140.
69. Moyle G, Higgs C, Teague A, Mandalia S, Nelson M, Johnson M, et al
. An open-label, randomized comparative pilot study of a single-class quadruple therapy regimen versus a 2-class triple therapy regimen for individuals initiating antiretroviral therapy. Antivir Ther 2006; 11:73–78.
70. DART. Virological response to a triple nucleoside/nucleotide analogue regimen over 48 weeks in HIV-1-infected adults in Africa. AIDS
71. Munderi P, Walker S, Kityo C, Kallebu P, Ssali F, Lyagoba F, et al. Discordance between virological/immunological and clinical outcomes at 48 weeks, in a randomised comparison of ZDV/3TC/NVP and ZDV/3TC/ABC in 600 patients with low CD4 counts in Africa. Proceedings of the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
; 22–25 July 2007; Sydney.
72. Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, et al
. Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr 2007; 46:125–133.
73. Saag M, Ive P, Heera J, Tawadrous M, DeJesus E, Clumeck N, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine [ZDV]/lamivudine [3TC]), for the treatment of antiretroviral naive patients infected with R5 HIV 1: week 48 results of the MERIT study. Proceedings of the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
; 22–25 July 2007; Sydney.
74. Johnston ER, Zijenah LS, Mutetwa S, Kantor R, Kittinunvorakoon C, Katzenstein DA. High frequency of syncytium-inducing and CXCR4-tropic viruses among human immunodeficiency virus type 1 subtype C-infected patients receiving antiretroviral treatment. J Virol 2003; 77:7682–7688.
75. Connell B, Michler K, Capovilla A, Venter W, Stevens W, Papathanasopoulos M. Emergence of X4 usage among HIV-1 subtype C: evidence for an evolving epidemic in South Africa. AIDS 2008; 22:896–899.
76. Goebel F, Yakovlev A, Pozniak AL, Vinogradova E, Boogaerts G, Hoetelmans R, et al
. Short-term antiviral activity of TMC278: a novel NNRTI – in treatment-naive HIV-1-infected subjects. AIDS 2006; 20:1721–1726.
77. Nieuwkerk PT, Oort FJ. Self-reported adherence to antiretroviral therapy for HIV-1 infection and virologic treatment response: a meta-analysis. J Acquir Immune Defic Syndr 2005; 38:445–448.
78. Mills EJ, Nachega JB, Buchan I, Orbinski J, Attaran A, Singh S, et al
. Adherence to antiretroviral therapy in sub-Saharan Africa and North America: a meta-analysis. JAMA 2006; 296:679–690.
79. Mills EJ, Nachega JB, Bangsberg DR, Singh S, Rachlis B, Wu P, et al
. Adherence to HAART: a systematic review of developed and developing nation patient-reported barriers and facilitators. PLoS Med 2006; 3:e438.
80. Simoni JM, Pearson CR, Pantalone DW, Marks G, Crepaz N. Efficacy of interventions in improving highly active antiretroviral therapy adherence and HIV-1 RNA viral load. A meta-analytic review of randomized controlled trials. J Acquir Immune Defic Syndr 2006; 43(Suppl 1):S23–S35.
81. Louis C, Ivers LC, Smith Fawzi MC, Freedberg KA, Castro A. Late presentation for HIV care in central Haiti: factors limiting access to care. AIDS Care 2007; 19:487–491.
82. Zachariah R. Comment on: Community support is associated with better antiretroviral treatment outcomes in a resource-limited rural district in Malawi. Trans R Soc Trop Med Hyg 2007; 101:627–628.
83. Van Griensven J, Corthouts A, Att E, Alonso J. Validity of WHO-recommended immunological criteria for treatment failure. The 2007 HIV/AIDS Implementers' Meeting
; 16–19 June 2007; Kigali.
84. An S, Koole O, Haverkamp M, Sculier D, Thai S, Lynen L. Predictors of virological failure in a Cambodian setting: findings from a cross-sectional study at Sihanouk Hospital Centre of HOPE, Phnom Penh. Proceedings of the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
; 22–25 July 2007; Sydney, Australia.
85. Meya D, Tibenderana H, John L, Spacek L, Namugga I, Magero S, et al. Evaluation of clinical and laboratory parameters to predict viral response to ART in Uganda. Proceedings of the 14th Conference on Retroviruses and Opportunistic Infections
; 25–28 February 2007; Los Angeles.
86. Bisson GP, Gross R, Strom JB, Rollins C, Bellamy S, Weinstein R, et al
. Diagnostic accuracy of CD4 cell count increase for virologic response after initiating highly active antiretroviral therapy. AIDS 2006; 20:1613–1619.
87. Moore DM, Mermin J, Awor A, Yip B, Hogg RS, Montaner JS. Performance of immunologic responses in predicting viral load suppression: implications for monitoring patients in resource-limited settings. J Acquir Immune Defic Syndr 2006; 43:436–439.
88. Grabar S, Le MV, Goujard C, Leport C, Kazatchkine MD, Costagliola D, Weiss L. Clinical outcome of patients with HIV-1 infection according to immunologic and virologic response after 6 months of highly active antiretroviral therapy. Ann Intern Med 2000; 133:401–410.
89. Tuboi SH, Brinkhof MW, Egger M, Stone RA, Braitstein P, Nash D, et al
. Discordant responses to potent antiretroviral treatment in previously naive HIV-1-infected adults initiating treatment in resource-constrained countries: The Antiretroviral Therapy in Low-Income Countries (ART-LINC) Collaboration. J Acquir Immune Defic Syndr 2007; 45:52–59.
90. Ferradini L. Clinico-immunological criteria for the detection of virological failures. Implications for the use of viral load in Cambodia. Proceedings of the 1st Phnom Penh Symposium on HIV Medicine
; 14–15 September 2006; Phnom Penh.
91. Chaiwarith R, Wachirakaphan C, Kotarathititum W, Praparatanaphan J, Sirisanthana T, Supparatpinyo K. Sensitivity and specificity of using CD4+ measurement and clinical evaluation to determine antiretroviral treatment failure in Thailand. Int J Infect Dis 2007; 11:413–416.
92. Badri M, Lawn SD, Wood R. Usefulness of CD4 cell count changes in predicting virological failure in patients receiving HAART in a resource-poor setting. Proceedings of the 14th Conference on Retroviruses and Opportunistic Infections
; 25–28 February 2007; Los Angeles.
93. Hosseinipour M, van Oosterhout J, Weigel R, Mzigangira D, Saukila N, Mhango B, et al. Validating clinical and immunological definitions of antiretroviral treatment failure in Malawi. Proceedings of the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
; 25–28 February 2007; Sydney.
94. Cardiello P, Pertraro P, Chalamilla G, Tharakan J. Does use of viral load result enhance accuracy in defining first line ARV failure? Proceedings of the HIV/AIDS Implementers Meeting
; 12–15 June 2006; Durban.
95. Haubrich RH, Currier JS, Forthal DN, Beall G, Kemper CA, Johnson D, et al
. A randomized study of the utility of human immunodeficiency virus RNA measurement for the management of antiretroviral therapy. Clin Infect Dis 2001; 33:1060–1068.
96. Gazzard B, Bernard AJ, Boffito M, Churchill D, Edwards S, Fisher N, et al
. British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2006). HIV Med 2006; 7:487–503.
97. Hammer SM, Saag MS, Schechter M, Montaner JS, Schooley RT, Jacobsen DM, et al
. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society–USA panel. JAMA 2006; 296:827–843.
98. Phillips AN, Pillay D, Miners AH, Bennett DE, Gilks CF, Lundgren JD. Outcomes from monitoring of patients on antiretroviral therapy in resource-limited settings with viral load, CD4 cell count, or clinical observation alone: a computer simulation model. Lancet 2008; 371:1443–1451.
99. Coutinho A, Mermin J, Ekwaru J, Were W, Bunnell R, Kaharuza F, et al. Utility of routine viral load, CD4 cell count, and clinical monitoring among HIV-infected adults in Uganda: a randomized trial. Proceedings of the 15th Conference on Retroviruses and Opportunistic Infections
; 3–6 February 2008; Los Angeles.
101. Development of AntiRetroviral Therapy in Africa. A randomised trial of monitoring practice and structured treatment interruptions in the management of antiretroviral therapy in adults with HIV infection in Africa. http://www.controlled-trials.com/ISRCTN13968779/
. [Accessed 16 May 2008]
102. Fiscus SA, Cheng B, Crowe SM, Demeter L, Jennings C, Miller V, et al
. HIV-1 viral load assays for resource-limited settings. PLoS Med 2006; 3:e417.
103. Calmy A, Ford N, Hirschel B, Reynolds SJ, Lynen L, Goemaere E, et al
. HIV viral load monitoring in resource-limited regions: optional or necessary? Clin Infect Dis 2007; 44:128–134.
104. Vijayaraghavan A, Efrusy MB, Mazonson PD, Ebrahim O, Sanne IM, Santas CC. Cost-effectiveness of alternative strategies for initiating and monitoring highly active antiretroviral therapy in the developing world. J Acquir Immune Defic Syndr
105. Le MV, Thiebaut R, Chene G, Leport C, Cailleton V, Michelet C, et al
. Predictors of long-term increase in CD4+ cell counts in human immunodeficiency virus-infected patients receiving a protease inhibitor-containing antiretroviral regimen. J Infect Dis 2002; 185:471–480.
106. Tenorio AR, Smith KY, Kuritzkes DR, Sha BE, Donoval B, Young R, et al
. HIV-1-infected antiretroviral-treated patients with prolonged partial viral suppression: clinical, virologic, and immunologic course. J Acquir Immune Defic Syndr 2003; 34:491–496.
107. Ledergerber B, Lundgren JD, Walker AS, Sabin C, Justice A, Reiss P, et al
. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes. Lancet 2004; 364:51–62.
108. Raffanti SP, Fusco JS, Sherrill BH, Hansen NI, Justice AC, D'Aquila R, et al
. Effect of persistent moderate viremia on disease progression during HIV therapy. J Acquir Immune Defic Syndr 2004; 37:1147–1154.
109. Deeks SG, Barbour JD, Grant RM, Martin JN. Duration and predictors of CD4 T-cell gains in patients who continue combination therapy despite detectable plasma viremia. AIDS 2002; 16:201–207.
110. Murri R, Lepri AC, Cicconi P, Poggio A, Arlotti M, Tositti G, et al
. Is moderate HIV viremia associated with a higher risk of clinical progression in HIV-infected people treated with highly active antiretroviral therapy: evidence from the Italian cohort of antiretroviral-naive patients study. J Acquir Immune Defic Syndr 2006; 41:23–30.
111. Duncombe C, Kerr SJ, Ruxrungtham K, Dore GJ, Law MG, Emery S, et al
. HIV disease progression in a patient cohort treated via a clinical research network in a resource limited setting. AIDS 2005; 19:169–178.
112. Grabar S, Le MV, Goujard C, Egger M, Leport C, Kazatchkine MD, et al
. Response to highly active antiretroviral therapy at 6 months and long-term disease progression in HIV-1 infection. J Acquir Immune Defic Syndr 2005; 39:284–292.
113. Riddler SA, Jiang H, Tenorio A, Huang H, Kuritzkes DR, Acosta EP, et al
. A randomized study of antiviral medication switch at lower- versus higher-switch thresholds: AIDS Clinical Trials Group Study A5115. Antivir Ther 2007; 12:531–541.
114. Aleman S, Soderbarg K, Visco-Comandini U, Sitbon G, Sonnerborg A. Drug resistance at low viraemia in HIV-1-infected patients with antiretroviral combination therapy. AIDS 2002; 16:1039–1044.
115. Bangsberg DR, Charlebois ED, Grant RM, Holodniy M, Deeks SG, Perry S, et al
. High levels of adherence do not prevent accumulation of HIV drug resistance mutations. AIDS 2003; 17:1925–1932.
116. Kantor R, Shafer RW, Follansbee S, Taylor J, Shilane D, Hurley L, et al
. Evolution of resistance to drugs in HIV-1-infected patients failing antiretroviral therapy. AIDS 2004; 18:1503–1511.
117. Kristiansen TB, Pedersen AG, Eugen-Olsen J, Katzenstein TL, Lundgren JD. Genetic evolution of HIV in patients remaining on a stable HAART regimen despite insufficient viral suppression. Scand J Infect Dis 2005; 37:890–901.
118. Hatano H, Hunt P, Weidler J, Coakley E, Hoh R, Liegler T, et al
. Rate of viral evolution and risk of losing future drug options in heavily pretreated, HIV-infected patients who continue to receive a stable, partially suppressive treatment regimen. Clin Infect Dis 2006; 43:1329–1336.
119. Cozzi-Lepri A, Phillips AN, Ruiz L, Clotet B, Loveday C, Kjaer J, et al
. Evolution of drug resistance in HIV-infected patients remaining on a virologically failing combination antiretroviral therapy regimen. AIDS 2007; 21:721–732.
120. Napravnik S, Edwards D, Stewart P, Stalzer B, Matteson E, Eron JJ Jr. HIV-1 drug resistance evolution among patients on potent combination antiretroviral therapy with detectable viremia. J Acquir Immune Defic Syndr 2005; 40:34–40.
121. Youle M. Overview of boosted protease inhibitors in treatment-experienced HIV-infected patients. J Antimicrob Chemother 2007; 60:1195–1205.
122. Hogg RS, Bangsberg DR, Lima VD, Alexander C, Bonner S, Yip B, et al
. Emergence of drug resistance is associated with an increased risk of death among patients first starting HAART. PLoS Med 2006; 3:e356.
123. Joly V, Descamps D, Peytavin G, Touati F, Mentre F, Duval X, et al
. Evolution of human immunodeficiency virus type 1 (HIV-1) resistance mutations in nonnucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1-infected patients switched to antiretroviral therapy without NNRTIs. Antimicrob Agents Chemother 2004; 48:172–175.
124. Koval CE, Dykes C, Wang J, Demeter LM. Relative replication fitness of efavirenz-resistant mutants of HIV-1: correlation with frequency during clinical therapy and evidence of compensation for the reduced fitness of K103N + L100I by the nucleoside resistance mutation L74V. Virology 2006; 353:184–192.
125. Sungkanuparph S, Manosuthi W, Kiertiburanakul S, Piyavong B, Chumpathat N, Chantratita W. Options for a second-line antiretroviral regimen for HIV type 1-infected patients whose initial regimen of a fixed-dose combination of stavudine, lamivudine, and nevirapine fails. Clin Infect Dis 2007; 44:447–452.
126. Seyler C, Adje-Toure C, Messou E, Dakoury-Dogbo N, Rouet F, Gabillard D, et al
. Impact of genotypic drug resistance mutations on clinical and immunological outcomes in HIV-infected adults on HAART in West Africa. AIDS 2007; 21:1157–1164.
127. Durant J, Clevenbergh P, Halfon P, Delgiudice P, Porsin S, Simonet P, et al
. Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomised controlled trial. Lancet 1999; 353:2195–2199.
128. Tural C, Ruiz L, Holtzer C, Schapiro J, Viciana P, Gonzalez J, et al
. Clinical utility of HIV-1 genotyping and expert advice: the Havana trial. AIDS 2002; 16:209–218.
129. Sax PE, Islam R, Walensky RP, Losina E, Weinstein MC, Goldie SJ, et al
. Should resistance testing be performed for treatment-naive HIV-infected patients? A cost-effectiveness analysis. Clin Infect Dis 2005; 41:1316–1323.
130. Weinstein MC, Goldie SJ, Losina E, Cohen CJ, Baxter JD, Zhang H, et al
. Use of genotypic resistance testing to guide HIV therapy: clinical impact and cost-effectiveness. Ann Intern Med 2001; 134:440–450.
131. Sendi P, Gunthard HF, Simcock M, Ledergerber B, Schupbach J, Battegay M. Cost-effectiveness of genotypic antiretroviral resistance testing in HIV-infected patients with treatment failure. PLoS ONE 2007; 2:e173.
132. Shafer RW. Rationale and uses of a public HIV drug-resistance database. J Infect Dis 2006; 194(Suppl 1):S51–S58.
133. Fox ZV, Geretti AM, Kjaer J, Dragsted UB, Phillips AN, Gerstoft J, et al
. The ability of four genotypic interpretation systems to predict virological response to ritonavir-boosted protease inhibitors. AIDS 2007; 21:2033–2042.
134. Chaix ML, Rouet F, Tony TD, Danel C, Moh R, Gabillard D, et al. Low rate of resistance to ARV drugs 6 months after HAART initiation in HIV-1-infected sub-Saharan African: The ANRS 1269 TRIVACAN trial. Proceedings of the 14th Conference on Retroviruses and Opportunistic Infections
; 25–28 February 2007; Los Angeles.
135. Spacek LA, Shihab HM, Kamya MR, Mwesigire D, Ronald A, Mayanja H, et al
. Response to antiretroviral therapy in HIV-infected patients attending a public, urban clinic in Kampala, Uganda. Clin Infect Dis 2006; 42:252–259.
136. Fischer A, Karasi JC, KiRi D, Omes C, Lambert C, Uwayitu A, et al
. Antiviral efficacy and resistance in patients on antiretroviral therapy in Kigali, Rwanda: the real-life situation in 2002. HIV Med 2006; 7:64–66.
137. Ramadhani HO, Thielman NM, Landman KZ, Ndosi EM, Gao F, Kirchherr JL, et al
. Predictors of incomplete adherence, virologic failure, and antiviral drug resistance among HIV-infected adults receiving antiretroviral therapy in Tanzania. Clin Infect Dis 2007; 45:1492–1498.
138. Ferradini L, Laureillard D, Prak N, Ngeth C, Fernandez M, Pinoges L, et al
. Positive outcomes of HAART at 24 months in HIV-infected patients in Cambodia. AIDS 2007; 21:2293–2301.
139. Wallis CL, Mahomed I, Morris L, Chidarikire T, Stevens G, Rekhviashvili N, Stevens W. Evaluation of an oligonucleotide ligation assay for detection of mutations in HIV-1 subtype C individuals who have high level resistance to nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors. J Virol Methods 2005; 125:99–109.
140. Grossman Z, Paxinos EE, Averbuch D, Maayan S, Parkin NT, Engelhard D, et al
. Mutation D30N is not preferentially selected by human immunodeficiency virus type 1 subtype C in the development of resistance to nelfinavir. Antimicrob Agents Chemother 2004; 48:2159–2165.
141. Pillay D, Walker AS, Gibb DM, De Rossi A, Kaye S, Ait-Khaled M, et al
. Impact of human immunodeficiency virus type 1 subtypes on virologic response and emergence of drug resistance among children in the Paediatric European Network for Treatment of AIDS (PENTA) 5 trial. J Infect Dis 2002; 186:617–625.
142. Humphreys EH, Hernandez LB, Rutherford GW. Antiretroviral regimens for patients with HIV who fail first-line antiretroviral therapy. Cochrane Database Syst Rev 2007:CD006517.
143. Deeks SG, Hoh R, Neilands TB, Liegler T, Aweeka F, Petropoulos CJ, et al
. Interruption of treatment with individual therapeutic drug classes in adults with multidrug-resistant HIV-1 infection. J Infect Dis 2005; 192:1537–1544.
144. Castagna A, Danise A, Menzo S, Galli L, Gianotti N, Carini E, et al
. Lamivudine monotherapy in HIV-1-infected patients harbouring a lamivudine-resistant virus: a randomized pilot study (E-184V study). AIDS 2006; 20:795–803.
145. Wei X, Liang C, Gotte M, Wainberg MA. Negative effect of the M184V mutation in HIV-1 reverse transcriptase on initiation of viral DNA synthesis. Virology 2003; 311:202–212.
146. Johnson M, Grinsztejn B, Rodriguez C, Coco J, DeJesus E, Lazzarin A, et al
. 96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS 2006; 20:711–718.
147. Madruga JV, Berger D, McMurchie M, Suter F, Banhegyi D, Ruxrungtham K, et al
. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet 2007; 370:49–58.
148. De Luca A, Di Giambenedetto S, Romano L, Gonnelli A, Corsi P, Baldari M, et al
. Frequency and treatment-related predictors of thymidine-analogue mutation patterns in HIV-1 isolates after unsuccessful antiretroviral therapy. J Infect Dis 2006; 193:1219–1222.
149. Cozzi-Lepri A, Ruiz L, Loveday C, Phillips AN, Clotet B, Reiss P, et al
. Thymidine analogue mutation profiles: factors associated with acquiring specific profiles and their impact on the virological response to therapy. Antivir Ther 2005; 10:791–802.
150. Flandre P, Descamps D, Joly V, Meiffredy V, Tamalet C, Izopet J, et al
. Predictive factors and selection of thymidine analogue mutations by nucleoside reverse transcriptase inhibitors according to initial regimen received. Antivir Ther 2003; 8:65–72.
151. Turner D, Brenner BG, Routy JP, Petrella M, Wainberg MA. Rationale for maintenance of the M184v resistance mutation in human immunodeficiency virus type 1 reverse transcriptase in treatment experienced patients. New Microbiol 2004; 27:31–39.
152. Rey D, Krebs M, Partisani M, Hess G, Cheneau C, Priester M, et al
. Virologic response of zidovudine, lamivudine, and tenofovir disoproxil fumarate combination in antiretroviral-naive HIV-1-infected patients. J Acquir Immune Defic Syndr 2006; 43:530–534.
153. Garcia-Lerma JG, MacInnes H, Bennett D, Reid P, Nidtha S, Weinstock H, et al
. A novel genetic pathway of human immunodeficiency virus type 1 resistance to stavudine mediated by the K65R mutation. J Virol 2003; 77:5685–5693.
154. Margot NA, Lu B, Cheng A, Miller MD. Resistance development over 144 weeks in treatment-naive patients receiving tenofovir disoproxil fumarate or stavudine with lamivudine and efavirenz in Study 903. HIV Med 2006; 7:442–450.
155. Gonzales MJ, Wu TD, Taylor J, Belitskaya I, Kantor R, Israelski D, et al
. Extended spectrum of HIV-1 reverse transcriptase mutations in patients receiving multiple nucleoside analog inhibitors. AIDS 2003; 17:791–799.
156. Chappell BJ, Margot NA, Miller MD. Long-term follow-up of patients taking tenofovir DF with low-level HIV-1 viremia and the K65R substitution in HIV-1 RT. AIDS 2007; 21:761–763.
157. Frankel FA, Invernizzi CF, Oliveira M, Wainberg MA. Diminished efficiency of HIV-1 reverse transcriptase containing the K65R and M184V drug resistance mutations. AIDS 2007; 21:665–675.
158. White KL, Chen JM, Feng JY, Margot NA, Ly JK, Ray AS, et al
. The K65R reverse transcriptase mutation in HIV-1 reverses the excision phenotype of zidovudine resistance mutations. Antivir Ther 2006; 11:155–163.
159. Brenner BG, Oliveira M, Doualla-Bell F, Moisi DD, Ntemgwa M, Frankel F, et al
. HIV-1 subtype C viruses rapidly develop K65R resistance to tenofovir in cell culture. AIDS 2006; 20:F9–F13.
160. Wallis CL, Bell C, Boulme R, Sanne I, Venter F, Papathanasopoulos M, Stevens W. Emerging ART drug resistance in subtype C: experience from the 2 clinics in Johannesburg, South Africa. Proceedings of the 14th Conference on Retroviruses and Opportunistic Infections
; 25–28 February 2007; Los Angeles.
161. Hall CS, Raines CP, Barnett SH, Moore RD, Gallant JE. Efficacy of salvage therapy containing ritonavir and saquinavir after failure of single protease inhibitor-containing regimens. AIDS 1999; 13:1207–1212.
162. Tebas P, Patick AK, Kane EM, Klebert MK, Simpson JH, Erice A, et al
. Virologic responses to a ritonavir: saquinavir-containing regimen in patients who had previously failed nelfinavir. AIDS 1999; 13:F23–F28.
163. de Mendoza C, Valer L, Ribera E, Barreiro P, Martin-Carbonero L, Ramirez G, Soriano V. Performance of six different ritonavir-boosted protease inhibitor-based regimens in heavily antiretroviral-experienced HIV-infected patients. HIV Clin Trials 2006; 7:163–171.
164. Clotet B, Bellos N, Molina JM, Cooper D, Goffard JC, Lazzarin A, et al
. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet 2007; 369:1169–1178.
165. Prioritizing second-line antiretroviral drugs for adults and adolescents: a public health approach. Report of a WHO Working Group Meeting
. Geneva: World Health Organization; 2007.
166. Arribas JR, Pulido F, Delgado R, Lorenzo A, Miralles P, Arranz A, et al
. Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study). J Acquir Immune Defic Syndr 2005; 40:280–287.
167. Swindells S, DiRienzo AG, Wilkin T, Fletcher CV, Margolis DM, Thal GD, et al
. Regimen simplification to atazanavir-ritonavir alone as maintenance antiretroviral therapy after sustained virologic suppression. JAMA 2006; 296:806–814.
168. Delfraissy JF, Flandre P, Delaugerre C, Ghosn J, Horban A, Girard PM, et al
. Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV-infected patients. AIDS 2008; 22:385–393.
169. Flandre P, Delaugerre C, Ghosn J, Chaix ML, Horban A, Girard PM, et al. Prognostic factors of virological success in antiretroviral-naive patients receiving LPV/r monotherapy in the MONARK trial. Proceedings of the 11th European AIDS Conference
; 24–27 October 2007; Madrid.
170. Hellinger J, Cohen C, Morris A, Sheble-Hall S, Gordon D, Foy C, et al
. Pilot study of saquinavir and lopinavir/ritonavir twice daily in protease inhibitor-naive HIV-positive patients. HIV Clin Trials 2005; 6:107–117.
171. Staszewski S, Babacan E, Stephan C, Haberl A, Carlebach A, Gute P, et al
. The LOPSAQ study: 48 week analysis of a boosted double protease inhibitor regimen containing lopinavir/ritonavir plus saquinavir without additional antiretroviral therapy. J Antimicrob Chemother 2006; 58:1024–1030.
172. Ribera E, Azuaje C, Lopez RM, Diaz M, Feijoo M, Pou L, et al
. Atazanavir and lopinavir/ritonavir: pharmacokinetics, safety and efficacy of a promising double-boosted protease inhibitor regimen. AIDS 2006; 20:1131–1139.
173. Boyd M, Mootsikapun P, Burger D, Chuenyam T, Ubolyam S, Mahanontharit A, et al
. Pharmacokinetics of reduced-dose indinavir/ritonavir 400/100 mg twice daily in HIV-1-infected Thai patients. Antivir Ther 2005; 10:301–307.
174. Konopnicki D, De Wit S, Poll B, Crommentuyn K, Huitema A, Clumeck N. Indinavir/ritonavir-based therapy in HIV-1-infected antiretroviral therapy-naive patients: comparison of 800/100 mg and 400/100 mg twice daily. HIV Med 2005; 6:1–6.
175. Murphy RL, Brun S, Hicks C, Eron JJ, Gulick R, King M, et al
. ABT-378/ritonavir plus stavudine and lamivudine for the treatment of antiretroviral-naive adults with HIV-1 infection: 48-week results. AIDS 2001; 15:F1–F9.
176. Sanne I, Piliero P, Squires K, Thiry A, Schnittman S. Results of a phase 2 clinical trial at 48 weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr 2003; 32:18–29.
177. Ananworanich J, Hirschel B. Intermittent therapy for the treatment of chronic HIV infection. AIDS 2007; 21:123–134.
178. Maggiolo F, Ripamonti D, Gregis G, Quinzan G, Callegaro A, Suter F. Effect of prolonged discontinuation of successful antiretroviral therapy on CD4 T cells: a controlled, prospective trial. AIDS 2004; 18:439–446.
179. Cooper D, Gatell J, Rockstroh J, Katlama C, Yeni P, Lazzarin A, et al. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Proceedings of the 14th Conference on Retrovirsuses and Opportunistic Infections
; 25–28 February 2007; Los Angeles.
180. Zolopa A, Mullen M, Berger D, Ruane P, Hawkins T, Zhong L, et al. The HIV integrase inhibitor GS-9137 demonstrates potent antiretroviral activity in treatment-experienced patients. Proceedings of the 14th Conference on Retrovirsuses and Opportunistic Infections
; 25–28 February 2007; Los Angeles.
181. Gulick RM, Van der Ryst E, Lampiris H, Fatkenheuer G, Raffi F, Lalezari J, et al. Efficacy and safety of once-daily (QD) compared with twice-daily (BID) maraviroc plus optimized background therapy (OBT) in treatment-experienced patients infected with CCR5-tropic-HIV-1: 24-week combined analysis of the MOTIVATE 1 and 2 studies. Proceedings of the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
; 22–25 July 2007; Sydney.
182. Van der Ryst E, Cooper D, Konourina I, Saag M, Goodrich J, Tawadrous M, et al. Efficacy of Maraviroc in combination with at least one other potent new antiretroviral drug: 24-week combined analysis of the MOTIVATE 1 and 2 studies. Proceedings of the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
; 22–25 July 2007; Sydney.
183. Gulick RM, Su Z, Flexner C, Hughes MD, Skolnik PR, Wilkin TJ, et al
. Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-infected, treatment-experienced patients: AIDS clinical trials group 5211. J Infect Dis 2007; 196:304–312.
184. Cahn P, Schuermann D, Reuss F, Wit F, Boehm E, Lange J. A phase-II study of 14 days monotherapy with the nucleoside-analogue Fosalvudine Tidoxil in treatment-naive HIV-1 infected adults. Proceedings of the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
; 22–25 July 2007; Sydney.
185. Madruga JV, Cahn P, Grinsztejn B, Haubrich R, Lalezari J, Mills A, et al
. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007; 370:29–38.
186. Phillips AN, Leen C, Wilson A, Anderson J, Dunn D, Schwenk A, et al
. Risk of extensive virological failure to the three original antiretroviral drug classes over long-term follow-up from the start of therapy in patients with HIV infection: an observational cohort study. Lancet 2007; 370:1923–1928.
187. Treating 3 million by 2005: making it happen: The WHO Strategy
. Geneva: World Health Organization; 2003.
188. Nunn AS, Fonseca EM, Bastos FI, Gruskin S, Salomon JA. Evolution of antiretroviral drug costs in Brazil in the context of free and universal access to AIDS treatment. PLoS Med 2007; 4:e305.
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antiretroviral therapy; adherence; HIV drug resistance; treatment failure; treatment monitoring; resource limited settings
© 2008 Lippincott Williams & Wilkins, Inc.
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