Protease inhibitor-based antiretroviral therapy in treatment-naive HIV-1-infected patients: the evidence behind the options

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1 J Antimicrob Chemother doi: /jac/dkq130 Protease inhibitor-based antiretroviral therapy in treatment-naive HIV-1-infected patients: the evidence behind the options Susanna Naggie* and Charles Hicks Division of Infectious Diseases, Duke University Medical Center, Durham, NC 27710, USA *Corresponding author. Tel: ; Fax: ; The introduction of protease inhibitors (PIs) to HIV treatment combinations in 1996 has significantly reduced morbidity and mortality due to HIV infection. Since the 1990s, multiple PIs have been approved, with several boosted PI regimens recognized as first-line regimens in antiretroviral therapy (ART)-naive patients. While the current guidelines recommend non-nucleoside reverse transcriptase inhibitor-, PI- and integrase inhibitor-based regimens as equal alternatives in ART-naive patients, there are clearly selected patients for whom PI-based regimens appear to be the best option because of specific toxicity or dosing issues. Due to the multiple options of therapy available for ART-naive patients, providers initiating PI-based ART can individualize therapy based on patient characteristics and needs, including pre-treatment resistance, drug drug interactions, adverse effect profiles and co-morbid conditions. Here, we discuss the current recommendations and recent guidelines, and the evidence available for various PI-based ART regimens in treatment-naive patients. We also discuss adverse effects and the use of PIs in special circumstances. Keywords: antiretroviral therapy, human immunodeficiency virus, acquired immunodeficiency syndrome Introduction The introduction of protease inhibitors (PIs) to HIV treatment combinations [creating the now standard highly active antiretroviral therapy (ART)] in 1996 has significantly reduced morbidity and mortality due to HIV infection. 1 While the goals of treatment have not changed over time, the number of persons receiving therapy and the range of options for initial treatment have expanded. The value of treatment for patients with CD4 counts of,350 cells/mm 3 or with an acquired immune deficiency syndrome (AIDS)-defining illness is well established, while, to date, the data supporting treatment for patients with higher CD4 counts (.350 cells/mm 3 ) are largely observational. 2 7 Nonetheless, recent reports emphasize the burden of non-aids-defining conditions (renal, hepatic and cardiac diseases) in HIV-infected patients as well as the underappreciated association of uncontrolled viral replication and immune activation as a driver of non-aids-associated morbidity and mortality. 8 This, in turn, has generated increased interest in starting ART at higher CD4 counts based on co-morbidities, risk of disease progression, and patient willingness and potential for adherence The goal of antiretroviral therapy is to reduce and maintain plasma HIV-1-RNA below 50 copies/ml Treatment guidelines for ART-naive patients are well defined and supported by the literature Currently recommended initial regimens use combinations of two nucleoside reverse transcriptase inhibitors (NRTIs) and either a non-nucleoside reverse transcriptase inhibitor (NNRTI), a ritonavir-boosted PI or an integrase inhibitor (INSTI). 9 Success rates are highest with initial therapy and diminish with subsequent regimens; thus, providers must be thoughtful in considering when to initiate therapy, what to use, how to manage the risks of drug toxicity and how to maximize the potential for optimal drug adherence. The impact of co-morbid conditions on drug selection and the risk of emergence of viral resistance must also be factored into decision making. Improvements in antiretroviral drugs and in combination ART regimens have facilitated higher rates of treatment success, e.g. ritonavir boosting significantly improves PI drug exposure and drug co-formulations decrease pill burden. These changes translate into a significant improvement in rates of HIV suppression and in CD4 cell count responses to early lines of therapy. Lastly, the availability of new drug classes, including the chemokine co-receptor-5 (CCR5) antagonist maraviroc and the integrase inhibitor raltegravir, has expanded treatment options for HIV-infected patients. Historical perspective on HIV PIs Enzymatic activity of HIV protease is required for the production of infectious virions. HIV PIs were designed to bind the protease enzyme, and prevent the cleavage of the gag and gag/pol polyproteins into functional structural proteins and enzymes. 12 Saquinavir was the first PI to gain approval from the US Food and Drug Administration (FDA), after demonstrating the ability to reduce HIV-RNA and increase CD4 cell counts in patients infected with HIV. 13 Initial studies paired saquinavir with one # The Author Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org 1094

2 JAC or two NRTIs, finding that larger CD4 cell increases and greater HIV-1 viral load reductions resulted from double- and triple-drug combinations. 14 Following the FDA approval of saquinavir in 1995, ritonavir, indinavir and nelfinavir were licensed by the FDA. Among these first four PIs, ritonavir dosed at 600 mg twice daily was found to result in impressive reductions in HIV-1 viral load and concomitant CD4 cell count increases. It was the first PI to demonstrate clinical survival benefit. 15,16 Both indinavir and nelfinavir were studied in combination with zidovudine and lamivudine, demonstrating significant improvements in the surrogate markers HIV-1 viral load and CD4 cell count. 17,18 Long-term follow-up demonstrated durable responses for these triple-drug combination regimens. Studies involving these initial PIs revolutionized HIV management, but the drugs all had significant weaknesses, including poor oral bioavailability (saquinavir), substantial drug drug interactions (ritonavir) and poor to fair tolerability. Indinavir and nelfinavir were relatively well tolerated, with reports of increased quality of life on these regimens, but requirements for dosing at 8 h intervals on an empty stomach (indinavir) and high rates of diarrhoea (nelfinavir) made both drugs suboptimal. As the overall use of PIs expanded, the development of drug resistance and the potential role of low-dose ritonavir to serve as a pharmacological enhancer were soon recognized. Current use of PIs Following the introduction into clinical practice of this first wave of PIs, additional agents (amprenavir, fosamprenavir, atazanavir, darunavir and tipranavir) have become available, and have demonstrated significant efficacy in ART-naive and in ARTexperienced patients. The most recently approved PI, darunavir, has shown excellent activity against the majority of viruses with PI resistance mutations. With this wide range of options for an initial PI-based regimen currently available, providers initiating PI-based ART can individualize therapy based on patient characteristics and needs, including pre-treatment resistance, drug drug interactions, adverse effect profiles and co-morbid conditions. As a class, one of the most notable features of PIs as first-line treatment is the relatively high barrier to the development of resistance, not only to PIs, but also to the backbone nucleosides for those patients who do not fully suppress HIV-RNA. 19 Negative features of PIs as initial therapy include side effects such as gastrointestinal (GI) disturbance, rash, and metabolic abnormalities, e.g. dyslipidaemia and insulin resistance. 20 Body shape changes (especially lipohypertrophy) have also been attributed to PI use. 20 When initiating antiretroviral therapy, individual patient characteristics may favour the use of PI-, NNRTI- or INSTI-based regimens, but there are few direct comparisons between these different treatment options. The AIDS Clinical Trials Group (ACTG) study A-5142 compared three treatment arms: a PI-based regimen, lopinavir/ritonavir plus two NRTIs; an NNRTIbased regimen, efavirenz plus two NRTIs; and an NRTI-sparing regimen of lopinavir/ritonavir in combination with efavirenz. 21 In this study, the PI-based regimen had lower rates of HIV suppression compared with the NNRTI-based treatment, but greater CD4 cell increases were seen in patients on the PI arm. There was also less development of major drug resistance mutations in patients failing PI-based therapy. Thus, PI and NNRTI regimens are both considered reasonable initial therapy in treatment-naive patients. Also, most initial PI-based regimens have now been approved as once-daily treatment regimens, simplifying administration. The majority of PI regimens are now boosted with low-dose ritonavir, an approach with improved pharmacokinetics, but with higher rates of GI symptoms and dyslipidaemias than seen in regimens without ritonavir. There are no clinical trial data comparing INSTI-based regimens with PI-based ones. The presently available INSTI, raltegravir, is currently dosed twice a day, has a relatively low genetic barrier for resistance and there is limited experience with NRTI combinations other than tenofovir/emtricitabine. Nonetheless, raltegravir plus tenofovir/ emtricitabine provided impressive results when compared with tenofovir/emtricitabine plus efavirenz. 22 Per the December 2009 US Department of Health and Human Services Antiretroviral Treatment Guidelines, two PIs are listed among the preferred drugs for initial ART: (i) once-daily dosing of atazanavir/ritonavir; and (ii) once-daily dosing of darunavir/ ritonavir. 9 These recommendations were based on evidence of superior or non-inferior virological efficacy compared with other PI-based regimens, a ritonavir boosting dose of 100 mg per day, once-daily dosing, a low pill count and good tolerability. 9 Other PI regimens are considered to be alternative regimens, which may still be preferred in certain patients, including onceor twice-daily dosing of fosamprenavir/ritonavir, once- or twicedaily dosing of co-formulated lopinavir/ritonavir and once-daily dosing of saquinavir/ritonavir. 9 Unboosted atazanavir is now identified as an acceptable, but less satisfactory, regimen and unboosted fosamprenavir is no longer recommended. Many studies have compared the preferred and alternative PI regimens in treatment-naive patients, with most designed as non-inferiority trials, and most have used lopinavir/ritonavir as the comparator arm. The designation of lopinavir/ritonavir as a preferred PI (and therefore the drug used as the comparator in subsequent trials) was established with the M study, which compared lopinavir/ritonavir with the previously preferred PI, nelfinavir, in treatment-naive patients. 23 Lopinavir/ritonavir was found to have superior virological efficacy, a finding later buttressed by long-term (7 year) efficacy data, with sustained viral suppression demonstrated in ART-naive patients treated with lopinavir/ritonavir and two nucleosides. 24 A follow-up study (M05-730) showed once-daily dosing of lopinavir/ritonavir to be non-inferior to the initial twice-daily dosing regimen. 25,26 Subsequent PI-based treatment studies that have compared lopinavir/ritonavir with other first-line PI-based regimens in ART-naive patients include: KLEAN, fosamprenavir/ritonavir plus abacavir/lamivudine; ARTEMIS, darunavir/ritonavir plus tenofovir/emtricitabine; and CASTLE, atazanavir/ritonavir plus tenofovir/emtricitabine. More recently, a small study comparing fosamprenavir/ritonavir and atazanavir/ritonavir (ALERT) was published (Table 1) The KLEAN study compared twice-daily fosamprenavir/ritonavir with twice-daily lopinavir/ritonavir and found similar treatment responses independent of baseline viral load and CD4 count, with virological failures being uncommon in either arm (6% 7%). 27 The ARTEMIS study compared once-daily darunavir/ritonavir with either twice- or once-daily lopinavir/ritonavir (although,25% of subjects received the once-daily lopinavir/ritonavir dosing regimen). 28 The difference in viral suppression rates between the two treatment arms 1095

3 Table 1. Trials of PI regimens Study name (NRTI backbone) No. of patients Viral suppression (%),,50 HIV-RNA copies/ml Comments KLEAN (ABC/3TC) 878 similar response by VL and CD4 markers fosamprenavir/r 700/100 BID weeks, weeks similar tolerability and lipid parameters lopinavir/r 400/100 BID weeks, weeks ARTEMIS (TDF/FTC) 689 DRV/r favourable response, but not superior darunavir/r 800/100 QD weeks DRV/r improved tolerability and lipid profile lopinavir/r 400/100 BID or 800/200 QD weeks CASTLE (TDF/FTC) 883 similar response between arms by VL strata atazanavir/r 300/100 QD weeks, weeks LPV/r lower viral suppression at low CD4 lopinavir/r 400/100 BID weeks, weeks ATV/r improved tolerability and lipid profile ALERT (TDF/FTC) 106 similar response by VL and CD4 markers fosamprenavir/r 1400/100 QD weeks similar tolerability and lipid profile atazanavir/r 300/100 QD weeks more hyperbilirubinaemia in ATV/r arm ABC, abacavir; 3TC, lamivudine; VL, HIV-1-RNA PCR; PI/r, ritonavir-boosted PI, dosing of each component denoted similarly (e.g. 700/100); BID, twice-daily dosing; QD, once-daily dosing; TDF, tenofovir; FTC, emtricitabine; DRV/r, darunavir with ritonavir boosting; LPV/r, lopinavir with ritonavir boosting; ATV/r, atazanavir with ritonavir boosting. at 48 weeks of follow-up favoured the darunavir/ritonavir regimen, achieving criteria for non-inferiority. The CASTLE study also found once-daily atazanavir/ritonavir to be non-inferior when compared with twice-daily lopinavir/ritonavir. 29 Both groups had lesser rates of viral suppression when pre-treatment HIV-RNA levels were cells/ml (72% 74% versus 81% 82%). Lastly, the ALERT study compared once-daily fosamprenavir/ritonavir with atazanavir/ritonavir with a nucleoside/tide tenofovir/emtricitabine backbone in treatment-naive patients, and found similar virological and CD4 response rates in both arms. 30 Among all patients experiencing virological failure in these studies, only one developed a genotypic PI mutation, confirming the high genetic barrier to resistance recognized for regimens using ritonavir-boosted PIs as initial therapy. Adverse effects As a class, PIs have been particularly associated with several adverse effects, including GI symptoms (such as diarrhoea, nausea and vomiting), dyslipidaemia, insulin resistance and fat redistribution (lipohypertrophy), some of which are wellrecognized risk factors for cardiovascular disease. 21 A 5 year cohort study of metabolic complications associated with prolonged PI exposure (ritonavir, indinavir, nelfinavir, saquinavir and amprenavir) found that PI therapy was associated with a 6-fold higher adjusted incidence rate ratio (IRR) of hypertriglyceridaemia, 2.8-fold higher IRR of hypercholesterolaemia (non-pi regimens had a 2.5-fold higher IRR), 5-fold higher IRR of hyperglycaemia and 5-fold IRR of lipodystrophy, when compared with HIV-infected patients never exposed to PI therapy. 31 The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study is a prospective, multinational, observational study comprising 11 cohorts from 21 countries, which on last analysis included person-years of longitudinal data. 32,33 This study found that there was an increased risk of myocardial infarction associated with increased exposure to certain PIs (lopinavir/ritonavir and indinavir), but not others (nelfinavir and saquinavir). This effect was partly accounted for by dyslipidaemia, but remained significant after adjustment {adjusted relative risk (arr) 1.09 [95% confidence interval (CI), ] and 1.08 (95% CI, ), respectively}. This study found no evidence of such an association with NNRTIs (efavirenz and nevirapine) arr 1.02 (95% CI, ) and 0.97 (95% CI, ), respectively. In addition, this study found the recent use of some NRTIs to also be independently associated with cardiovascular events (abacavir and didanosine), while cumulative exposure of these same drugs did not show the same risk. 33 The variation in cardiac risk noted between different ART classes and even among different PIs may, in part, be due to different mechanistic pathways. For example, the association of PI-based therapy and hyperglycaemia and insulin resistance has been elucidated for several pathways: inhibition of insulinstimulated glucose disposal via the GLUT4 transporter, sterol regulatory element-binding protein (SREBP) processing and adipokine secretion. 34 The impact of various PIs on these mechanisms may differ, as was noted in the study of the inhibition of the GLUT4 transporter, where amprenavir, lopinavir/ritonavir and ritonavir demonstrated more potent glucose uptake inhibition than did atazanavir. 34 While the clinical relevance of any such differences is still uncertain, it is reasonable to consider the metabolic profile of each PI individually when weighing the risk and benefit of initiating a new ART regimen. More data are clearly needed to fully appreciate the implications of these observations to the clinical management of HIV-infected persons. When choosing among the various PI regimens, one important consideration for clinicians is the specific adverse event profile associated with each drug, as there appear to be some differences among the various drugs for characteristics such as GI effects, glucose metabolism and dyslipidaemia. Head-to-head comparative studies could help to define these differences. For 1096

4 JAC example, lopinavir/ritonavir and fosamprenavir/ritonavir appear to have very similar GI tolerability profiles, with 11% and 13% having diarrhoea and 5% and 6% having nausea, respectively. 27 There were no significant differences between these drugs in fasting lipid parameters. In contrast, darunavir/ritonavir and atazanavir/ritonavir appear to have improved GI tolerability profiles (diarrhoea and nausea) when compared with lopinavir/ ritonavir. 28,29 In addition, statistically significant differences in dyslipidaemia were noted in favour of darunavir/ritonavir and atazanavir/ritonavir when they were compared with lopinavir/ ritonavir. For example, data from the ARTEMIS study showed that darunavir/ritonavir had lesser rates of elevated total cholesterol (18%) than did lopinavir/ritonavir (28%) at 96 weeks (P¼0.0019) and similar results were reported for serum triglyceride levels: 4% experienced Grade 2 4 elevations versus 13%, respectively (P,0.0001). 34,35 Although comparative data are limited, the PI with the least atherogenic profile appears to be atazanavir. When compared with lopinavir/ritonavir, atazanavir/ ritonavir had lower fasting lipid levels at 48 weeks, including total cholesterol (24% versus 12%, P,0.0001), non-high-density lipoprotein (21% versus 7%, P, ) and triglycerides (51% versus 13%, P,0.0001). 29 Several comparisons of atazanavir/ ritonavir versus unboosted atazanavir have not shown a difference in the tolerability profile, including rates of dyslipidemia. 36,37 These findings have been further validated by a comprehensive systematic review of studies of first-line regimens with a focus on changes in plasma lipid profiles. 38 This review identified atazanavir/ritonavir and darunavir/ritonavir as having lesser observed increases in lipid profiles (total cholesterol and triglycerides) when compared with lopinavir/ritonavir or fosamprenavir/ritonavir. Several small studies have also evaluated early changes in glucose metabolism due to various PIs. Among those tested, indinavir, ritonavir and lopinavir/ritonavir have all shown early changes in glucose metabolism and insulin resistance, while nelfinavir, fosamprenavir, atazanavir/ ritonavir and darunavir/ritonavir appear less likely to generate similar changes. 39,40 Use of PI therapy in special circumstances There are certain clinical circumstances that may warrant deviating from the traditional management strategies used in most HIV-1-infected patients. Such circumstances may include concerns about adherence to a complicated regimen, anticipated poor tolerance of a proposed regimen or pregnancy. The goal of avoiding toxicities associated with some NRTIs has led to studies of PIs in combination with agents from other classes of drugs. In this latter category are studies involving the two most recent ART drug classes, the INSTI raltegravir and the CCR5 antagonist maraviroc. Currently available data on such combinations are quite limited, but trials underway include a pilot study of maraviroc and atazanavir/ritonavir in ART-naive patients ( Attempts to reduce the costs of antiretroviral (ARV) treatment as well as to limit the overall exposure to ART include studies investigating the role of PI monotherapy. Results have, in general, been mixed, but approaches that use PI monotherapy as part of a regimen simplification strategy appear more promising than do studies of PI monotherapy as the full starting ARV regimen. For example, the MONARK study was a randomized trial comparing lopinavir/ ritonavir monotherapy with lopinavir/ritonavir plus zidovudine/ lamivudine in ART-naive patients. 41 In the intention-to-treat analysis at 96 weeks, only 47% of patients receiving lopinavir/ ritonavir monotherapy achieved viral suppression (HIV-RNA,50 copies/ml) and 34% had discontinued the study treatment. Other studies of lopinavir/ritonavir monotherapy as initial treatment in ART-naive patients have shown similar results. 42,43 The use of PI monotherapy following standard initial three-drug ART (simplification) has been somewhat more promising, particularly in the MONET study, which assessed darunavir/ritonavir, and the National Agency for AIDS Research (ANRS) study entitled MONOI. 44,45 Both drug simplification studies showed noninferiority of the PI monotherapy arms and rates of PI resistance mutations were not significantly increased. However, these two small preliminary studies may not fully account for the risk of incomplete viral suppression with the generation of HIV resistance mutations during prolonged viraemia (which may be more common outside of a clinical trial setting), a result that may be amplified by suboptimal adherence (which may be more problematic among persons using monotherapy). Taken together, these data indicate that PI monotherapy is not currently recommended as first-line initial therapy for ART-naive patients and until further data are available on the role of PI monotherapy after regimen simplification, this therapeutic option should be reserved for clinical trial settings. HIV-infected women who are pregnant represent a particularly important special population for whom the initiation of ART must be considered and one for which the Public Health Service Task Force has made extensive recommendations. 45 Based on accumulated experience, the most recent US Department of Health and Human Services treatment guidelines recommend lopinavir/ritonavir and zidovudine/lamivudine as the preferred regimen for pregnant women. 9 The appropriate use of ART has been shown to significantly reduce perinatal transmission rates, at least in part, by lowering maternal antepartum HIV-RNA. Recommendations regarding the use of PI regimens other than lopinavir/ritonavir are limited by inadequate experience with newer regimens. The use of some drugs is further limited by specific risks either to the mother (nevirapine if CD4.250 cells/mm 3 ) or to the developing fetus (teratogenicity associated with efavirenz). With the availability of expanded options for PI use occurring over the past decade, a recent observational study found that PIs have been used as part of the ART regimen in.60% of ARV-treated pregnant women, with a switch over time from nefinavir- to ritonavir-boosted PI regimens, most commonly lopinavir/ritonavir. 46 Due to the changed pharmacokinetics of drugs (including PIs) during pregnancy (significant increases in the apparent volume of distribution), achieving adequate concentrations of PIs in pregnancy is a concern and further research into appropriate dosing must be done. Due to limited experience with the use of atazanavir/ritonavir, darunavir/ritonavir or fosamprenavir/ritonavir in pregnancy, lopinavir/ ritonavir remains the preferred PI in pregnant women. Lastly, there is anecdotal evidence that HIV PIs may be of value in the management of HIV-infected persons with Kaposi sarcoma (KS). 47 Because antiretroviral treatment regimens have significantly reduced the incidence of KS in HIV-infected patients, randomized controlled trials data to support this contention are lacking. 1097

5 Conclusions The impressive improvements in HIV-associated morbidity and mortality that have been achieved during the highly active ART era are, in large measure, a consequence of improvements in the individual drugs that comprise combination ART. Given the number of drugs available, providers should now consider specific patient characteristics when determining the best option for an initial regimen in an ART-naive patient. While the current guidelines recommend NNRTI-, PI- and INSTI-based regimens as equal alternatives in ART-naive patients, there are clearly selected patients for whom PI-based regimens appear to be the best option, because of specific toxicity or dosing issues. In addition, the substantial rates of transmitted resistance to NNRTIs (K103N) in some areas suggest that there is an important population of ART-naive patients who are not appropriate candidates for initial NNRTI-based therapy. Moreover, the apparent increased genetic barrier to resistance that is seen with ritonavir-boosted PI regimens may favour PI use for patients in whom there is significant concern regarding adherence to therapy. Among the available PIs, differences in dosing and adverse event profiles should be considered for each patient most patients benefit from once-daily dosing schedules and more contemporary PIs have lower numbers of pills that must be taken [atazanavir/ritonavir (two pills) and darunavir/ritonavir (three pills)]. While the preferred and alternative PIs are relatively comparable in terms of viral and immunological efficacy, there are clear differences with regard to tolerability and adverse event profiles. The weight of evidence (including a systematic review) suggests that darunavir/ritonavir and atazanavir/ritonavir have the best tolerability profile, particularly with regard to dyslipidaemia. A clinical trial comparing darunavir/ritonavir and atazanavir/ ritonavir, to include assessing changes in lipid parameters, is currently underway and may provide additional guidance as to which drug is preferred for ARV-naive patients ( Finally, the use of boosted PI monotherapy as an initial regimen is not supported by the available evidence and, thus, is not recommended. In all cases, a thoughtful discussion of the pros and cons of the various available options between the provider and the patient is of utmost importance, so that the best regimen is chosen for each individual patient. Transparency declarations S. N. reports receiving prior research funding from Abbott. S. N. has no other disclosures. C. H. reports receiving grant support from Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Tibotec, Gilead Sciences, Myriad Sciences and Merck, and has served as a consultant for Bristol-Myers Squibb, GlaxoSmithKline, Tibotec, Gilead Sciences, Myriad Sciences and Merck. C. 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