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Clinical implications of fixed-dose coformulations of antiretrovirals on the outcome of HIV-1 therapy

Llibre, Josep M.a; Arribas, José R.b; Domingo, Perec; Gatell, Josep M.d; Lozano, Fernandoe; Santos, José R.a; Rivero, Antoniof; Moreno, Santiagog; Clotet, Bonaventuraathe Spanish Group for FDAC Evaluation

doi: 10.1097/QAD.0b013e3283499cd9

The substitution by generic equivalents of some of the drugs included in fixed-dose antiretroviral coformulations (FDACs) poses the potential risk of disrupting these combinations and administering the components separately in order to incorporate the new generic drug, which offers a more competitive sales price. This may represent a step backwards in the advances achieved in simplicity and adherence to therapy, posing an increased risk of selective noncompliance of some of the separately administered drug substances. Available antiretroviral drugs must be administered for life in the affected individuals – both children and adults. The FDACs represent a significant advance in the simplification of antiretroviral therapy, facilitating adherence to complex and chronic treatments, and contributing to a quantifiable improvement in patient quality of life. These drug coformulations reduce the risk of treatment error, are associated with a lower risk of hospitalization, and can lessen the possibility of covert monotherapy in situations of selective noncompliance. Thus, FDACs can reduce the risk of selection of HIV-1 resistances, which not only adversely affect the treatment options of the individual patient but also constitute a public health problem, and further increase the cost and complexity of therapy. With the exception of those cases requiring dose adjustments, the preferential use of FDACs should be recommended for the treatment of HIV-1 infection in those situations when the agents included in the coformulation are drugs of choice.

aLluita Contra la SIDA Foundation, University Hospital Germans Trias i Pujol, Badalona

bHospital Universitario La Paz, Madrid

cHospital Sant Pau, Barcelona

dHospital Clinic, IDIBAPS, Barcelona

eHospital Universitario de Valme, Sevilla

fHospital Reina Sofía, Córdoba

gHospital Ramón y Cajal, Madrid, Spain.

Correspondence to Josep M. Llibre, Fundació Lluita contra la SIDA, Hospital Universitari Germans Trias i Pujol, Ctra de Canyet s/n, 08916 Badalona, Spain. Tel: +34 934978887; e-mail:

Received 2 February, 2011

Revised 12 May, 2011

Accepted 7 June, 2011

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HIV-1 infection causes gradual destruction of host cellular immunity, and persistent activation of the entire immune system and associated nonspecific inflammatory mechanisms. It is a world pandemic, one of the main public health problems worldwide since the late 20th century, and also probably the most significant success story in modern medicine [1–5]. Antiretroviral drugs administered in effective combinations persistently suppress HIV-1 replication, allow gradual recovery of the CD4+ T-lymphocyte counts, and reduce patient morbidity and mortality [6–8]. In sum, these treatments are able to revert the ominous prognosis of HIV-1 disease and restore patient survival and quality of life to almost normal longevity, with a radical change in the clinical spectrum of the illness [2,9,10]. Likewise, the control of HIV-1 replication drastically reduces the risk of transmission to the general population, and avoids vertical transmission to the offspring of infected mothers [11–16].

Antiretroviral therapy (ART) represents one of the strategies with favorable cost–efficacy ratios in the healthcare systems of the Western world [5,17–21]. The consensus guides on ART developed in different countries by government organizations and national and international scientific societies are continuously subjected to revision – updating and optimizing the ideal timing for starting therapy, the optimum first-choice combinations, and many other aspects related to ART [22–27].

It presently can be firmly stated that in countries with universal public healthcare coverage and free access to ART, HIV-1 infection detected on time is a treatable chronic disease allowing patients to lead lives similar in all aspects to those of noninfected persons, including occupational activity [1].

Individually replacing a drug with a usually less expensive generic equivalent is a generally accepted practice when drug protection by patent rights runs out. However, in the Western world the introduction of generic equivalents of some of the drugs included in fixed-dose antiretroviral coformulations (FDACs), or of generic equivalents presumed to have characteristics similar to those of some of the drugs included in FDACs [like emtricitabine (FTC) and lamivudine (3TC)], poses the potential risk of disrupting these combinations and administering the components separately in order to incorporate the new generic drug which offers a more competitive sales price. This may represent a step backwards in the advances achieved in simplicity and adherence to therapy, with an additional risk of selective noncompliance of some of the separately administered drugs, treatment failure, and selection of HIV-1 variants resistant to antiretroviral agents [28–31].

On the contrary, local approval in certain centers or countries of the possibility of disrupting FDACs may imply significant healthcare disparities with access to different levels of excellence in ART, administered on the basis of economy-oriented criteria depending on the geographical area of residency.

The present study reviews the existing knowledge on the importance of FDACs in ART.

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Implications of long-term antiretroviral treatment

Whereas the cure is still seemingly impossible for a retroviral infection, ART must be administered for life in the affected individuals [32]. Success of ART requires constant patient adherence to treatment regimens that are often complex and with possible adverse effects over the short and long term.

The evaluation of different controlled treatment interruption strategies failed to demonstrate clinical benefits, and treatment interruption moreover was found to be associated with an increase in opportunistic diseases and other disorders associated with the proinflammatory state derived from uncontrolled HIV-1 replication [4,33–35]. Therefore, it is likewise not possible to reduce the economical cost or toxicity of ART by administering it intermittently [36,37].

Unlike other treatable chronic conditions (e.g. arterial hypertension, type 2 diabetes mellitus or hypercholesterolemia), in which the ultimate control achieved after several years depends on the total period of time for which the patient has undergone correct treatment, irregular adherence to ART for only a few weeks may lead to definitive loss of efficacy of the treatment provided, selection of resistance to the drugs administered, and even cross-resistance to other drugs which the patient has not received [13,38]. For this reason, the long-term morbidity and mortality of HIV-1 infection does not only depend on ‘average’ adherence over the entire course of ART, but on the resistance selected during the periods of patient noncompliance [39]. This represents one of the most difficult aspects to control in the chronic management of this disease.

Antiretroviral drug resistance implies loss of treatment options, requires more complex, expensive and toxic rescue therapies, and can be transmitted [38,40]. At present, 10–14% of the treated population in Europe is infected with HIV-1 strains resistant to some antiretroviral agents [41–43].

Optimized virological control of the HIV-1-infected population therefore ultimately results in a lesser risk of transmission of resistant strains, and thus better response rates in recently infected individuals who start ART [40]. For this reason, once effective ART is made freely available and at no cost, sustained patient adherence to such treatment is the key factor for preventing failure.

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Factors related to adherence to antiretroviral therapy

Long-term adherence to ART is of utmost importance for long-term outcomes and has been extensively investigated for years. The presence of psychiatric problems, active substance abuse, poverty, low educational level, comorbidities, frequency of doses, number of tablets, and short-term or long-term toxicity of ART are all significantly related to inadequate adherence [23,25,44]. Not surprisingly, adherence and type of treatment were the modifiable factors most strongly associated with survival [45,46].

It should be stressed that not only the percentage of missed doses is important, but also the suboptimal adherence patterns involved. In effect, treatment interruptions (defined as more than 2 days without taking any drug) have a greater impact upon virological response than occasional failure to take a dose, depending on the regimen involved [39,47]. On the contrary, improved adherence results in lower associated global economical costs, and is also significantly associated with a lower risk of hospitalization [19].

For this reason, all HIV units worldwide have focused on improving adherence to ART, with implication of the nursing personnel, psychologists and pharmacists of the different centers in the effort. Likewise, in the different consensus documents on ART, the chapter addressing the optimization of treatment compliance has become particularly important [23–25].

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The use of fixed-dose drug combinations: the model represented by other treatable chronic diseases

A reduction in the number of different containers and medicines which the patient must control, and in the number of daily doses and tablets, results in improved adherence to therapy in chronic diseases requiring combined treatments [48]. Such reduction lessens the risk of error and the possibility of incomplete adherence to the regimen due to selective noncompliance.

As an example, most patients with arterial hypertension require combined treatments involving several drugs. Consequently, the American Society of Hypertension favors the use of fixed-dose drug combinations (FDCs) as a practical need to improve adherence in chronic treatments, reducing the risk of error in following therapy [48].

An infectious disease requiring prolonged treatment is an example much more similar to HIV-1 infection, and in this sense tuberculosis has been the closest model. The use of FDC not only affords convenience and improves adherence but also prevents the patient from self-administering monotherapy with any of the individual drugs – thereby avoiding the selection of resistance [49]. For many years, the scientific societies working on the treatment of tuberculosis have actively promoted the use of FDCs of antituberculous drugs, and have requested the authorities and even stimulated the drug companies to increase their production and diffusion [50,51]. Even in those situations when dose adjustments may be required, the use of a FDC is recommended, associated with the drug supplement needed for dose adjustment, with a view to avoiding covert monotherapy and the selection of resistance, which represent a genuine public healthcare problem. The WHO and the International Union Against Tuberculosis and Lung Disease presently recommend the use of FDCs as an additional measure to guarantee optimum treatment and avoid the selection and spread of drug-resistant strains of Mycobacterium tuberculosis [52] – designing specific programs to ensure that these FDCs are of high quality in their manufacture.

A recent meta-analysis has evaluated the efficacy of FDCs in nine randomized studies on the treatment of different diseases, such as hypertension (n = 4), tuberculosis (n = 2), diabetes mellitus (n = 2) and HIV-1 infection (n = 1). Lastly, the use of FDCs afforded a 26% reduction in the risk of treatment noncompliance with respect to administration of the same drugs separately [relative risk (RR) 0.74; 95% confidence interval (CI) 0.69–0.80, P < 0.0001] [53]. There is therefore no doubt that FDCs improve adherence to therapy in chronic illnesses that require combined treatments – though there is still uncertainty regarding the magnitude of such improvement and its impact upon therapeutic efficacy [54].

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The use of fixed-dose antiretroviral coformulations in HIV-1 infection

Research by the pharmaceutical industry has contributed to improve adherence to ART, by lowering the daily pill count, and developing drugs with pharmacokinetic/dynamic characteristics that allow once-daily administration, as well as dosing in FDACs.

Different studies have demonstrated patient preference for treatments involving a single daily dose and as few tablets as possible [30,55]. A recent meta-analysis of 11 controlled clinical trials (involving a total of 3029 patients) has confirmed that adherence is greater with single daily dosing regimens than with two daily doses (P = 0.003) [30]. Likewise, many studies have reported improved overall quality of life and better adherence to therapy in patients who are able to simplify their ART to a single daily tablet – retaining the same virological and immunological efficacy [30,31,56,57]. This improvement has been documented independently of whether the patients were receiving treatment based on non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors [31]. Such findings have been documented in patients receiving efavirenz (EFV), tenofovir (TDF), and FTC or 3TC in a single dose but administered separately, and who changed to a single FDAC with the same compounds [56]. On the contrary, adherence to ART and percentage of virological response were also greater with a regimen involving a single tablet once daily, in a cohort of marginally housed patients with baseline factors that made adherence particularly problematic [29]. Indeed, patients receiving TDF, FTC and EFV as one pill daily are more likely to maintain the regimen after 1 year than patients receiving the same regimen as two pills a day [58]. Thus, simplicity importantly affects outcomes of chronic therapies. The risk factors associated in multivariate analysis with ART modification during the first year of treatment were months since HIV-1 diagnosis, existence of prior AIDS-defining conditions, and not receiving a coformulated ART [58,59].

In fact, the massive use of FDACs has been correlated to an increase in regimen persistence and a decrease in the prevalence of antiretroviral drug resistance mutations in the period 2003–2008, and even to a decrease in those mutations specifically related to the drugs included in such combinations (K65R and M184V/I), although a causal relationship has not been established [59,60]. Thus, FDACs, by preventing partial noncompliance and hidden monotherapy, could reduce the risk of development of HIV-1 drug resistance.

Moreover, patients who received their ART as a once-daily single-tablet regimen were significantly more likely to be highly adherent to therapy and were associated with a lower risk of hospitalization compared to patients on two or more pills per day regimens, even though the study could not assess causality [61].

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Pairs of nucleoside reverse transcriptase inhibitors coformulated in fixed-dose antiretroviral coformulations: importance of pharmacokinetic homogeneity of the included drugs

When a FDAC is designed, it must meet a series of criteria in order to ensure its long-term efficacy. The coformulated drugs must not present similar or additive toxicities or require individual dose adjustments, and their pharmacokinetic profile must be concordant. This latter condition refers not only to frequency of administration but also to the elimination half-life (t 1/2), which is a pivotal factor when the patient fails to take some doses or interrupts ART. Nucleoside reverse transcriptase inhibitor (NRTI) efficacy is correlated to the intracellular levels of the drug (Table 1) [23,25,62–64]. The plasma and intracellular t 1/2 values of FTC are significantly longer than those of 3TC, and more concordant with those of TDF and EFV in the existing coformulation. This point is extremely important for avoiding the selection of resistant mutants in every ART interruption, since the t 1/2 values of the three drugs are overlapped, thus avoiding sequential terminal monotherapy when the concentrations of them drop to below the IC50 of HIV-1, when resistant mutants are easily selected.

Table 1

Table 1

Emtricitabine and 3TC have similar chemical structures, are administered once a day, act on the same target, select the same resistance pathways, and offer similar efficacy in treatment-naïve patients. As a result, both drugs are considered to be interchangeable in some ART guides [23,24]. Thus, even though the table of preferred antiretroviral regimens lists the exact combination used in pivotal trials in which efficacy has been demonstrated, a footnote states that 3TC may substitute for FTC or vice versa [23]. Nevertheless, there are some differences between 3TC and FTC that should be taken into consideration. The IC50 of HIV-1 is usually about 11 times greater for 3TC than for FTC, though the clinical relevance of this fact has not been confirmed, since the plasma or intracellular levels of the drug remain far above the mentioned concentration [65,66]. On the contrary, FTC-triphosphate offers greater (about nine times) efficacy than 3TC-triphosphate in incorporation during RNA-dependent viral DNA synthesis catalyzed by reverse transcriptase [67]. All this would result in a greater maximum polymerization rate and greater affinity for FTC. In fact, in vitro, appearance of the M184V/I mutant occurs earlier in cultures with 3TC than with FTC [68].

Assessing the clinical relevance of these minor differences in vivo in the context of triple regimens is not simple. Nevertheless, in a randomized, double-blind trial comparing 3TC with FTC together with nevirapine (or EFV) and stavudine, and which included 468 naive patients, the M184V/I mutation rate (associated to high resistance to both drugs) was lower with FTC than with 3TC (30 vs. 65% of the virological failures with available genotype, P = 0.01) [66] – though in contrast the virological failure rate was greater with FTC than with 3TC (12.8 vs. 7.3%, P = 0.046) [69].

An in-vitro study involving HIV-1 strains resistant to antiretrovirals without the M184V/I mutation but with thymidine-analog mutations (TAMs), K65R, Q151M or L74I/V, showed cross-resistance to both drugs to be similar in the presence of the K65R, Q151M or L74I/V mutations, though in the presence of TAMs the impact upon phenotypic resistance of FTC was greater than on 3TC (P < 0.001) [70]. However, it is not common in clinical practice to find these mutations without having selected M184V/I.

On the contrary, retrospective analysis of episodes of virological failure revealed a significantly higher resistance rate in regimens with TDF/3TC than with TDF/FTC [71,72]. Interestingly the K65R mutation has been reported in trials in which TDF was combined with 3TC [73], but not with FTC (both used with EFV) [74].

Replacing 3TC with FTC has been shown not to be inferior in a clinical trial, whereas the opposite situation, that is, replacing FTC with 3TC, has not been evaluated [75].

Therefore, although the molecules are similar, 3TC and FTC have differential pharmacokinetic characteristics that do not allow us to rule out the possibility of different resistance rates in the event of virological failure, and the efficacy of replacing FTC with 3TC (particularly in the context of FDAC) remains uncertain. Thus, until adequate studies are carried out, such replacement should be avoided in view of the potential risk involved.

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Positioning of the scientific societies and official organisms in consensus documents regarding the use of fixed-dose antiretroviral coformulations

The following FDACs are now available: zidovudine/3TC, zidovudine/3TC/ABC, ABC/3TC, TDF/FTC, EFV/TDF/FTC, and lopinavir/ritonavir. New coformulations are in the pipeline [74,75].

The North American guides on ART, the CDC, the FDA, and the NIH consider that fixed-dose coformulations offer an important advantage, and that among other factors, the number of tablets and the frequency of dosing are elements on which the choice of ART is to be based [23]. They likewise specifically recommend the use of pairs of coformulated NRTIs (TDF/FTC or ABC/3TC). In turn, the European AIDS Clinical Society specifically recommends the use of these coformulations [24], in the same way as the British guides [26]. The Spanish guides include an important chapter on the simplification of ART [25], recommending the adoption of once-daily regimens whenever possible (level A, maximum level of evidence from randomized studies). Likewise, whenever possible, nucleosides should be coformulated as preferential treatment regimen (level A). The IAS – USA also recommends pairs of NRTIs in coformulation (TDF/FTC or ABC/3TC) in starting therapy [27].

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Fixed-dose antiretroviral coformulations represent a significant advance in the simplification of ART, facilitating adherence to chronic treatments, and contributing to a quantifiable improvement in patient quality of life. The drug coformulations may reduce the risk of treatment error and consequently the possibility of functional monotherapy in situations of selective noncompliance. They therefore may reduce the risk of developing HIV-1 resistance to antiretrovirals. Resistance not only adversely affects the treatment options of the individual patient as well as its cost and complexity, but is transmissible and constitutes a public health concern. Patients receiving ART as a once-daily single-tablet regimen are significantly more likely to be highly adherent to therapy and have a lower risk of hospitalization. With the exception of those cases in which dose adjustment is required, the preferential use of FDACs should be recommended for the treatment of HIV-1 infection in those situations in which the agents included in the coformulation are drugs of choice. Thus, both the authorities and the drug industry must maximize efforts to preserve the use of FDACs when the introduction of a generic equivalent to any of the drugs in the coformulation poses the risk of disrupting the fixed combination and separate administration. However, for the sake of the ART budget, as soon as all components of currently available FDACs become available as generics, FDACs built with them should be pursued.

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Members of the Spanish Group for FDAC Evaluation also include Antonio Antela (Complejo Hospitalario Universitario, Santiago de Compostela, Spain), José López-Aldeguer (Hosp Univ La Fe, Valencia, Spain), José Moltó (Lluita contra la SIDA Fndn, Univ Hosp Germans Trias i Pujol, Badalona, Spain), Celia Miralles (Hosp Xeral, Vigo, Spain), Enrique Ortega (Hosp General Univ, Valencia, Spain), Piedad Arazo (Hosp. Univ. Miguel Servet, Zaragoza, Spain), and Melcior Riera and Concepción Villalonga (Hosp Son Dureta, Palma de Mallorca, Spain).

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Conflicts of interest

J.M.L. has received funding for research or payment for conferences or participation on advisory boards from Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Jansen-Cilag, Merck Sharp & Dohme, Pfizer, Roche, Tibotec and ViiV Healthcare.

J.R.A. has received consulting fees, speaker fees or grant support from Merck, Abbott, Tibotec, Janssen, Gilead, GSK, Pfizer, Biogen, Avexa, BMS.

P.D. has received funding for research or payment for conferences or participation on advisory boards from Abbott Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Janssen Cilag, Merck Sharp & Dohme, Pfizer, Roche and ViiV Healthcare.

J.M.G. has received funding for research or payment for conferences or participation on advisory boards from Boehringer-Ingelheim, Merck Sharp & Dohme, Janssen, Tibotec, Abbott, Tobira, Gilead and ViiV Healthcare.

F.L. has received funding for research or payment for conferences or participation on advisory boards from Abbott Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Janssen Cilag, Merck Sharp & Dohme, Pfizer, Roche and ViiV Healthcare.

J.R.S. has received funding for research or payment for conferences or participation on advisory boards from Abbott, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, and Jansen.

J.L.-A. has received funding for research or payment for conferences or participation on advisory boards from Abbott, Boehringer-Ingelheim, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, Roche, Tibotec and ViiV Healthcare.

C.M. has received funding for research or payment for conferences or participation on advisory boards from Abbott, Bristol-Myers Squibb, Boehringer-Ingelheim, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, Roche, Tibotec and ViiV Healthcare.

E.O. has received funding for research or payment for conferences or participation on advisory boards from Abbott, Bristol-Myers Squibb, Boehringer-Ingelheim, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, Roche, Tibotec and ViiV Healthcare.

P.A. has received funding for research or payment for conferences or participation on advisory boards from Abbott, Bristol-Myers Squibb, Boehringer-Ingelheim, Gilead Sciences, GlaxoSmithKline, Pfizer, Jansen and ViiV Healthcare.

S.M. has received funding for research or payment for conferences or participation on advisory boards from Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Jansen-Cilag, Merck Sharp & Dohme, Pfizer, Roche, Tibotec and ViiV Healthcare.

B.C. has served during the past 2 years as a consultant on advisory boards or participated in speakers’ bureaus or conducted clinical trials with Boehringer-Ingelheim, Abbott, GlaxoSmithKline, Gilead, Janssen, Merck, Shionogi and ViiV.

J.M.L. ideated and drafted the manuscript. All authors reviewed and approved the final document.

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1. van Sighem AI, Gras LA, Reiss P, Brinkman K, de WF. Life expectancy of recently diagnosed asymptomatic HIV-infected patients approaches that of uninfected individuals. AIDS 2010; 24:1527–1535.
2. Hamers FF, Downs AM. The changing face of the HIV epidemic in western Europe: what are the implications for public health policies?. Lancet 2004; 364:83–94.
3. Tien PC, Choi AI, Zolopa AR, Benson C, Tracy R, Scherzer R, et al. Inflammation and mortality in HIV-infected adults: analysis of the FRAM study cohort. J Acquir Immune Defic Syndr 2010; 55:316–322.
4. Kuller LH, Tracy R, Belloso W, De WS, Drummond F, Lane HC, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008; 5:e203.
5. Beck EJ, Harling G, Gerbase S, DeLay P. The cost of treatment and care for people living with HIV infection: implications of published studies. Curr Opin HIV AIDS 2010; 5:215–224.
6. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338:853–860.
7. Palella FJ Jr, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT, et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 2006; 43:27–34.
8. Lohse N, Hansen AB, Pedersen G, Kronborg G, Gerstoft J, Sorensen HT, et al. Survival of persons with and without HIV infection in Denmark. Ann Intern Med 2007; 146:87–95.
9. Llibre JM, Falco V, Tural C, Negredo E, Pineda JA, Munoz J, et al. The changing face of HIV/AIDS in treated patients. Curr HIV Res 2009; 7:365–377.
10. Palella FJ Jr, oria-Knoll M, Chmiel JS, Moorman AC, Wood KC, Greenberg AE, et al. Survival benefit of initiating antiretroviral therapy in HIV-infected persons in different CD4+ cell strata. Ann Intern Med 2003; 138:620–626.
11. Wilson DP, Law MG, Grulich AE, Cooper DA, Kaldor JM. Relation between HIV viral load and infectiousness: a model-based analysis. Lancet 2008; 372:314–320.
12. Sperling RS, Shapiro DE, Coombs RW, Todd JA, Herman SA, McSherry GD, et al. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1996; 335:1621–1629.
13. Bartlett JA, Buda JJ, von SB, Mauskopf JA, Davis EA, Elston R, et al. Minimizing resistance consequences after virologic failure on initial combination therapy: a systematic overview. J Acquir Immune Defic Syndr 2006; 41:323–331.
14. Townsend CL, Cortina-Borja M, Peckham CS, de RA, Lyall H, Tookey PA. Low rates of mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland. AIDS 2008; 22:973–981.
15. Russo G, Lichtner M, Traditi F, Vullo V. Is the time for an AIDS-free new generation different in resource-limited and industrialized countries?. AIDS 2009; 23:293–296.
16. Attia S, Egger M, Muller M, Zwahlen M, Low N. Sexual transmission of HIV according to viral load and antiretroviral therapy: systematic review and meta-analysis. AIDS 2009; 23:1397–1404.
17. Bender MA, Kumarasamy N, Mayer KH, Wang B, Walensky RP, Flanigan T, et al. Cost-effectiveness of tenofovir as first-line antiretroviral therapy in India. Clin Infect Dis 2010; 50:416–425.
18. 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.
19. Nachega JB, Leisegang R, Bishai D, Nguyen H, Hislop M, Cleary S, et al. Association of antiretroviral therapy adherence and healthcare costs. Ann Intern Med 2010; 152:18–25.
20. Simpson KN. Economic modeling of HIV treatments. Curr Opin HIV AIDS 2010; 5:242–248.
21. Freedberg KA, Losina E, Weinstein MC, Paltiel AD, Cohen CJ, Seage GR, et al. The cost effectiveness of combination antiretroviral therapy for HIV disease. N Engl J Med 2001; 344:824–831.
22. Kitahata MM, Gange SJ, Abraham AG, Merriman B, Saag MS, Justice AC, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009; 360:1815–1826.
23. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011; 1-166. Available at Accessed January 16, 2011.
24. EACS Guidelines. Clinical management and treatment of HIV infected adults in Europe. Version 5-2. November 2009. [Accessed 16 January 2011]
25. Panel de expertos de GESIDA y Plan Nacional del SIDA. Documento de consenso de Gesida/Plan Nacional sobre el Sida respecto al tratamiento antirretroviral en adultos infectados por el virus de la inmunodeficiencia humana (Actualización enero 2011).
26. Gazzard BG, Anderson J, Babiker A, Boffito M, Brook G, Brough G, et al. British HIV Association Guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008. HIV Med 2008; 9:563–608.
27. Thompson MA, Aberg JA, Cahn P, Montaner JS, Rizzardini G, Telenti A, et al. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA 2010; 304:321–333.
28. Llibre JM, Antela A, Arribas JR, Domingo P, Gatell JM, Lopez-Aldeguer J, et al. Role of fixed-dose combinations of antiretrovirals in HIV-1 therapy. Enferm Infecc Microbiol Clin 2010; 28:615–620.
29. Bangsberg DR, Ragland K, Monk A, Deeks S. A one-pill, once daily fixed dose combination (FDC) of efavirenz, emtricitabine, and tenofovir disoproxil fumarate (EFV/FTC/TDF) regimen is associated with higher unannounced pill count adherence than nonone pill, once-daily therapy. In 17th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA, USA, February 16–19, 2010. Abstract 510.
30. Parienti JJ, Bangsberg DR, Verdon R, Gardner EM. Better adherence with once-daily antiretroviral regimens: a meta-analysis. Clin Infect Dis 2009; 48:484–488.
31. Dejesus E, Young B, Morales-Ramirez JO, Sloan L, Ward DJ, Flaherty JF, et al. Simplification of antiretroviral therapy to a single-tablet regimen consisting of efavirenz, emtricitabine, and tenofovir disoproxil fumarate versus unmodified antiretroviral therapy in virologically suppressed HIV-1-infected patients. J Acquir Immune Defic Syndr 2009; 51:163–174.
32. Trono D, Van Lint C, Rouzioux C, Verdin E, Barre-Sinoussi F, Chun TW, et al. HIV persistence and the prospect of long-term drug-free remissions for HIV-infected individuals. Science 2010; 329:174–180.
33. 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.
34. Phillips AN, Carr A, Neuhaus J, Visnegarwala F, Prineas R, Burman WJ, et al. Interruption of antiretroviral therapy and risk of cardiovascular disease in persons with HIV-1 infection: exploratory analyses from the SMART trial. Antivir Ther 2008; 13:177–187.
35. Neuhaus J, Jacobs DR Jr, Baker JV, Calmy A, Duprez D, La RA, et al. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis 2010; 201:1788–1795.
36. Hirschel B, Flanigan T. Is it smart to continue to study treatment interruptions?. AIDS 2009; 23:757–759.
37. Ruiz L, Paredes R, Gomez G, Romeu J, Domingo P, Perez-Alvarez N, et al. Antiretroviral therapy interruption guided by CD4 cell counts and plasma HIV-1 RNA levels in chronically HIV-1-infected patients. AIDS 2007; 21:169–178.
38. Llibre JM, Schapiro JM, Clotet B. Clinical implications of genotypic resistance to the newer antiretroviral drugs in HIV-1-infected patients with virological failure. Clin Infect Dis 2010; 50:872–881.
39. Parienti JJ, Ragland K, Lucht F, de la BA, Dargere S, Yazdanpanah Y, et al. Average adherence to boosted protease inhibitor therapy, rather than the pattern of missed doses, as a predictor of HIV RNA replication. Clin Infect Dis 2010; 50:1192–1197.
40. Gill VS, Lima VD, Zhang W, Wynhoven B, Yip B, Hogg RS, et al. Improved virological outcomes in British Columbia concomitant with decreasing incidence of HIV type 1 drug resistance detection. Clin Infect Dis 2010; 50:98–105.
41. Bannister WP, Cozzi-Lepri A, Clotet B, Mocroft A, Kjaer J, Reiss P, et al. Transmitted drug resistant HIV-1 and association with virologic and CD4 cell count response to combination antiretroviral therapy in the EuroSIDA Study. J Acquir Immune Defic Syndr 2008; 48:324–333.
42. Cozzi-Lepri A, Phillips AN, Clotet B, Mocroft A, Ruiz L, Kirk O, et al. Detection of HIV drug resistance during antiretroviral treatment and clinical progression in a large European cohort study. AIDS 2008; 22:2187–2198.
43. Wensing AM, van d V, Angarano G, Asjo B, Balotta C, Boeri E, et al. Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management. J Infect Dis 2005; 192:958–966.
44. Atkinson MJ, Petrozzino JJ. An evidence-based review of treatment-related determinants of patients’ nonadherence to HIV medications. AIDS Patient Care STDS 2009; 23:903–914.
45. Wood E, Hogg RS, Yip B, Harrigan PR, O'Shaughnessy MV, Montaner JS. Effect of medication adherence on survival of HIV-infected adults who start highly active antiretroviral therapy when the CD4+ cell count is 0.200 to 0.350 × 10(9) cells/L. Ann Intern Med 2003; 139:810–816.
46. Garcia de OP, Knobel H, Carmona A, Guelar A, Lopez-Colomes JL, Cayla JA. Impact of adherence and highly active antiretroviral therapy on survival in HIV-infected patients. J Acquir Immune Defic Syndr 2002; 30:105–110.
47. Nachega JB, Hislop M, Dowdy DW, Chaisson RE, Regensberg L, Maartens G. Adherence to nonnucleoside reverse transcriptase inhibitor-based HIV therapy and virologic outcomes. Ann Intern Med 2007; 146:564–573.
48. Gradman AH, Basile JN, Carter BL, Bakris GL, Materson BJ, Black HR, et al. Combination therapy in hypertension. J Am Soc Hypertens 2010; 4:90–98.
49. Moulding T, Dutt AK, Reichman LB. Fixed-dose combinations of antituberculous medications to prevent drug resistance. Ann Intern Med 1995; 122:951–954.
50. Norval PY, Blomberg B, Kitler ME, Dye C, Spinaci S. Estimate of the global market for rifampicin-containing fixed-dose combination tablets. Int J Tuberc Lung Dis 1999; 3 (11 Suppl 3):S292–S300.
51. Aguado JM, Rufi G, García Rodríguez J, Solera J, Moreno S. Tuberculosis. Protocolos Clínicos de la Sociedad Española de Infecciones y Microbiologia Clínica (SEIMC). Protocolo VII. In Disponible en Consultado el 28 de junio de; 2010.
52. Blomberg B, Spinaci S, Fourie B, Laing R. The rationale for recommending fixed-dose combination tablets for treatment of tuberculosis. Bull World Health Organ 2001; 79:61–68.
53. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med 2007; 120:713–719.
54. Connor J, Rafter N, Rodgers A. Do fixed-dose combination pills or unit-of-use packaging improve adherence? A systematic review. Bull World Health Organ 2004; 82:935–939.
55. Laurent C, Kouanfack C, Koulla-Shiro S, Nkoue N, Bourgeois A, Calmy A, et al. Effectiveness and safety of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine in HIV-1-infected adults in Cameroon: open-label multicentre trial. Lancet 2004; 364:29–34.
56. Airoldi M, Zaccarelli M, Bisi L, Bini T, Antinori A, Mussini C, et al. One-pill once-a-day HAART: a simplification strategy that improves adherence and quality of life of HIV-infected subjects. Patient Prefer Adherence 2010; 4:115–125.
57. Hodder SL, Mounzer K, Dejesus E, Ebrahimi R, Grimm K, Esker S, et al. Patient-reported outcomes in virologically suppressed, HIV-1-Infected subjects after switching to a simplified, single-tablet regimen of efavirenz, emtricitabine, and tenofovir DF. AIDS Patient Care STDS 2010; 24:87–96.
58. Perez-Valero I, Martin N, San Jose B, Mora M, Bernardino-Serra J, Gonzalez J, et al. Naïve patients receiving TDF/FTC + EFV (2 pills) are more likely to modify regimen components than patients receiving TDF/FTC/EFV (1 pill). J Intl AIDS Soc 2010; 13 (Suppl 4):122.
59. Bae JW, Guyer W, Grimm K, Altice FL. Medication persistence in the treatment of HIV infection: a review of the literature and implications for future clinical care and research. AIDS 2011; 25:279–290.
60. Guyer B, Miller M, Ho J, Haddad M, Coakley E, McColl D. Trends in HIV-1 resistance mutations and antiretroviral prescription data from 2003–2008. J Managed Care Pharmacy 2010; 16:165.
61. Sax P, Meyers J, Mugavero M, Davis K. Adherence to antiretroviral treatment regimens and correlation with risk of hospitalization among commercially insured HIV patients in the United States. J Intl AIDS Assoc 2010; 13 (Suppl 4):O3.
62. Rousseau FS, Kahn JO, Thompson M, Mildvan D, Shepp D, Sommadossi JP, et al. Prototype trial design for rapid dose selection of antiretroviral drugs: an example using emtricitabine (Coviracil). J Antimicrob Chemother 2001; 48:507–513.
63. Schinazi RF. Assessment of the relative potency of emtricitabine and lamivudine. J Acquir Immune Defic Syndr 2003; 34:243–245.
64. Modrzejewski KA, Herman RA. Emtricitabine: a once-daily nucleoside reverse transcriptase inhibitor. Ann Pharmacother 2004; 38:1006–1014.
65. Feng JY, Anderson KS. Mechanistic studies comparing the incorporation of (+) and (−) isomers of 3TCTP by HIV-1 reverse transcriptase. Biochemistry 1999; 38:55–63.
66. Schinazi RF, Lloyd RM Jr, Nguyen MH, Cannon DL, McMillan A, Ilksoy N, et al. Characterization of human immunodeficiency viruses resistant to oxathiolane-cytosine nucleosides. Antimicrob Agents Chemother 1993; 37:875–881.
67. Hazen R, Lanier ER. Assessment of the relative potency of emtricitabine and lamivudine. J Acquir Immune Defic Syndr 2003; 34:245–246.
68. Ross LL, Parkin N, Gerondelis P, Chappey C, Underwood MR, St Clair MH, et al. Differential impact of thymidine analogue mutations on emtricitabine and lamivudine susceptibility. J Acquir Immune Defic Syndr 2006; 43:567–570.
69. Maserati R, De SA, Uglietti A, Colao G, Di BA, Bruzzone B, et al. Emerging mutations at virological failure of HAART combinations containing tenofovir and lamivudine or emtricitabine. AIDS 2010; 24:1013–1018.
70. Svicher V, Alteri C, Artese A, Forbici F, Santoro MM, Schols D, et al. Different evolution of genotypic resistance profiles to emtricitabine versus lamivudine in tenofovir-containing regimens. J Acquir Immune Defic Syndr 2010; 55:336–344.
71. 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.
72. 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.
73. Benson CA, van der HC, Lamarca A, Haas DW, McDonald CK, Steinhart CR, et al. A randomized study of emtricitabine and lamivudine in stably suppressed patients with HIV. AIDS 2004; 18:2269–2276.
74. German P, Warren D, West S, Hui J, Kearney BP. Pharmacokinetics and bioavailability of an integrase and novel pharmacoenhancer-containing single-tablet fixed-dose combination regimen for the treatment of HIV. J Acquir Immune Defic Syndr 2010; 55:323–329.
75. Ramanathan S, Warren D, Wei L, Kearney BP. Pharmacokinetic boosting of atazanavir with the pharmacoenhancer GS-9350 versus ritonavir. In 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 12–15, 2009. A1-1301.

AIDS; antiretroviral treatment; combined treatment; fixed-dose combinations; human immunodeficiency virus infection; recommendation

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