Roger J Pomerantz; David L Horn


Nat Med. 2003;9(7) 

In This Article

1996-1998: Metabolic Complications; Adherence Issues; Viral Resistance; Genotypic and Phenotypic Testing

The original exuberance felt by patients and health-care workers about the use of triple combination therapy was tempered by the recognition of sometimes fatal metabolic complications, such as lactic acidosis, diabetes mellitus, lipodystrophy and pancreatitis.[28,29,30,31] Another major obstacle to sustaining effective therapy was the difficulty for some patients to stay on complicated regimens requiring high pill burdens, multiple daily administrations and differing interactions with food.[32,33] This difficulty has been overcome in part by combining low-dose ritonavir with other protease inhibitors such as indinavir,[34] saquinavir[35] and lopinavir,[36] the latter being approved by the FDA as a fixed drug combination. Combined pill formulations allow fewer pills to be taken per day and less frequently.

Despite these problems, HAART has dramatically changed the face of AIDS in the developed world by significantly reducing morbidity and mortality.[37] Health-care expenses for treating AIDS patients and drug-use costs have decreased.[38] It is very important to optimize therapy, as the risk of HIV-1 drug resistance is markedly decreased with complete suppression of HIV-1 replication. The development of resistance to therapy by the virus, especially in regimens that are only partially suppressive, limits the durability of viral inhibition and hinders subsequent treatment.[39]

Resistance testing of HIV isolates has become part of standard HIV-1 care. There are phenotypic and genotypic assays available to help predict which drugs are likely to have activity against HIV-1 and which agents are likely to fail because of resistance. Phenotypic assays measure drug susceptibility directly. Genotypic assays identify mutations in HIV-1 that are known to confer phenotypic changes. Genotypic testing, which is more widely used than phenotypic testing, is an example of one of the earliest applications of gene sequencing in clinical medicine.[40,41]

Interpretation of the results of genotypic and phenotypic testing can be difficult, as cross-resistance between agents of the same class frequently occurs. Genotypic testing, nonetheless, has been shown to be clinically useful in prospective randomized trials.[42,43] Another major limitation of HIV-1 drug resistance testing is that the HIV-1 population within any given individual is composed of innumerable variants. This quasispecies nature of HIV-1 contributes to the inability to detect minor populations of drug-resistant variants, thereby undermining the accuracy of both genotypic and phenotypic methods of testing.[41] This problem is particularly common in individuals with complicated treatment histories and in patients who have discontinued therapy. When resistance testing is used to modify a failing regimen, it is important to obtain plasma samples before withdrawing the failing therapy, which exerts a selective pressure on the competing myriad of quasispecies present at any one time in any one individual.

As both primary resistance, which occurs in individuals initially infected with a resistant HIV-1 strain, and secondary resistance, which develops in an infected individual, increase in magnitude and scope, treating HIV-1 infections, at least in the developed world, may begin to resemble the paradigms used for treating multidrug-resistant tuberculosis.[44,45]