For the initial treatment of HIV-infected adults, a combination regimen that includes lopinavir-ritonavir is well tolerated and has antiviral activity superior to that of a nelfinavir-containing regimen.

Mathematical models provide an understanding of in vivo replication kinetics of human immunodeficiency virus type 1 (HIV-1). With a novel intervention designed for increased potency, we have more accurately deduced the half-lives of virus-producing CD4؉ T cells, 0.7 day, and the generation time of HIV-1 in vivo, approximately 2 days, confirming the dynamic nature of HIV-1 replication.In 1996, we developed a mathematical model to analyze a set of plasma human immunodeficiency virus type 1 (HIV-1) RNA data from five chronically infected individuals treated with ritonavir monotherapy (5). On the basis of these results, we estimated the half-life (t 1/2 ) of free virions to be 0.24 day and the t 1/2 of productively infected CD4ϩ T cells to be 1.6 days. These turnover rates were considered minimum estimates because the analysis assumed that viral replication was completely suppressed by the therapy. From these data and measured baseline viral loads, we calculated minimal daily virion production to be ϳ10 10 particles in a typical patient. Moreover, the dynamic turnover of HIV-1 and productively infected cells formed the scientific rationale for combination antiretroviral therapy (1, 5), which has led to significant reductions in HIV-1-related morbidity and mortality (3).We have subsequently performed two additional experiments to better define c, the clearance rate constant of plasma virions. The results of these studies (6) allowed us to adjust the previous estimate for virion t 1/2 to a new value of ϳ30 min. Similarly, we have also adjusted the estimate for ␦, the rate of loss of productively infected CD4 ϩ T cells, in a follow-up study (4). The new estimate of the t 1/2 of virus-producing cells was ϳ1.1 days, again assuming that the combination antiretroviral therapy used was completely suppressive.Advances in the development of antiretroviral agents have yielded a number of drugs that are more effective in blocking HIV-1 replication in vivo (7). Thus, we have better tools in hand to readdress the issue of the relative potency of our therapeutic regimens and, hence, to better estimate ␦. As we have previously reported, the slope of the initial phase of plasma HIV-1 RNA decline depends on the degree of suppression of viral replication, as well as on ␦ (1, 4, 5). As the potency of combination therapy approaches 100%, the determination of ␦ becomes more precise. We now report findings from a Rockefeller University Institutional Review Board-approved novel interventional trial to reassess ␦, as well as the relative potency of our current antiretroviral therapies.Nine chronically HIV-1-infected individuals (Table 1) were treated with lopinavir-ritonavir (1,066 and 266 mg/day, respectively), efavirenz (600 mg/day), lamivudine (300 mg/day), and tenofovir DF (300 mg/day). Study subjects were hospitalized for the first 72 h of therapy, when plasma viral loads were measured by reverse transcription-PCR (Roche Amplicor Ultrasensitive Cobas 1.5; detection limit of 50 copies/ml) at 6-h intervals. Thereafter, measurements were ...

The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir. By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor ABT-378, which has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease (Ki = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC50], 0.006 to 0.017 μM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC50, ≤0.06 μM). The metabolism of ABT-378 was strongly inhibited by ritonavir in vitro. Consequently, following concomitant oral administration of ABT-378 and ritonavir, the concentrations of ABT-378 in rat, dog, and monkey plasma exceeded the in vitro antiviral EC50 in the presence of human serum by >50-fold after 8 h. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of ritonavir enhanced the area under the concentration curve of ABT-378 in plasma by 77-fold over that observed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exceeded the EC50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.

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Coadministration with the human immunodeficiency virus (HIV) protease inhibitor ritonavir was investigated as a method for enhancing the levels of other peptidomimetic HIV protease inhibitors in plasma. In rat and human liver microsomes, ritonavir potently inhibited the cytochrome P450 (CYP)-mediated metabolism of saquinavir, indinavir, nelfinavir, and VX-478. The structural features of ritonavir responsible for CYP binding and inhibition were examined. Coadministration of other protease inhibitors with ritonavir in rats and dogs produced elevated and sustained plasma drug levels 8 to 12 h after a single dose. Drug exposure in rats was elevated by 8- to 46-fold. A > 50-fold enhancement of the concentrations of saquinavir in plasma was observed in humans following a single codose of ritonavir (600 mg) and saquinavir (200 mg). These results indicate that ritonavir can favorably alter the pharmacokinetic profiles of other protease inhibitors. Combination regimens of ritonavir and other protease inhibitors may thus play a role in the treatment of HIV infection. Because of potentially substantial drug level increases, however, such combinations require further investigation to establish safe regimens for clinical use.