THE EFFECTIVENESS of COMBINED SAQUINAVIR and KETOCONAZOLE TREATMENT in REDUCING HIV VIRAL Load Wilbert C

THE EFFECTIVENESS OF COMBINED SAQUINAVIR AND KETOCONAZOLE TREATMENT IN REDUCING HIV VIRAL LoAD Wilbert C. Jordan, MD, MPH Los Angeles, California

With the advent of protease inhibitors, the treatment of persons infected with the human immunodeficiency virus (HIV) has resulted in lower levels of the virus in the blood. The first of these protease inhibitors was saquinavir, which inhibits the HIV protease enzyme respon- sible for post-translational processing of Gag and Gag-Pol poly protein precursors into their functional products. Studies have suggested that ketoconazole, given in combination with saquinavir, increases the bioavailability of saquinavir. This study compared the HIV viral load in patients treated with saquinavir alone and in combination with ketoconazole. Results showed that while all patients who received saquinavir exhibited a positive response, patients who also received ketoconazole had a greater drop in viral load levels. In addition, a greater number of patients had undetectable viral levels after 3 months on the ketoconazole/ saquinavir regimen. These results indicate that the combination of saquinavir/ketoconazole for the treatment of HIV requires further study. (J Nat Med Assoc. 1998;90:622-624.)

Key words: saquinavir * ketoconazole disease arena. Many physicians feel that if the viral * human immunodeficiency virus load can be maintained at zero or on detectable blood levels, then there is a possibility of a complete Since the introduction of protease inhibitors, per- viral washout over a prolonged period. The protease sons infected with human immunodeficiency virus inhibitor, a new class of drug designed to prevent the (HIV) and the affected community have experienced protease enzyme from cleaving the "new viral parti- changes. First, there has been a change in the health cle" and thus preventing completion of the virus, has status of many HIV-infected patients, including some been the key player in this new approach. with full-blown acquired immunodeficiency syn- The first of the new inhibitors was saquinavir. drome (AIDS) with multisystem involvement. Saquinavir is a hydroxyethylamine transition-state Second, there has been a change in the attitude of the analog of the HIV-negative protease cleavage site HIV/AIDS affected community. There is a feeling of that has potent in-vitro inhibiting activity against a hope, and many feel we have entered the chronic wide variety of laboratory and clinical isolates of HIV.1 Early studies showed saquinavir to have a From the Department of Internal Medicine and Family Practice, bioavailability about a third the strength of ritonavir Charles R. Drew University of Medicine and Science, King-Drew or indinavir. Studies also suggested that ketocona- Medical Center, Los Angeles, California. Requests for reprints zole, given as a 200-mg daily dose, increased the should be addressed to Dr Wilbert C Jordan, Dept of Internal bioavailability of saquinavir. Saquinavir inhibits the Medicine and Science, King-Drew Medical Center, 12021 S HIV protease enzyme responsible for post-transla- Wilmington Ave, Los Angeles, CA 90059. tional processing of Gag and Gag-Pol poly protein

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Table 1. Comparison of Polymerase Chain Reaction Table 2. Comparison of Polymerase Chain Reaction (PCR)-RNA Viral Loads in Patients Receiving Saquinavir (PCR)-RNA in Patients Receiving Saquinavir Versus Alone and in Combination With Ketoconazole Saquinavir Plus Ketoconazole Initial PCR 3 Months Initial 3 Months Saquinavir Alone Saquinavir Alone 47,200 20,000 No. patients 20 20 54,000 15,000 Average PCR 69,363 15,992 11,000 0 Log change .5 17,000 450 No. patients with non- 18,000 6000 detectable levels at 3 59,000 33,000 months 2 788,000 20,000 Saquinavir Plus Ketoconazole 104,000 40,000 100,000 20,000 No. patients 20 20 72,000 12,000 Average PCR 64,142 1785 10,000 1400 Log change 1.5 6000 0 No. patients with non- 324,000 48,000 detectable levels at 3 86,000 20,000 months -12 45,000 12,000 58,000 20,000 84,000 24,000 precursors into their functional products. Evidence 19,700 4,000 suggests saquinavir is extensively metabolic by the 20,000 8,000 cytochrome P450 enzymes, which are present in the liver and the gut wall. Therefore, low absorption Average and low bioavailability of high first pass metabolism. 69,363 15,992 This raised the question of how this impacted the fall in viral load and whether it was sustained. Saquinavir Plus Ketoconazole This study compared the HIV viral load in 102,000 10,000 patients treated with saquinavir alone and in combi- 41,000 0 nation with ketoconazole. 10,000 0 83,000 0 MATERIALS AND METHODS 21,000 4000 All patients who had been on combination anti- 10,000 0 retroviral therapies were evaluated. Those having a 5000 0 decline in CD4 count were the first to be started on 100,000 0 saquinavir. Patients started on saquinavir during the 17,500 0 33,000 0 first month were started on the drug alone. Those 284,000 12,000 patients receiving the drug during the second month 126,000 4000 of its availability were started with ketoconazole 200 47,200 524 mg daily. 7000 0 Excluded were patients <13 years, lactating or 19,000 0 pregnant women, and patients who felt they were 53,000 0 not ready to handle this regimen. 56,000 1200 44,000 0 RESULTS 150,000 2200 All patients who received saquinavir exhibited a positive response (Table 1). However, patients who Average also received ketoconazole had a greater drop in 64,142 1785 viral load levels. In addition, a greater number of patients had undetectable viral levels after 3 months

JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 90, NO. 10 623 SAQUINAVIR & KETOCONAZOLE on the ketoconazole/saquinavir regimen (Table 2). patients? None of the study patients on the saquinavir/ketoconazole regimen had tolerance DISCUSSION problems, and only seven patients had mild eleva- The advent ofprotease inhibitors has raised more tions in their LFITs. Finally, does indinavir resistance hope than probably any other HIV treatment dur- in patients automatically render them resistant to ing the AIDS crisis. We now have the ability to at saquinavir? These questions require fiurther investi- least lower to undetectable levels the viral particles gation. in the blood. This obviously leads to several ques- tions. First, can these low levels be sustained? Literature Cited Second, if so, will these patients over time rid them- 1. Callier AC, Coombs RW, Schoenfeld DA, Basset RL, selves of all virus by tissue cultures? The longer we Timpone J, Baruch A, et al. Treatment of human immuno-defi- ciency virus injection with saquinavir, zidovudine, and zal- can maintain patients at this level, the better. Third, citabine. NEnglJMed. 1996;334:1011-1107. will the new soft-gel capsules be easily tolerated by

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