The field of antiretroviral therapy has witnessed remarkableprogress during the past 15 years. There are now 16 approvedtherapeutic agents for infection with the human immunodeficiencyvirus (HIV), a pathogen that once caused nearly uniformly fatalillness. These agents target two essential enzymes of the virus,the reverse transcriptase and the protease (see Figure). Theera of potent antiretroviral therapy, also termed highly activeantiretroviral therapy, began in 1996 and has been marked bydramatic declines in morbidity and mortality due to HIV diseasein the developed world. These advances have not been withouttheir cost in terms of drug resistance and side effects, particularlymetabolic abnormalities such as lipodystrophy. Concern aboutthese negative effects has led to a more conservative approachto the timing of the initiation of therapy and to clinical trialsof intermittent therapy in an attempt to decrease the totalexposure to drugs over time. Immune-based approaches such astherapeutic vaccination may someday permit viremia to be controlledin the absence of drugs.
The Life Cycle of Human Immunodeficiency Virus Type 1 (HIV-1) and Major Antiviral Targets.
Entry inhibitors (e.g., enfuvirtide, or T-20) and integrase inhibitors are currently under development. Approved reverse-transcriptase inhibitors include the nucleoside analogues (zidovudine, didanosine, zalcitabine, stavudine, lamivudine, and abacavir), a nucleotide analogue (tenofovir disproxil fumarate), and the nonnucleoside reverse-transcriptase inhibitors (nevirapine, delavirdine, and efavirenz). Approved protease inhibitors include saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir–ritonavir.
Antiretroviral management brings a complex series of choices:when to initiate therapy, what regimen to use, which drugs withineach class of drugs to use, when to change therapy, and whichalternative drugs to use. In this issue of the Journal, Walmsleyand colleagues (see pages 2039–2046) report on an importantstudy that illustrates the increasing number of choices facingclinicians and patients. The study compared the efficacy andsafety of the most recently approved protease inhibitor, lopinavir(coformulated with low-dose ritonavir), with the efficacy andsafety of nelfinavir in patients who had not previously receivedantiretroviral therapy and who also received two nucleosideanalogues (stavudine and lamivudine). The results demonstratea consistently superior virologic response over a period of48 weeks in the lopinavir–ritonavir group, as measuredby the proportion of subjects with plasma levels of HIV type1 (HIV-1) RNA below 400 or 50 copies per milliliter. The durabilityof the virologic response and the genotypic drug-resistancepattern of the viral strains from the subjects with virologicfailure were also more favorable with lopinavir–ritonavir.There was no difference between the two groups in the CD4 cellresponse.
Currently, the three most commonly prescribed initial antiretroviralregimens are a protease inhibitor (with or without low-doseritonavir as an enhancer) plus two nucleoside analogues; a nonnucleosidereverse-transcriptase inhibitor plus two nucleoside analogues;and three nucleoside analogues. As the study by Walmsley etal. highlights, differences in antiviral potency within eachof these types of regimens are becoming increasingly discernible.
How should we incorporate these findings into clinical practice?Should lopinavir–ritonavir now be considered one of thedrugs of choice for initial antiretroviral regimens? The answeris not as straightforward as it may appear, for a number ofreasons. There is a trend toward prescribing regimens for initialtherapy that do not include protease inhibitors, because ofconcern about metabolic toxic effects. And Walmsley et al. doreport a higher incidence of hyperlipidemia in the lopinavir–ritonavirgroup. Moreover, lopinavir–ritonavir has excellent activityas the core component of alternative regimens in patients inwhom initial treatment has failed. Thus, many clinicians maychoose to reserve lopinavir for later use. The effects of otherapproved protease inhibitors — indinavir, saquinavir,and amprenavir — can all be enhanced with low-dose ritonavir,which creates additional choices for clinicians. In the long-termmanagement of HIV disease, a 48-week study that demonstratesthe virologic but not the immunologic superiority of one agentover another represents an important finding, but it may notultimately translate into the desired clinical outcome manyyears, and potentially several regimens, later.
The chief take-home message from the article by Walmsley etal. is that improvements are being made in the potency of antiretroviraldrugs, and this bodes well for the future of the field. Antiviralpotency is the key to the initial success of drug regimens,as well as to the durability of their success, the restorationof immune function, the prevention of the emergence of resistance,and ultimately the prevention of disease progression. The keyis to link potency with the other desirable aspects of a therapeuticregimen: low pill burden, excellent tolerability, absence ofmajor drug interactions, absence of long-term toxic effects,and absence of cross-resistance to other agents.
Although the article in this issue of the Journal highlightsthe progress that has been made by using the existing classesof antiretroviral drugs, it also reminds us that drug developmentin the HIV field remains dynamic. Newer antiretroviral agents,such as entry inhibitors and integrase inhibitors, hold greatpromise. Encouraging clinical results have already been reportedfor the HIV fusion inhibitor enfuvirtide, or T-20 (see Figure).Future progress in antiretroviral therapy will bring more choicesfor physicians and patients and will make an already complexfield both more challenging and more rewarding.
Scott M. Hammer, M.D. Columbia Presbyterian Medical Center New York, NY 10032
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