To put lipid-related complications seen in

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1 MANAGING REGIMEN DIFFICULTIES: MEETING THE CHALLENGES OF SAFETY AND TOLERABILITY * Simon A. Mallal, MBBS, FRACP, FRCPA ABSTRACT HIV-infected patients who are naive to antiretroviral therapy usually demonstrate decreased lipid levels as a consequence of infection. Treatment with antiretroviral agents may be generally associated with a return-to-baseline phenomenon that should be considered when evaluating clinical trial findings. The older protease inhibitors (PIs) saquinavir, indinavir, ritonavir, nelfinavir, and amprenavir have been associated with the development of hypertriglyceridemia, insulin resistance, and dyslipidemia. New PIs have been developed that have more favorable lipid profiles, offer more dosing options, and are associated with fewer short-term side effects. This article summarizes the complications associated with the older and newer PIs and offers guidance for the clinical management of metabolic complications in patients taking antiretroviral therapy. (Adv Stud Med. 2003;3(10B):S981-S986) *Based on a presentation given by Dr Mallal at a symposium held in conjunction with the 2nd IAS Conference on HIV Pathogenesis and Treatment. Professor and Executive Director, Centre for Clinical Immunology and Biomedical Statistics, Murdoch University; Clinical Immunologist, Department of Clinical Immunology and Biochemical Genetics, Royal Perth Hospital, Perth, Western Australia. Address correspondence to: Simon A. Mallal, MBBS, FRACP, FRCPA, Royal Perth Hospital, Centre for Clinical Immunology and Biomedical Statistics, Wellington Street, 2nd Level, North Block, Perth, Western Australia Mallal@prodigal.murdoch.edu.au. To put lipid-related complications seen in HIV-infected persons in proper context, one must consider the epidemic of the metabolic syndrome occurring in the healthy, HIV-uninfected populations of the developed world. This syndrome is associated with visceral obesity, high lipid levels, and insulin resistance, factors found to be the main drivers of cardiovascular risk. HIV infection itself may actually abrogate many of these factors, providing a variable degree of protection to infected individuals via favorable lipid changes. Antiretroviral drug therapy can result in a trend returning toward baseline values and lead to fat accumulation and visceral obesity. It is important to keep this in mind when considering lipid data from clinical trials. Baseline factors that are predictive for cardiovascular disease include sex, ethnicity, and increasing age. In addition, time-related factors, such as duration of exposure to antiretroviral agents, also contribute to the risk. The risk factors may be divided into those that are modifiable and those that are not. It is only after an evaluation of these risks that the physician can consider how the choice of antiretroviral agents might modify these risks. The currently proposed models of lipodystrophy favor the concept that nucleoside reverse transcriptase inhibitors (NRTIs) in particular certain thymidine analogs drive the constellation of factors that promote fat wasting. This is supported in part by data from ACTG 5005s, the metabolic substudy of ACTG384 showing that at 80 weeks of treatment, stavudine/didanosine was associated with a significantly greater decline in median limb fat compared with zidovudine/lamivudine. 1 In contrast, the protease inhibitors (PIs) have been linked to development of the metabolic syndrome, which increases cardiovascular risk. The metabolic syndrome is defined by having at least 3 of the follow- Advanced Studies in Medicine S981

2 ing characteristics obesity, elevated triglycerides, low high-density lipoprotein (HDL) cholesterol, blood pressure greater than 130/85 mm Hg, and a fasting glucose level exceeding 110 mg/dl. The overall ageadjusted prevalence of the metabolic syndrome is 32% in the general population of uninfected individuals. 2 This prevalence rises with advancing age, differs somewhat between men and women, and is higher among those of African descent, especially women, compared with those of Caucasian lineage. LIPID CHANGES IN HIV-INFECTED PATIENTS HIV infection is associated with a drop in total cholesterol, an early and marked decrease in HDL cholesterol, and a later reduction in low-density lipoprotein (LDL) cholesterol, which parallels the decline in CD4 cell count (Figure). 3 Highly elevated triglyceride levels are a late manifestation of disease particularly associated with the occurrence of AIDS. Data from the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study reinforce the concept that the higher a patient s CD4 count, the higher his or her total cholesterol level. 4 Cholesterol levels in patients with high CD4 counts were lowest in patients naive to treatment, and increased in order from patients taking therapy with NRTIs to treatment with NRTI/non-NRTI (NNRTI), NRTI/PI, and NRTI/ PI/NNRTI. The same pattern of elevated cholesterol is seen in relation to viral load. LIPODYSTROPHY The Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study, a large study supported by the National Institutes of Health, is evaluating an HIV-infected population of patients from around the United States. 5-8 Controls were subjects from the Coronary Artery Risk Development in Young Adults (CARDIA) database, a prospective cohort of patients 33 to 45 years of age. The main findings reported from the FRAM study are that the major difference between HIV-infected patients and control subjects is the presence of lipoatrophy in the HIV-positive patients. Lipoatrophy is a rare occurrence in HIV-negative individuals, unlike the metabolic syndrome. Patients who reported fat loss in the FRAM study did not have any more central fat compared with controls. In addition, buffalo humps were not more prevalent among HIVinfected patients in the FRAM study, although they were larger than those seen in controls. PIS AND LIPID LEVELS Indinavir and nelfinavir are believed to promote both insulin resistance and a dyslipidemic profile similar to that seen in patients with diabetes, with high levels of triglycerides, low HDL levels, and the presence of triglyceride-rich particles In contrast, ritonavir has been linked to hypertriglyceridemia and increased hepatic very-low-density lipoprotein and apolipoprotein B production with no or little effect on insulin resistance This profile may increase vascular risk. The precise effect on this profile and on vascular risk of using ritonavir at lower doses in boosted regimens, as with lopinavir/ritonavir, is to be determined. However, increased levels of total cholesterol as well as triglycerides were observed in patients treated with lopinavir/ritonavir for 48 weeks. 20 In general, compared with the older PIs, phase 3 data for new PIs show that atazanavir and 908 have favorable lipid profiles. EVALUATING THE NEWER PIS LIPIDS Atazanavir, approved by the US Food and Drug Administration (FDA) in June 2003, has been associated with minimal lipid abnormalities or improvements compared with efavirenz in a pivotal phase 3 trial. 21 Switching from nelfinavir to atazanavir was also associated with an improvement in lipid levels in earlier studies. 22 Favorable lipid effects of atazanavir have also been observed in trials of this new PI in antiretroviral therapy Figure. Lipid Profile Changes Observed in HIV Infection Cholesterol LDL HDL Triglycerides HIV Infection (late) (early) ~30% (AIDS, IFN-α) LDL = low-density lipoprotein; HDL = high-density lipoprotein; IFN = interferon. S982 Vol. 3 (10B) November 2003

3 (ART)-experienced patients. 23,24 Especially notable is the good lipid profile when atazanavir was boosted with ritonavir. 24 In this study, more patients who received the comparator, lopinavir/ritonavir, required lipid-lowering therapy compared with those who received a combination of atazanavir and ritonavir. For 908 (fosamprenavir, approved by the FDA in October 2003), its unboosted twice-daily use in a 48-week phase 3 trial resulted in comparable lipid levels to those seen in ART-naive patients treated with nelfinavir and remained within acceptable National Cholesterol Education Program (NCEP) guidelines. 25 Boosting 908 with ritonavir in a once-daily regimen also resulted in minimal lipid elevations. 26 Levels of total cholesterol and LDL cholesterol did not exceed the NCEP cutoffs for initiating lipid-lowering therapy; however, mean triglyceride levels remained between borderline high and high. Nevertheless, these results are notable given the use of low-dose ritonavir in this phase 3 trial. Furthermore, such lipid elevations in general may in part reflect the returnto-baseline phenomenon that often occurs when ART-naive patients initiate treatment. A similarly good lipid profile with both once-daily and twice-daily boosted 908 was also observed in interim results of a third phase 3 trial evaluating 908 in ART-experienced patients, with generally more favorable results observed in both 908 arms compared with lopinavir/ritonavir. 27 NONMETABOLIC EFFECTS In addition to their more favorable lipid profiles, new PIs also differ from the older PIs with respect to their nonmetabolic (eg, short-term) effects. The older agents in this class were frequently associated with diarrhea, gastrointestinal intolerance/nausea, retinoid side effects, and hyperbilirubinemia short-term side effects that can make a regimen intolerable and potentially lead to discontinuation of therapy. Among the newer PI agents, atazanavir treatment has consistently been associated with elevated bilirubin levels with a lower, but steady, occurrence of jaundice and scleral icterus. Of potentially greater immediate clinical concern is that levels of atazanavir may be lowered by tenofovir disoproxil fumarate as well as by efavirenz. 28 Ritonavir-boosted atazanavir (300/100 mg daily) is recommended for concurrent use with either of these 2 drugs. Regarding other drug interactions, the use of H 2 blockers and proton pump inhibitors is restricted in patients taking atazanavir. Moreover, food restrictions apply. For fos- Table 1. Some Advantages and Disadvantages of the Newer PIs Atazanavir Fosamprenavir ( 908 ) Tipranavir TMC-114 ADVANTAGES 2 (soon to be 1) Dosing flexibility Good activity Good activity in cap/dose/day (4 pills/day; in multiple-pi multiple-pi Minimal/improved bid ± RTV, qd experienced experienced lipid abnormalities + RTV) patients (phase patients (phase vs EFV (unboosted Good GI tolerability 2 results) 2 results) in AI ), Minimal lipid LPV/RTV (boosted perturbation vs in AI ) NFV (boosted in Improved lipids SOLO), LPV/RTV when switched from NFV (boosted in CONTEXT) Comparable lipids unboosted vs NFV (NEAT) No food restrictions DISADVANTAGES Role in PI- RTV boosting Poor bioavailability Activity not yet experienced patients required for High incidence of well defined not fully defined qd dosing GI side effects Risk of short-?relative potency Increased Induces metabolism term side effects Commonly triglycerides when of RTV No clinical data associated with used with RTV No clinical data in ART-naive hyperbilirubinemia (minimal) in ART-naive patients (potential for patients Formulation not jaundice) yet determined H 2 blockers, proton pump inhibitor use restricted TDF and EFV each lower levels of ATV PIs = protease inhibitors; EFV = efavirenz; LPV = lopinavir; RTV = ritonavir; NFV = nelfinavir; GI = gastrointestinal; TDF = tenofovir; ATV = atazanavir; ART = antiretroviral therapy. Advanced Studies in Medicine S983

4 amprenavir ( 908 ), concerns that this new prodrug of amprenavir would retain the side-effect profile of its active metabolite are likely overestimated. The side-effect profile of 908 is substantially improved, and diarrhea, gastrointestinal intolerance, and nausea were significantly lower with 908 in all phase 3 trials to date. There are also no food restrictions with 908, in contrast to amprenavir. 29 Fewer data are available for both tipranavir and TMC-114. Tipranavir has poor bioavailability, and gastrointestinal intolerance/nausea is associated with its use. 30,31 Tipranavir induces the metabolism of ritonavir; thus, boosting of tipranavir requires a higher ritonavir dose of 400 mg daily. The most commonly reported side effects in patients treated with TMC-114 were gastrointestinal events. 32 A summary of some of the relative advantages and disadvantages among the newer PIs are listed in Table 1. CLINICAL MANAGEMENT OF METABOLIC ABNORMALITIES Before initiating ART, it is a good idea to obtain fasting lipid measurements, keeping in mind the effects of HIV infection on lowering lipid levels (Table 2). An elevated LDL cholesterol level prior to initiating therapy is worrisome and may indicate preexisting dyslipidemia. Before starting treatment, it is also important to exclude diabetes mellitus and assess the patient s overall cardiovascular risk. Once a patient begins ART, it is necessary to monitor changes in lipids as well as fasting glucose. A minimal assessment of lipids should include fasting total cholesterol, HDL cholesterol, and triglycerides. Treatment of hypertension can be helpful in reducing cardiovascular risk. Treatment with statins is warrant- Table 2. Clinical Management of Metabolic Abnormalities BEFORE CHOOSING/COMMENCING ART Obtain fasting lipids Consider effect of HIV per se (especially with HDL cholesterol, low LDL cholesterol) LDL cholesterol likely to be significant, suggestive of preexisting dyslipidemia Exclude diabetes mellitus Oral glucose tolerance test to exclude impaired glucose tolerance Assess overall cardiovascular risk (NCEP III or similar risk calculator ) Age Family history (vascular disease, diabetes mellitus) Smoking Hypertension Assess risk of metabolic abnormalities associated with older PI therapy Exercise; dietary history AFTER CHOOSING/COMMENCING ART Monitor fasting lipids (every 6 to 12 months) Consider recovery effect with lipids/lipoproteins returning to normal levels Minimal assessment includes total cholesterol, HDL cholesterol, triglycerides Importance of non-hdl cholesterol in metabolic syndrome Monitor fasting glucose (± oral glucose tolerance test) Manage overall cardiovascular risk Interventions for smoking, hypertension Treatment with statins when 10-year vascular risk >20% Encourage lifestyle changes to reduce risk of metabolic abnormalities associated with older PIs Exercise; dietary history Monitor nonmetabolic side effects and adherence IF METABOLIC COMPLICATIONS OCCUR Characterize phenotype Comparison with baseline levels (preexisting dyslipidemia) Predominantly triglycerides or metabolic syndrome phenotype? Evidence of diabetes mellitus or impaired glucose tolerance? Assess impact on overall cardiovascular risk Interventions for smoking, hypertension may be effective for decreasing cardiovascular risk Treatment with statins supported when 10-year vascular risk >20% Encourage lifestyle changes to reduce risk of metabolic abnormalities associated with older PIs Exercise; dietary history Consider other management options Adjunctive therapy (statins, fibrates, insulin-sensitizing agents) Switching (intraclass or switching PI to NNRTI/NRTI) ART = antiretroviral therapy; HDL = high-density lipoprotein; LDL = low-density lipoprotein; NCEP = National Cholesterol Education Program; PI = protease inhibitor; NNRTI = nonnucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor. S984 Vol. 3 (10B) November 2003

5 ed when the 10-year vascular risk exceeds 20%. It is necessary to encourage modification of lifestyle-associated factors, such as smoking, exercise, and diet, to help manage overall vascular risk as well as the risk of metabolic abnormalities. If metabolic complications occur, the physician has the option to add a lipid-lowering agent or an insulinsensitizing agent, such as metformin, or to consider switching therapy. Addition of a lipid-lowering agent will not interfere with the antiretroviral sequencing strategy but does introduce the potential for drug interactions with PIs. Switching agents may also introduce drug interactions, which must be considered when devising alternative regimens. It is important to keep in mind that the diabetic dyslipidemia profile is fairly resistant. Lipid-lowering therapy may produce only a moderate effect in these patients. Intensification of the lipid-lowering treatment does not yield a substantially greater effect but does increase side effects. Therefore, if a patient had good lipid levels before starting ART and experiences a return to baseline values, management with a switch strategy may be preferable. Statins are not very effective in treating the profiles induced by some of the older PIs, whereas switch strategies may improve these profiles. CONCLUSION Continued research is important in refining our understanding of the metabolic complications of PI therapy. Rather than focusing on so-called class effects of PIs, the results of more recent studies have made possible a more individualized approach that distinguishes modifiable from unmodifiable risk factors, emphasizes prevention and monitoring, and tailors treatment to the specific patient. In general, the newer PIs offer important advantages over the older agents, with improved lipid profiles and fewer short-term side effects, characteristics that improve tolerability of new PI-based regimens. 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