T h e n e w e ng l a n d j o u r na l o f m e dic i n e Initial Treatment for HIV Infection — An Embarrassment of Riches
Bernard Hirschel, M.D., and Alexandra Calmy, M.D.
Drugs that are used to treat patients with human tease inhibitor? Phase 4 studies that compare immunodeficiency virus (HIV) infection are classi­ treatment strategies are desirable, but they are fied according to their target. The first ones to be difficult to do. In a rapidly moving field such as developed were nucleoside reverse­transcriptase HIV therapy, what is the “reference treatment”? inhibitors (NRTIs), which lead to premature termi­ Trials have to be large and continue for a long nation of the nascent DNA chain, and nonnucleo­ time, and patients may vote with their feet and side reverse­transcriptase inhibitors (NNRTIs), refuse to continue with a therapy that they judge, which bind and inhibit reverse transcriptase. rightly or wrongly, to be inferior to the latest The viral protease inhibitors were next. NRTIs, miracle drug. And large trials that continue for a NNRTIs, and protease inhibitors remain the long time are expensive. Drug companies have lit­ staples of highly active antiretroviral therapy, but tle to gain, and much to lose, from comparing one other targets, such as the CCR5 receptor, the fu­ of their already marketed drugs with another that sion peptide, and viral integrase, have recently may be better. The National Institutes of Health, through the Clinical Trials Network, have very At this time, eradication of HIV is impossible. properly undertaken trials such as the Strategies Rebound inevitably follows cessation of therapy, for Management of Antiretroviral Therapy (SMART; and therapy must therefore be lifelong. With ClinicalTrials.gov number, NCT00027352),3 which more than 20 drugs to choose from, there is an showed that intermittent treatment was inferior embarrassment of riches. Possible combinations to continuous treatment for patients with HIV in­ are almost endless, as are the possibilities of side fection.
effects, either beneficial or damaging drug inter­ In this issue of the Journal, Riddler et al.4 actions, and the development of viral resistance. report on the AIDS Clinical Trials Group Study Early in the antiretroviral­therapy era, the com­ A5142, which compared three drug combinations bination of indinavir (a protease inhibitor) and in the initial therapy of 753 patients with HIV zidovudine and lamivudine (both NRTIs) pre­ infection: efavirenz plus two NRTIs (efavirenz dominated as the reference treatment. In 1999, group), lopinavir–ritonavir plus two NRTIs (lopi­ the NNRTI efavirenz, in combination with zido­ navir–ritonavir group), and lopinavir–ritonavir vudine and lamivudine, proved to be more effec­ plus efavirenz (NRTI­sparing group). As previously tive in diminishing the plasma concentration of noted, the first two regimens were popular and HIV type 1 (HIV­1) RNA (the “viral load”) than widely prescribed. The third is theoretically at­ the reference treatment.1 Indinavir has since been tractive, since it avoids the use of NRTIs, which largely replaced by atazanavir or lopinavir com­ are suspected of contributing to side effects. An bined with a small dose of ritonavir to boost ab­ uncontrolled study of 86 patients showed that this combination would be effective, although it Current guidelines recommend initiating anti­ was not well tolerated: after 48 weeks, 24% of retroviral therapy with two NRTIs in combination patients either discontinued the study regimen with either an NNRTI or a protease inhibitor.2 because of adverse events or were lost to follow­ So the first question is, Which NRTIs and which up.5 A study by Boyd et al. looked at efavirenz protease inhibitor do we choose? And the second with ritonavir­boosted indinavir as an NRTI­spar­ question is, Which is better, an NNRTI or a pro­ ing option, with similar conclusions.6 n engl j med 358;20 www.nejm.org may 15, 2008 Downloaded from www.nejm.org on May 15, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved. The results of the study by Riddler et al. are formulation in the lopinavir–ritonavir capsule has difficult to put in a nutshell. We want regimens been replaced by tablets that produce a more con­ that win in all categories: suppression of HIV­1 sistent plasma drug level11 and are perhaps asso­ RNA, an increase in the CD4 cell count, a lack of ciated with less diarrhea and nausea. Extended­ emergence of resistance, low toxicity, and sim­ release stavudine has never been marketed because plicity. However, the study by Riddler et al. yields of pancreatic toxicity.12 Tenofovir and emtricita­ a split decision. When the regimens were ranked bine (a drug that was not used in the study) have according to suppression of HIV­1 RNA, the efa­ become the reference NRTI combination. In sum­ virenz group had the best results, closely followed mary, these reservations cast doubt on the future by the NRTI­sparing group and the lopinavir– applicability of the study’s findings — doubts ritonavir group, although the difference between that will not be easily resolved by further studies.
the efavirenz group and the NRTI­sparing group Nonetheless, on the basis of this study, it was not significant. When the regimens were seems that efavirenz plus two NRTIs is hard to ranked according to the emergence of drug resis­ beat. In addition to the stated results, one has tance, the winner was the lopinavir–ritonavir to consider the low pill burden, since brand­ group, followed by the efavirenz group and the name formulations contain efavirenz, emtricita­ NRTI­sparing group, and again the difference be­ bine, and tenofovir for a one­pill daily regimen, tween the lopinavir–ritonavir group and the efa­ and the fact that in most countries, efavirenz virenz group was not significant. Finally, as costs less than lopinavir–ritonavir. These data measured by the proportion of patients who dis­ should challenge the 40% of clinicians who start continued or changed their treatment, all three antiretroviral treatment with a protease inhibi­ groups had similar rates of adverse events.
tor and should reassure those who, in resource­ Patients who participate in clinical trials differ limited settings, must use combinations of NRTIs from the majority who do not participate — one and NNRTIs because they are cheaper.
reason why clinical practice often cannot repro­ Will new drugs dethrone efavirenz? Etravirine duce published results. Efavirenz causes side ef­ (an NNRTI),13 raltegravir (an integrase inhibi­ fects involving the central nervous system, in­ tor),14 and maraviroc (a CCR5 inhibitor)15 are cluding sleep disturbances with vivid dreams, targeted to patients with drug­resistant virus. dizziness, and daytime drowsiness.7 Such symp­ But because of their excellent pharmacokinetics toms are frequent and troublesome early on; they and initially favorable side­effect profiles, these largely disappear after a few weeks of therapy. drugs have a potential for earlier use16 and in a Nonetheless, in all studies we are aware of, a siz­ few years may even be successfully combined.
able percentage of patients discontinued efavi­ Dr. Hirschel reports receiving consulting and lecture fees from renz because of these effects; the proportion was Merck, serving on advisory boards for Merck and Tibotec, and particularly high among patients who acquired receiving travel grants from Bristol­Myers Squibb, GlaxoSmithKline, and Roche. No other potential conflict of interest relevant to this HIV through illicit drug use, partly because efa­ article was reported.
virenz interferes with methadone. We are struck From the Department of Infectious Diseases, Geneva Univer- by the fact that Riddler et al. did not record much sity Hospital, Geneva.
of this type of discontinuation in their study. This suggests that their patients were greatly 1. Staszewski S, Morales­Ramirez J, Tashima KT, et al. Efavi­
renz plus zidovudine and lamivudine, efavirenz plus indinavir, motivated to continue their prescribed regimen, and indinavir plus zidovudine and lamivudine in the treatment perhaps through their repeated and close con­ of HIV­1 infection in adults. N Engl J Med 1999;341:1865­73.
tact with the investigators — a type of Hawthorne 2. Guidelines for the use of antiretroviral agents in HIV­1–
infected adults and adolescents. (Accessed April 18, 2008, at effect8 that is difficult to duplicate in routine http:/ aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.) 3. The Strategies for Management of Antiretroviral Therapy
Another problem with the study relates to the (SMART) Study Group. CD4+ count–guided interruption of anti­ retroviral treatment. N Engl J Med 2006;355:2283­96.
NRTIs that were administered in the efavirenz 4. Riddler SA, Haubrich R, DiRienzo AG, et al. Class­sparing
group and the lopinavir–ritonavir group. All pa­ regimens for initial treatment of HIV­1 infection. N Engl J Med tients received lamivudine, but the second NRTI 2008;358:2095­106.
5. Allavena C, Ferré V, Brunet­François C, et al. Efficacy and
was zidovudine (which was assigned to 42% of tolerability of a nucleoside reverse transcriptase inhibitor­spar­ patients), extended­release stavudine (24%), or ing combination of lopinavir/ritonavir and efavirenz in HIV­1­ tenofovir (34%). NRTIs differ in both side ef­ infected patients. J Acquir Immune Defic Syndr 2005;39:300­6.
6. Boyd MA, Srasuebkul P, Khongphattanayothin M, et al.
fects9 and efficacy.10 Since the study started, the Boosted versus unboosted indinavir with zidovudine and lamivu­ n engl j med 358;20 www.nejm.org may 15, 2008 Downloaded from www.nejm.org on May 15, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e dine in nucleoside pre­treated patients: a randomized, open­label at http://www.drugs.com/drug­interactions/videx­ec_d00078_ trial with 112 weeks of follow­up (HIV­NAT 005). Antivir Ther stavudine­extended­release_d03773.html.) 13. Lazzarin A, Campbell T, Clotet B, et al. Efficacy and safety
7. Fumaz CR, Tuldrà A, Ferrer MJ, et al. Quality of life, emo­
of TMC125 (etravirine) in treatment­experienced HIV­1­infected tional status, and adherence of HIV­1­infected patients treated patients in DUET­2: 24­week results from a randomised, double­ with efavirenz versus protease inhibitor­containing regimens. blind, placebo­controlled trial. Lancet 2007;370:39­48.
J Acquir Immune Defic Syndr 2002;29:244­53.
14. Grinsztejn B, Nguyen BY, Katlama C, et al. Safety and ef­
8. Coats AJ. Clinical trials, treatment guidelines and real life. ficacy of the HIV­1 integrase inhibitor raltegravir (MK­0518) in
treatment­experienced patients with multidrug­resistant virus: 9. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and a phase II randomised controlled trial. Lancet 2007;369:1261­9.
safety of tenofovir DF vs stavudine in combination therapy in 15. Lalezari J, Goodrich J, DeJesus E, et al. Efficacy and safety of
antiretroviral­naive patients: a 3­year randomized trial. JAMA maraviroc plus optimized background therapy in viremic, ART­ experienced patients infected with CCR5­tropic HIV­1: 24­week 10. Gallant JE, Dejesus E, Arribas JR, et al. Tenofovir DF, emtri­
results of phase 2b/3 studies. Presented at the 14th Conference citabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz on Retroviruses and Opportunistic Infections, Los Angeles, Feb­ for HIV. N Engl J Med 2006;354:251­60.
11. Klein CE, Chiu YL, Awni W, et al. The tablet formulation of 16. Markowitz M, Nguyen B­Y, Gotuzzo E, et al. Rapid onset and
lopinavir/ritonavir provides similar bioavailability to the soft­ durable antiretroviral effect of raltegravir (MK­0518), a novel gelatin capsule formulation with less pharmacokinetic variabil­ HIV­1 integrase inhibitor, as part of combination ART in treat­ ity and diminished food effect. J Acquir Immune Defic Syndr ment HIV­1 infected patients: 48­week data. Presented at the 4th International AIDS Society Conference on HIV Pathogenesis, 12. Drugs.com. Interactions between videx­ec (didanosine) and Treatment and Prevention, Sydney, July 22–25, 2007. abstract.
stavudine extended release (stavudine). (Accessed April 25, 2008, Copyright 2008 Massachusetts Medical Society. Multiple Biomarker Panels for Cardiovascular Risk Assessment
James A. de Lemos, M.D., and Donald M. Lloyd-Jones, M.D., Sc.M.
Guidelines for the assessment of cardiovascular quantify improvements in screening perfor­ risk remain focused squarely on established risk mance.3,4 factors.1 Although it is known that tools based on One strategy that has been proposed to im­ these risk factors, such as the Framingham Risk prove on the limitations of individual biomarkers Score, have a number of limitations when applied is to combine multiple biomarkers into an inte­ in clinical practice — performing reasonably well grated score or algorithm. However, an evaluation for groups but not necessarily for individuals and of 3209 participants from the Framingham Heart underestimating long­term risk among younger Study failed to validate this approach.5 Although persons2 — it has proved surprisingly difficult persons with high biomarker scores had an in­ to improve on established risk factors for the pre­ creased risk of death as compared with those diction of cardiovascular disease. Of the many with low scores, the increment in the C statistic strategies that have been proposed to improve over the model with traditional risk factors was risk stratification, the measurement of plasma small. Similarly, in the Cardiovascular Health biomarkers is particularly attractive as compared Study, which included 5808 older Americans, the with alternatives such as cardiovascular imaging. addition of six novel biomarkers did not improve Numerous biomarkers have been proposed to discrimination beyond established risk factors have mechanistically plausible links to clinical among subjects with or without chronic kidney cardiovascular disease, with many reported to disease.6 Thus, despite decades of research and identify people at an increased risk for future car­ the introduction of numerous candidate biomark­ diovascular events independently of the presence ers and putative risk factors, risk prediction for of established risk factors. Typically, however, cardiovascular disease in the population appears the risk increment captured by elevated levels of to have progressed only marginally.
these markers is modest, and little improvement An article in this issue of the Journal suggests is seen in traditional measures of discrimination that measurable progress with the use of bio­ such as the C statistic or the area under the re­ markers could be possible. Zethelius et al.7 report ceiver­operating­characteristic curve. Much of the data from an evaluation of multiple biomarkers recent debate over emerging biomarkers focuses in a community cohort of elderly men. Among on the questions of how much incremental val­ 1135 men with a mean age of 71 years at study ue is provided and what the best metrics are to entry (661 of whom were free of cardiovascular n engl j med 358;20 www.nejm.org may 15, 2008 Downloaded from www.nejm.org on May 15, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved.

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