Session 69
Antiretroviral Chemotherapy: Treatment-Experienced Patients

• Poster 531: ACTC 364: Nelfinavir (NFV) and/or Efavirenz (EFV) in Combination with New NRTIs in Nucleoside-Experienced Subjects (Subj): Week-48 Ultrasensitive (US) HIV RNA Results (Authored by M. Albrecht, D. Katzenstein, R. Bosch, S. Liou, and S. Hammer. NIAID-Sponsored AIDS Clin. Trials Group, Bethesda, MD)
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• Poster 532: ABT-378/Ritonavir (ABT-378/r) Suppresses HIV RNA to <400 Copies/ml in 84% of Protease Inhibitor-Experienced Patients at 48 weeks (Authored by S. Deeks, S. Brun, Y. Xu, K. Real, C. Benson, H. Kessler, R. Murphy, D. Wheeler, C. Hicks, J. Eron, J. Feinberg, R. Gulick, P. Sax, R. Stryker, S. Riddler, M. Thompson, M. King, A. Potthoff, A. Hsu, R. Bertz, A. Molla, H. Mo, D. Kempf, A. Japour, and E. Sun for the M97-765 Study Group. Univ. of California, San Francisco; Univ. of Colorado; Rush; Northwestern; Inf. Dis. Physicians; Duke; Univ. of North Carolina; Univ. of Cincinnati; Cornell; Harvard; Pacific Oaks Res.; Univ. of Pittsburgh; AIDS Res. Consortium of Atlanta; and Abbott Labs)
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• Poster 534: Ritonavir Intensification in Indinavir Recipients with Detectable HIV RNA Levels (Authored by N. Shulman, A. Zolopa, D. Havlir, J. Gallant, E. Race, W. Lam, L. Hill, A. Japour, D. Kempf, E. Sun, and A. Hsu for the M98-985 Study Group. Abbott Labs., IL)
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Fifteen posters were presented which reviewed trials of HAART in people with prior therapy (treatment-experienced). A few of the most important ones are reviewed below.

Poster 531: ACTC 364- Nelfinavir (NFV) and/or Efavirenz (EFV) in Combination with New NRTIs in Nucleoside-Experienced Subjects (Subj): Week-48 Ultrasensitive (US) HIV RNA Results

This report is a further analysis of data from this study of people who had extensive prior NRTI treatment experience. The study compared adding either, NFV, EFV, or both to new RTIs. This question may be less important now, than when this study was begun several years ago, as fewer people are starting treatment with only one or two NRTIs. However, the results have some general applicability since the study found that the best result was obtained when people received drugs from two new classes -- a protease inhibitor and a NNRTI, (EFV plus NFV), 67% had HIV RNA <50 at 48 weeks. Also, this study showed a very poor outcome in the NFV group, compared to EFV, 22% versus 44% with HIV RNA <50 at 48 weeks. All of the people in this study had extensive prior treatment with NRTIs, averaging four or five years.

Poster 532: ABT-378/Ritonavir (ABT-378/r) Suppresses HIV RNA to <400 Copies/ml in 84% of Protease Inhibitor-Experienced Patients at 48 weeks

People who had failed one prior protease inhibitor, and had never received an NNRTI, were randomized to a blinded ABT-378/r dose (400/100 vs. 400/200 mg BID) plus nevirapine (Viramune) and two NRTIs (at least one new). Seventy people were entered into the trial. Previous protease inhibitors included IDV (44%), NFV (36%), SQV (13%), RTV (6%), and APV (1%). After 48 weeks, 49/58 (84%) of all people on treatment had VL <400 copies/ml, 70% based on intent-to-treat (all people who began on the study).

Of significant interest is that 11 patients with >4-fold reduced susceptibility to ABT-378 at baseline, 7 had VL <400 copies/ml at week 48 and one had VL <400 copies/ml at their last visit. The blood levels achieved with ABT-378 are very high and may even suppress HIV in people with some resistance to ABT-378 (see: poster 731) In general, ABT-378 was relatively well tolerated, except for some moderate nausea and diarrhea. Mean increase from baseline in CD4 cells at week 48 was 125 cells. Both doses were well tolerated, with only three discontinuations for adverse events related to ABT-378/r through 48 weeks.

Poster 534: Ritonavir Intensification in Indinavir Recipients with Detectable HIV RNA Levels

Ritonavir (RTV) improves indinavir (IDV) blood levels, and permits twice-daily dosing of IDV, without fasting. This study asked whether adding RTV -- to people with detectable levels of HIV on IDV regimens -- will enhance antiretroviral potency and viral suppression, even in patients with reduced IDV susceptibility.

Patients on IDV, three times a day, and two NRTIs, and viral loads between 50-50,000, switched to combination regimen RTV/IDV 400mg/400mg by dose titration of RTV, (or 200 mg x two days, then 300 mg x three days).

There were significant improvements in HIV RNA observed in many of the 35 people in this study. After 16 weeks, of the 17 people who stayed on the study for the full 16 weeks, 59% of people had HIV RNA <400, and 53% had HIV RNA <50. IDV minimal blood levels increased 272%, peak levels decreased, and total daily levels (or "area under the curve," AUC) remained similar. Five patients, of 26 enrolled, discontinued treatment due to adverse events. The study confirms that IDV blood levels are substantially improved in patients receiving RTV/IDV, 300-400/400 mg twice a day, versus IDV, 800 mg three times a day. Short-term virologic and immunologic improvements were seen in a majority of patients, likely due to the improvement of IDV blood levels.

One concern in interpreting this data is that lower levels of RTV, 200 mg or even 100 mg can allow for twice-daily dosing of IDV, at 800 mg, without food restrictions. So, is the enhanced viral suppression due to the higher blood levels of IDV, or the 400 mg of RTV. We do not know which dosing schema will be better. It may be that the answer will be different for people with good viral suppression, versus the people studied in this report, without good viral suppression. Additionally, adding any RTV increases problems with cholesterol and triglycerides, as was seen in 7/27 people in this study.