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HIV protease inhibitors
General information
All the HIV protease inhibitors have in common a specific effect against the aspartic HIV protease that cleaves viral proteins to yield structural proteins. Competitive inhibition of this process by the protease inhibitors results in the production of immature, non-infectious virus particles. These drugs are also characterized by their high specificity, being more than a thousand-fold more active against viral than human aspartic proteases.
Combination therapy including a protease inhibitor resulted in the first breakthrough of antiviral treatment in the mid-1990s, since when several protease inhibitors have been developed. However, results from in vitro and clinical studies clearly showed that these drugs share a cross-resistance pattern, probably due to secondary conformational changes of the protease outside the active binding site of the protease inhibitor. Nevertheless, some patients may benefit from a second protease inhibitor if therapy is promptly switched before multiple mutations have accumulated.
Drug studies
Observational studies
Combinations of NRTIs and protease inhibitors
A variable-dose plasma concentration-controlled approach to combination antiretroviral therapy (zidovudine, lamivudine, and indinavir) has been compared with conventional fixed-dose therapy in 40 patients in a randomized, 52-week, open trial [ ]. Significantly more concentration-controlled recipients achieved the desired concentrations for all three drugs: there was a good response in 15 of 16 concentration-controlled recipients compared with nine of 17 conventional regimen recipients. However, there was no difference in the occurrence of drug-related clinical events or laboratory abnormalities between the two regimens. Three patients withdrew because of gastrointestinal adverse reactions, one because of a peripheral neuropathy, and one with headache and anemia. There was nephrolithiasis in four cases.
The combination of indinavir + ritonavir 400/400 mg bd plus two NRTIs has been studied in 93 patients in an open, uncontrolled, multicenter trial [ ]. Raised triglycerides (n = 78) and cholesterol (n = 63) were the commonest adverse reactions, followed by nausea (n = 22) and circumoral paresthesia (n = 9). Withdrawal was required in four cases of nausea, four of lipodystrophy, one of diarrhea, and one of osteonecrosis.
Combinations of NRTIs, NNRTIs, and protease inhibitors
In an open, 48-week, single-arm, multicenter phase II study in 99 patients abacavir 300 mg bd, amprenavir 1200 mg bd, and efavirenz 600 mg/day were associated with rashes in 50 patients, possibly because of abacavir hypersensitivity; 17 permanently discontinued one or more drugs as a result [ ]. Other adverse reactions included nausea (n = 41), diarrhea (n = 27), sleep disorders (n = 27), dizziness (n = 25), fatigue (n = 23), hypertriglyceridemia (n = 18), neutropenia (n = 8), hyperamylasemia (n = 4), leukopenia (n = 3), hypercholesterolemia (n = 2), raised alkaline phosphatase (n = 1), and raised aspartate aminotransferase (n = 1).
In infants and children assigned to different combinations of one or two NRTIs plus an NNRTI and/or a protease inhibitor, the numbers of patients with moderate or severe adverse events were as shown in Table 1 [ ]. In cases of rash, the rash was worse in those who were taking nevirapine-containing regimens.
Table 1
Numbers (%) of infants and children with moderate or severe adverse events in a study of one or two NRTIs plus an NNRTI and/or a protease inhibitor
| System affected by the adverse event | Regimen | |||
|---|---|---|---|---|
| Stavudine + nevirapine + ritonavir (n = 41) |
Stavudine + nevirapine + nelfinavir n = 44) |
Stavudine + lamivudine + nevirapine + nelfinavir (n = 44) |
Stavudine + lamivudine + nelfinavir (n = 52) |
|
| Respiratory | 12 (29%) | 18 (41%) | 23 (52%) | 50 (96%) |
| Hematologic (neutropenia) | 17 (41%) | 9 (20%) | 14 (32%) | 23 (44%) |
| Gastrointestinal (nausea/vomiting) | 29 (71%) | 32 (73%) | 18 (41%) | 15 (29%) |
| Liver | 12 (29%) | 14 (32%) | 18 (41%) | 23 (44%) |
| Skin | 27 (66%) | 41 (93%) * | 32 (73%) | 17 (33%) * |
| Body temperature (fever) | 24 (59%) | 30 (68%) * | 20 (45%) | 10 (19%) * |
| Other | 10 (24%) | 25 (27%) | 18 (41%) | 19 (37%) |
Organs and systems
Nervous system
In a randomized comparison of a protease inhibitor-containing regimen and an efavirenz-containing regimen, nervous system adverse reactions were specifically sought [ ]. Patients were randomized to two NRTIs plus one or more protease inhibitors (n = 49) or two NRTIs plus efavirenz (n = 51). The patients who took the protease inhibitors reported the following at week 4: light-headedness (8%), dizziness (5%), difficulty in sleeping (4%), nervousness (4%), and headaches (3%). They reported the following at week 48: difficulty in sleeping (4%), nervousness (3%), headaches (3%), and light-headedness (2%). Three patients withdrew because of adverse events: diarrhea (n = 2) and nephrolithiasis (n = 1).
Sensory systems
The ophthalmoscopic changes of retinal lipemia include a milky-white discoloration of the retinal vessels, beginning at the periphery but progressing to involve the posterior pole as the triglyceride concentration rises. The fundus can appear salmon-colored, owing to the effect of triglycerides on the choroidal circulation.
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Lipemia retinalis and pancreatitis have been reported in a 39-year-old man with HIV infection associated with protease inhibitor therapy [ ]. He developed lipemia retinalis after switching to an antiretroviral regimen including ritonavir and saquinavir (together with zalcitabine and delavirdine). He had previously been taking zidovudine, lamivudine, and indinavir.
Experience from HIV-negative patients with hyperlipidemia has shown that plasma triglyceride concentrations must be at least 28 mmol/l (2500 mg/dl) for lipemia retinalis to occur (reference value below 1.52 mmol/l). This patient had a plasma triglyceride concentration of 53 mmol/l. On withdrawal of ritonavir and saquinavir the appearance of his retinal vessels returned to normal in parallel with a fall in his plasma triglycerides.
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