Protease Inhibitors

If cure of HIV infection is to be accomplished, it will require the elimination of proviral DNA. The kinetics of HIV-1 DNA clearance were assessed in 11 protease inhibitor naïve patients at the time of initiation of highly active antiretroviral therapy. When adjusted for number of CD4 T cells, a 71% decline was seen at one month, with an additional 50% decline through six months. (Abstract I-250.)

Pharmacodynamics. Many HIV-1 protease inhibitors bind avidly to alpha-1 acid glycoprotein, a normal constituent of plasma that is an acute phase reactant. Binding reduces the activity of drugs because it is only the unbound fraction that is active. The increase in mean serum concentrations of alpha-1 acid glycoprotein seen in the presence of acute infections is associated with a reduction in activity of protease inhibitors against some strains of HIV-1. Indinavir appears to be the least affected, while amprenavir, ritonavir, and nelfinavir are the most affected. (Abstract A-42.) This suggests that intercurrent infection may impair the antiretroviral activity of these drugs in vivo.

BID Dosing. Evaluation of bid dosing of indinavir in regimens in which it is the only protease inhibitor used in combination with NRTIs has been abandoned because of the results of a 24-week interim analysis of data that showed that the tid regimen was more effective than the twice-daily regimen in reducing levels of viral RNA to less than 400 copies/mL in patients initiating therapy. At week 24, 91% of patients on the approved dosing regimen had achieved viral levels below 400 copies/mL, compared to 64% of patients on the twice-daily regimen.

Trials examining bid dosing of indinavir in combination with another protease inhibitor or an NNRTI, however, continue. Thirty-seven antiretroviral naïve patients with viral loads less than 35,000 copies/mL and a median CD4 count of 247/mm3 (range, 4-616/mm3) were treated with the following, with all drugs given bid: two NRTIs, indinavir (400 mg per dose), and ritonavir (400 mg per dose). Twelve of 12 patients who reached 16 weeks of treatment had plasma HIV RNA less than 500 copies/mL. (Abstract I-213.) This bid regimen allows indinavir to be taken without regard to food intake.

Twice daily dosing of nelfinavir (1250 mg bid) appears to be as effective as thrice daily dosing (750 mg tid), in patients with less than six months prior NRTI experience (most of whom were 3TC-naïve) when it is given together with d4T and 3TC for as long as 48 weeks. Diarrhea occurred with equal frequency in both groups. (Abstracts I-216, I-218.)

Metabolic and Other Adverse Effects. Comparison of HgbA1c and fasting lipid profiles found no differences between patients receiving and not receiving protease inhibitor therapy. (Abstract I-72.) Endocrinologic investigation of six diabetic HIV-infected patients receiving protease inhibitor therapy provided evidence of insulin resistance with relative insulin deficiency as well as hyperglucagonemia. (Abstract I-90.) Eight protease inhibitor treated men (median HIV RNA, 13,200 copies/mL) with hypertriglyceridemia (median, 1803 mg/dL) were given gemfibrozil at a dose of 200 mg qd for a median of 175 days. The median triglyceride level decreased 83% to 300 mg/dL (P = 0.012) after institution of gemfibrozil therapy. There was, however, no change in cholesterol or HDL cholesterol. Triglycerides increased significantly in three gemfibrozil recipients whose protease inhibitor was changed to nelfinavir, suggesting an interaction between these two drugs. (Abstract I-88.)

The cumulative probability of developing lipodystrophy during protease inhibitor therapy was 3.2% at six months, 10.7% at 12 months, 29.1% at 18 months, 62.5% at 24 months, and 75% at 30 months. The risk was not affected by the individual or combination protease inhibitor used (nelfinavir was not used in these patients). (Abstract I-92.) On the other hand, a separate retrospective study found that the greatest relative risk for development of hypercholesterolemia was associated with ritonavir use. (Abstract I-95.)

A retrospective study found that ritonavir use was associated with a six-fold greater risk of severe hepatotoxicity (ALT or AST > 5 ´ ULN or > 3.6 ´ abnormal baseline) than other PIs. The relative risk was 4.8 for ritonavir recipients (P = 0.001) and 32% for ritonavir + saquinavir recipients (P = 0.001). HCV infection did not appear to predispose to protease inhibitor associated severe hepatotoxicity. (Abstract H-116.) The latter finding was confirmed in a separate study. (Abstract H-118.) The occurrence of adverse side effects correlates closely with the plasma concentration of ritonavir. (Abstract A-75.)

Three men, ages 41-49 years, receiving protease inhibitor-based therapy developed aseptic necrosis of the hip. Two of the three had a history of alcohol abuse. (Abstract I-71.)

RTIs: Adefovir and Abacavir

Adefovir. One hundred sixty-four antiretroviral naïve patients with a CD4 count of greater than 100/mm3 and HIV RNA more than 5000 copies/mL were randomized to receive either adefovir dipivoxil + indinavir + either ZDV, 3TC, d4T, or ZDV and 3TC; or indinavir + 3TC + ZDV. At 20 weeks, the proportion of patients whose viral load had decreased to less than 400 copies/mL was similar in each group, as were the absolute increases in CD4+ T cell counts. However, almost 40% of patients in the four drug arm had dropped out. (Abstract I-107.)

Four hundred forty-two patients with HIV RNA greater than 2500 copies/mL (bDNA) and CD4 count of more than 200 cells/mm3 were randomized to have either adefovir dipivoxil or placebo added to their standard antiretroviral regimen (all were also given (L-carnitine). Close to 40% of patients altered their background therapy during the study, somewhat confounding interpretation of the results. At 24 weeks, there was a mean decrease of plasma HIV RNA of 0.4 log10 in those assigned adefovir (P < 0.001 vs placebo result); this result was also sustained through 48 weeks. There was no significant change in CD4 cell count. Administration of this nucleotide analog prodrug was associated with an unexplained mean decrease in body weight of 5.3 pounds vs. no change in placebo recipients (P < 0.001). Vomiting or diarrhea occurred more frequently in the adefovir group. Abnormalities of proximal renal tubular function occurred in 1% of adefovir recipients at 24 weeks; after an additional, 24-week open label phase, the incidence had increased to 39.1% in those who had received adefovir dipivoxil for 48 weeks. (Abstract I-108.)

Three-fourths of a group of highly NRTI experienced patients who were entered into a trial in which adefovir or placebo were added to their existing regimens had the 3TC-associated M184V mutation at baseline, and one-half had multiple mutations associated with ZDV resistance. Despite these findings, the mean decrease in plasma HIV RNA at 24 weeks in adefovir dipivoxil recipients in the group overall was 0.39 log10 and was 0.53 log10 (P < 0.0001 when compared to placebo response) in a subset of patients undergoing intense virological studies. A significant decrease in viral load was also noted in those with 3TC-resistant or high-level ZDV/3TC resistant virus at baseline (-0.94 log10), but not in those with only high-level ZDV resistance (-0.5 log10). Furthermore, the decrease in viral load at 24 weeks in patients whose virus developed new NRTI-associated resistance mutation during adefovir dipivoxil was a mean of 0.64 log10 (P = 0.0003) when compared to placebo response). (Abstract I-84.) The latter finding is consistent with data indicating increased susceptibility of virus with the 3TC-associated M184V mutation to adefovir .

Abacavir. Seventy patients receiving one or more NRTIs for at least eight weeks, with plasma HIV RNA of more than 50,000 copies/mL and CD4 count of more than 50 cells/mm3, were started on Combivir plus abacavir (patients on ZDV at the time of study were excluded). Fifty percent of patients had plasma HIV RNA less than 50 copies/mL at eight weeks, while 78% had values less than 400 copies/mL. This combination appears to provide us with a potent NNRTI- and PI-sparing regimen. (Abstract I-98.)

The AUC of abacavir is increased 41% by coadministration of ethanol. (Abstract A-67.)