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European Review for Medical and Pharmacological Sciences 2012; 16: 10-18 Positioning of HIV-protease inhibitors in clinical practice M. ANDREONI, C.F. PERNO Department of Public Health and Cell Biology, School of Medicine, University of Rome Tor Vergata, Rome (Italy) Abstract. – The availability of more than 20 drugs for the treatment of HIV infection, and the success of the current antiretroviral regimens, should not overlook the difficulty of longterm maintaining the control of viral replication. The therapy needs to be continued for decades, if not for lifetime, and there are clear evidences that, even in patients fully suppressed for many years, HIV starts again its replication cycles in case antiviral pressure is removed. The development of resistance is a natural event at the time of virological failure, that needs to be taken into account in the global strategy against HIV in each particular patient. Taking all together, therapeutic regiments must be embedded, since the beginning, in a long-term strategy whose main task is the stable control of the replication of HIV. To do so, the choice of the first antiviral regimen has to be highly appropriate to keep the virus in check, and at the same time maintain future therapeutic options. Change of therapy at the time of failure has to be also appropriate, in term of timing, diagnostic strategy, and selection of drugs. Under these circumstances, the use of protease inhibitors in the first line acquires a strong rationale, that balances the greater pure potency of non-nucleoside reverse transcriptase inhibitors (NNRTI), and makes them a valuable options for many patients that need to start antiviral therapy. Key Words: HIV, Protease inhibitors, Antiviral therapy, Virus replication, Resistance. Introduction The primary goal of HIV-1 antiretroviral therapy is to extend maximal viral suppression for the longest possible time (ideally lifetime), to prevent HIV progression and AIDS complications, and maintain patients in good health. 10 Prospects for long-term virus suppression depend greatly on the choice of initial therapy. The preferred first regimen consists, today in the large majority of cases, of two reverse transcriptase inhibitors (NRTI) and either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI) (the choice of an integrase inhibitor represents a rare event today, despite the great efficacy and low toxicity of this class, mostly because of the higher costs). These regimens are highly effective in suppressing HIV-1 RNA to less than 50 copies/mL (“undetectable”) within the first 24 weeks in most patients who reliably take medications. Based on the substantial clinical data demonstrating efficacy, potency, and tolerability of these regimens, they have been designated as “preferred” for initial treatment in most of the current international and national guidelines. Virological Failure Despite the excellent performance of today’s antiretroviral regimens, a small but consistent minority of patients fail to achieve and/or to maintain viral replication below the level of detection of common methods for the evaluation of viral load (usually 50 copies/ml, sometimes 40). Reasons for virologic failure include lack of adherence, toxicity, suboptimal virologic activity, and genetic resistance (mostly linked, in first line regimens, to the acquisition of resistant strains from treated, failing patients). The goal of subsequent therapy in patients with antiretroviral experience is then to restore maximum virologic suppression. In the past the perception was that complete virological suppression could be not achievable in highly advanced-, resistant-patients. Therefore, the goals of therapy were mostly directed to preserve immune function and to prevent clinical disease progression. Today this approach is no longer considered acceptable, and complete suppression of virus replication stands as the gold standard at Corresponding Author: Massimo Andreoni, MD; e-mail: [email protected] Positioning of HIV-protease inhibitors in clinical practice all stages of the disease, in all types of patients. This result is even more achievable today, when the number of multiresistant-, highly advancedpatients is shrinking, and the large majority of failing patients have low viral load virus or, at worst, had failed therapy with limited appearance of mutations conferring resistance to one or two class (thus leaving options for all the others). This is particularly true if the diagnosis of virological failure is made early, that is when the virus rebounds, or shortly after having defined that viral load has not properly fallen to undetectable levels. Early definition of failure, and the consequent rapid change of therapy, helps in reducing the chances of development of full blown resistance, and consequently the therapeutic options remained available. Therefore, one of the cornerstones of today’s antiviral therapy is the rapid definition of virological failure, and a similarly rapid therapy change. Patients should never remain in a failing regimen more than just the time required for a proper diagnostic assessment; they should never be suggested, indirectly or directly, to maintain such failing regimen, even if they like it. Indeed, it is true that the driving force of therapeutic decision is the agreement of patient and doctor in choosing the best option for each patient, though this should never let doctors choose therapy on the basis of what patient likes most, if the doctor is not fully convinced about the quality of the therapy prescribed. The responsibility remains in the hands of the doctors, and the consequent decisions taken stand on their side. There is another class of failing patients, that is those that fail therapy with high/very high viral load. In the large majority, these patients do not take properly antivirals; therefore, the virological failure occurs usually without any mutation conferring resistance. In these circumstances, the chances of achieving undetectable virus are nearly identical to those at the time of first treatment, provided that the patient takes properly the new therapy. It is then clear that we today are in an optimal position to define a correct strategy aimed at keeping viral replication under long-term control, either in first line, or in subsequent lines of therapy.This is because we have many different drugs available, and the damage at the time of first virological failures is usually limited, if properly handled. The application of appropriate drug sequencing strategies will help preserving suppressive options over time. Long-Term Strategies to Protect Next-Line Regimens The long-term efficacy and durability of second-line and salvage regimens depends mostly on preserving NRTI activity within the first regimen1. Not as a paradox, the best ways to preserving next regimens are both the maintenance of a maximal viral suppression (HIV RNA less than 50 copies/mL) for the longest period of time, and the improvement of immune function. Initial regimens should then be chosen on the basis of superior efficacy, potency, tolerability, and durability. Not only do these criteria promote optimal clinical outcome, but they also help limiting the emergency of resistance. Resistance to antivirals is one of the primary reasons for treatment failure. It occurs when mutations conferring resistance to antivirals appear in the genome of HIV. In order to do so, HIV must be in replicative cycling. In other words, non-replicating HIV (because kept fully under control of antivirals) cannot evolve and develop mutations. Therefore, one necessary (though not sufficient) condition for the development of resistance is the presence of ongoing replicative cycles of HIV (Figure 1)2. During such replicative cycles, resistance mutations emerge due to viral replication errors: HIV indeed replicates rapidly and is highly prone to error. On average, 10 billion HIV particles are produced and cleared every day, with one new mutation introduced, on average, in each new virus genome (mutation rate of 10-4) in the untreated patient3,4. Antiretroviral drugs by themselves do not cause resistance, but provide the selective pressure that, in conditions of incomplete control of virus replication, favours emergency of drug-resistance mutations able to decrease the sensitivity to drugs. When selected under antiviral pressure, these drug-resistant strains, over time tend to substitute wild-type virus, and ultimately predominate. As a collateral event, such mutated strain may be resistant also to other drugs of the same class. This phenomenon, called cross-resistance, may burn an entire class through the development of single mutations directed toward a single drug. This is the case of TAMs (Thymidine-associated mutations) that, selected under the pressure only of AZT and d4T, do cause cross-resistance to the entire class of NRTI (with a minor exception of 3TC and FTC). Similarly, mutations selected under nevirapine or efavirenz burn both drugs of this NNRTI class, and may affect, at least some of 11 M. Andreoni, C.F. Perno Figure 1. Selection of resistant virus under pharmacological pressure. (From DD Richman, mod.)2. them, also the second generation NNRTI such as etravirine and rilpivirine. Finally, mutations for raltegravir cross-react with elvitegravir (Integrase inhibitor not-yet in the market) and some of them affect also dolutegravir (another very promising drug of the same class of integrase inhibitors). In other words, intra-class cross-resistance is an expected phenomenon, that may burn many drugs, despite not yet being used. Cross-resistance is a phenomenon that needs to be avoided as much as possible in clinical practice. Resistance and Adherence What is the best condition for the development of resistance. As another (only apparent) paradox, the optimal situation for the development of resistance is the suboptimal suppression of viral replication. As mentioned above, the drug-induced, complete suppression of viral lifecycle excludes the possibility of developing mutations and resistance. At the same time, just at the opposite, the complete absence of antiviral pressure let virus replicate freely, and so resistant viral strains, being usually characterized by a fitness lower than wild type, do not emerge. This emergency occurs only when an incomplete antiviral pressure, sufficient to eliminate wild type virus, let virus replicate enough to generate and select a viral strain that is resistant to such drugs. Under these conditions, these mutations are expected to emerge quite rapidly, also at low viral load. How do conditions of incomplete viral suppression occur in clinical practice? While many factors may play a role in this game (erratic ab12 sorption by the gut, drug-drug interactions, improper dosage and combination of drugs, lack of booster, etc), the major cause is the lack of complete adherence to prescribed drugs. Suboptimal adherence reduces the ability to suppress virus and accelerates the emergence of resistant strains5-7. There are different levels of non-adherence associated for each class to the development of resistance, nevertheless it has been calculated that leaving adherence to levels lower than 85% represents a condition that highly favours the development of resistance for all classes8. In practice, this means that forgetting only one out of six doses (that is, one daily dose in a week or so) is already a potentially dangerous condition! This brings again the issue of adherence as a top factor in the maintenance of virological success, and the avoidance of resistance development. Therapeutic Sequencing The process of applying knowledge of resistance patterns to the selection of initial and subsequent therapy, better known as “sequencing,” begins with the recommended choices for initial and subsequent therapy. These choices are indicated based on efficacy, tolerability and safety, convenience, and disease stage. From this point of view, an early initiation of therapy in the natural history of infection may have several advantages: earlier suppression of viral replication, preservation of immune function, prolongation of disease-free survival, lower risk of resistance with complete viral suppression and decreased risk of HIV transmission. Positioning of HIV-protease inhibitors in clinical practice Protease inhibitor (PI)-based regimens have demonstrated virologic potency, durability, and high barriers to resistance. In patients who experience virologic failure during their first PI-based regimen, few or no PI mutations are detected at failure. So, despite the fact that each PI has its own virologic potency, adverse effect profile, and pharmacokinetic properties, in case of failure of a first regimen containing a boosted PI, all PIs behave similarly in preventing the accumulation of mutations. This is mostly driven by the so called “high genetic barrier”, that makes virus less prone to develop mutations to these drugs, since many mutations (and not a single one, as it is for NNRTIs) are required to make virus fully resistant to a PI (Figure 2)9,10. This result also suggests that, under conditions of first line therapy, in the majority of cases all commonly used PIs are sufficient to warrant therapeutic success, provided that there are appropriate companion drugs, that the adherence to therapy is proper, and that the choice of drugs takes into proper account potential drug-drug interactions. In selecting a boosted PI-based regimen for a treatment-naïve patient, clinicians should consider factors such as dosing frequency, food requirements, pill burden, daily ritonavir dose, drug interaction potential, baseline hepatic function, toxicity profile of the individual PI, and pregnancy status. A number of metabolic abnormalities, including dyslipidemia and insulin resistance, have been associated with PI use. The currently available PIs differ in their propensity to cause these metabolic complications, which are also dependent on the dose of ritonavir used as a pharmacokinetic boosting agent. These complications may result in adverse long-term consequences, such as increased cardiovascular events. The potent inhibitory effect of ritonavir on the cytochrome P450 3A4 isoenzyme has allowed the addition of low-dose ritonavir to other PIs (with the exception of nelfinavir) as a pharmacokinetic booster to increase drug exposure and prolong plasma half-lives of the active PI. This allows for reduced dosing frequency and/or pill burden, which may improve overall adherence to the regimen. The increased trough concentration (Cmin) may improve the antiretroviral activity of the active PI, which can be beneficial when the patient harbors HIV strains with reduced susceptibility to the PI11-13, and also may contribute to the lower risk of resistance upon virologic failure compared to unboosted PIs. In the case of ritonavir-boosted darunavir (800/100 mg once daily) and atazanavir (300/100 mg once daily), there are large numbers of headto-head trials demonstrating non inferiority or superiority compared with lopinavir/ritonavir, with less gastrointestinal and lipid toxicity. Ritonavir boosting of atazanavir, given as a total of two pills once daily, enhances the concentrations of atazanavir and improves virologic activity compared with unboosted atazanavir in a clinical trial 14] The CASTLE study compared once-daily atazanavir/ritonavir with twice-daily lopinavir/ritonavir, each in combination with tenofovir/emtricitabine, in 883 antiretroviral- Figure 2. Genetic barriers of NNRTI and protease inhibitors. (From AD Luber; DA Katzenstein, mod.)9,10. 13 M. Andreoni, C.F. Perno naïve participants. In this open-label, noninferiority study, analysis at 48 weeks 15 and at 96 weeks16 showed similar virologic and CD4 T-cell count responses of the two regimens. More hyperbilirubinemia and less gastrointestinal toxicity were seen in the ritonavir-boosted atazanavir arm. This study supports the designation of boosted atazanavir in combination with tenofovir/emtricitabine as a preferred regimen in most international guidelines. The ARTEMIS study compared darunavir/ritonavir (800/100 mg once daily, three pills per day) with lopinavir/ritonavir (once or twice daily), both in combination with tenofovir/emtricitabine, in a randomized, open-label, noninferiority trial. The study enrolled 689 treatment-naïve participants who had a median CD4 count of 225 cells/mm3 and a median plasma HIV RNA level of 4.85 log10 copies/mL. At 48 weeks, darunavir/ ritonavir was non-inferior to lopinavir/ritonavir (p < 0.001). The virologic response rates were lower in the lopinavir/ritonavir arm among those participants whose baseline HIV RNA levels were > 100,000 copies/mL (p < 0.05). Grades 2 to 4 adverse events, primarily diarrhea, were seen more frequently in lopinavir/ritonavir recipients (p < 0.01)17. At 96 weeks, virologic response to darunavir/ritonavir was superior to response to lopinavir/ritonavir (p = 0.012). It should be said that the study was not designed for superiority, so straight conclusions need to taken with great caution at this time18 (Figure 3). The KLEAN trial compared twice-daily ritonavir-boosted fosamprenavir with lopinavir/ritonavir, each in combination with abacavir and lamivudine, in treatment-naïve patients. At weeks 48 and 144, similar percentages of subjects achieved viral loads of < 400 copies/mL19,20. Clinical and laboratory adverse events did not differ between the regimens. In this study of treatment-naïve participants, twice-daily ritonavir-boosted fosamprenavir was noninferior to twice-daily lopinavir/ritonavir. Metabolic adverse effects occurred at similar frequencies with boosted fosamprenavir as with lopinavir/ritonavir in the KLEAN study. Figure 3. Boosted PIs in ARV-Naive Pts: virologic suppression at Wk48. (From JM Molina et al; R Ortiz et al; J Jr Eron et al; S Walmsley et al, mod.)15,17,19,23. 14 Positioning of HIV-protease inhibitors in clinical practice Lopinavir/ritonavir is the only available coformulated boosted PI. In Italian guidelines it is indicated, such as atazanavir/ritonavir and darunavir/ritonavir, as a first choice of protease inhibitor for the third agent for the initial therapy21. However, the need for 200 mg/day of ritonavir, and the higher rate of gastrointestinal side effects and hyperlipidemia when compared with boosted PIs using ritonavir 100 mg/day, make it, in DHHS guidelines22, an alternative rather than preferred PI for PI-naïve patients. Nevertheless, several clinical trials show that regimens containing twice-daily lopinavir/ritonavir with two NRTIs have virologic activity in treatment-naïve patients. Finally, the GEMINI study compared saquinavir/ritonavir (1,000/100 mg twice daily) with lopinavir/ritonavir, both given twice daily, in combination with tenofovir/emtricitabine given once daily, in 337 treatment-naïve participants who were monitored over 48 weeks. Similar levels of viral suppression (64.7% vs. 63.5%) and increases in CD4 counts were seen in both arms 23. Triglyceride levels were significantly higher in the lopinavir/ritonavir arm. The higher pill burden (6 pills per day), need for twice-daily dosing, and use of 200mg of ritonavir make (at best) ritonavir-boosted saquinavir at best an alternative PI for treatment-naive patients, despite the fact that recent EACS guidelines do not discriminate between PIs, provided that there are non-inferiority, comparative data supporting such choice. Protease Inhibitors for Therapeutic Sequencing These results support a number of thoughts. The first, is that protease inhibitors represent a valid option in first line therapy of HIV-infected patients. The second, potency is crucial for the achievement of remarkable success, but, in first line therapy, all major PIs seem to behave similarly; this is an indirect sign that their intrinsic potency is on average sufficient to achieve virological success at this stage of the disease. The third, is that PIs represent an important option for sequencing, if one of the major objectives of first line therapy is to maintain viable all therapeutic choices also in case of virological failure. Indeed, the lack of mutations in the protease at the time of failure is an event that has been confirmed in many trials and observational studies beside those described in this article. In addition, when combined with NRTIs, the use of PIs markedly decreases also the rate of mutations in reverse transcriptase, limiting them to a number of M184Vs (typical of 3TC or FTC) that remains far lower than that detected at the time of failure of NNRTI-based regimens (Figure 4)24. Taken together, the high genetic barrier of PIs represents a hurdle that the virus has difficulties to overcome. Thus, potential failures of 1st lines based on PIs still leave all therapeutic options available. The full drugs availability represents today, as it will be for the future, one of the most important conditions to maintain the virus under control for decades. From these points of view atazanavir offers several characteristics that favour initial use, including once-daily administration, little or no adverse effects on blood lipids, and a distinctive resistance profile. The antiviral activity of atazanavir has been established in treatmentnaive and treatment-experienced patients25-28. The genotypic resistance to atazanavir is rare. The signature resistance mutation selected by atazanavir is I50 L, which has been detected in isolates from patients treated with unboosted atazanavir, and in multifailing patients; its detection in patients failing first-line regimen including boosted atazanavir is a rare (or even absent!) event. Of note, mutations I50L is irrelevant for the large majority of the other PIs and, if something, in-vitro phenotypic susceptibility to other PIs may be enhanced in the presence of I50 L. By contrast, atazanavir, as other PIs, looses efficacy when general primary PIs mutation accumulate under the pressure of other PIs. Therefore, PI-mutations need to be avoided in all cases in which this is possible (that is, rapid change of failing regimens)29,30. Conclusions The goal of antiretroviral drug sequencing is to maintain suppressive treatment options over the patient’s life span. This goal can be accomplished in several ways: Early treatment (CD4+ cell count >350 cells/mm3) with a maximally suppressive regimen. A widely accepted initial regimen includes 2 NRTI/NtRTIs with an NNRTI or a PI. Current international guidelines offer specific examples of preferred and alternate regimens. In addition to virological activity, factors such as tolerability and adherence must also be considered when se15 M. Andreoni, C.F. Perno Figure 4. Resistance is significantly lower in patients starting ritonavir-boosted protease inhibitors versus NNRTI-countaing regimen. (From R Gupta et al, mod.)24. lecting the first regimen. Primary resistance testing (genotype more than phenotype) is always advisable, and may be particularly crucial in areas with a high rate of primary resistance. Selection of antiviral treatment based on drug resistance profile is essential to maintaining optimal response to therapy. Studies have shown the relative benefit of genotype- and phenotypeguided treatment decisions compared with choosing HAART regimens arbitrarily based on prior treatment history31-36. If results of resistance testing at the time of virological failure, indicate resistance to one or more drugs, the regimen should be changed as soon as possible, to one that includes as many active drugs as possible. All other measures to ensure optimal virological response must be considered: tolerability, patient preference, adherence, etc. This paper describes several strategies to maximize suppressive options over the continuum of 16 HIV care, using NRTI backbone and NNRTI- or PI-based regimens for the cornerstone. New treatment options, such as the integrase inhibitor or CCR5 inhibitor, and strategies, such as induction maintenance, may extend the potential for maximal and durable viral suppression. References 1) LANGE J. 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Long-term clinical efficacy of resistance testing: results of the CERT trial. Antivir Ther 2002; 7: S129. Abstract 158. PEREZ-ELIAS MJ, GARCIA-ARATA I, MORENO S, MUNOZ V, SANTOS J, SANZ J, ABRAIRA V, ARRIBAS JR, GONZALES J, D RONDA F, A NTELA A, M ORENO A, C ASADO JL, PUMARES M, MARTÌ-BELDA P, GEIJO P AND THE REALVIRFEN STUDY GROUP. Baseline testing information given by a real phenotype (real Ph) or a virtual phenotype (virtual Ph) test in a randomized study (Realvirfen study): influence in final outcome. Antivir Ther 2002; 7: S89. Abstract 109.