Ritonavir+Indinavir. Jon Condra from Merck discussed how a higher indinavir trough level should translate into a more potent regimen. Abbott recommends that the combination of indinavir+ritonavir should be dosed 400 mg of each drug twice daily for both salvage and for initial therapy. Merck suggests that 800mg indinavir+200 mg ritonavir ought to be more effective for salvage because the 800/200 dose produces a higher trough level of indinavir. Using ritonavir with indinavir raises the blood levels of indinavir and the raised levels are sustained through the dosing period. Abbott recommends that no food or hydration restrictions are necessary. As well, in addition to Condra's talk there were two posters presented on clinical studies of indinavir+ritonavir both using 800/200 dosing. At the Retrovirus Conference there was a poster showing the use of ritonavir as intensification to an indinavir regimen when a person did not reach undetectable. This report is available on the NATAP web sit in the Retrovirus Conference Summaries. It's true that the 800/200 dosing regimen produces trough levels of indinavir than the 400/400 dosing regimen. Two key questions are --will the incidence of kidney stones increase when indinavir blood levels are higher, as with the 800/200 dose; the second consideration is safety, tolerability, and antiviral efficacy: Will the 800/200 dose have more antiviral activity and be as tolerable and safe? The ACTG has a pilot study comparing the 800/200 dose to 400/400 for individuals who failed a protease inhibitor regimen. Two private practitioners reported their retrospective analyses of patients who had used 800/200. Grossman's report on 41 patients found no cases of kidney stones. The second report by Campo from the University of Miami did not mention whether or not they observed kidney stones.

In Condra's report he presented in vitro data from looking at a panel of 20 PI-resistant viral isolates from patients who experienced long-term virologic failure of IDV monotherapy, patients failing nelfinavir as their first PI, and from patients who failed IDV following their initial nelfinavir failure. All viral isolates except one contained multiple IDV mutations. The one exception had NFV related mutations only (D30N). Condra reported that most of the viral isolates had extensive phenotypic resistance to IDV, RTV, and NFV (corrected for human serum protein binding). Protein binding reduces the amount of drug that the virus is exposed to in the blood. Different protease inhibitors have different degrees of protein binding. Using in vitro testing, Condra said that the 800/200 dose resulted in IDV drug levels 70 times higher than that necessary to suppress 95% of viral replication (IC95). He said the IDV drug levels achieved exceeded the IC95 in at least 18 of the 20 viral isolates. The IDV trough levels achieved with the 800/200 dose are higher than that achieved with the 400/400 or 800/100 dose. He suggests that the high IDV drug levels in the blood may explain the antiviral potency and clinical success of this regimen.

From data initially reported at the 6th Retrovirus Conference in 1999, Condra reported that the 12 hour trough of IDV (using a high-fat meal) with the 400/400 dose was 1891 nM, with the 800/100 dose 2233 nM, and with 800/200 it was 5344 nM.

The data reported at the 6th Retrovirus Conference in 1999 can be seen on the NATAP web site by clicking here.

Both studies were retrospective analyses of patient's medical charts. Howard Grossman reported on 41 patients who were treatment experienced (30/41 (73%) had prior NNRTI experience) and had a median viral load of 30,000 copies/ml. Their median CD4 was 258 (range 113-378). The mean observed time on study therapy was 7.2 months. Using an as-treated analysis, the proportion of patients that had <400 copies/ml at 3, 6, and 9 months were 51% (21/41), 56% (17/30) and 62% (10/16), respectively. The dose was 800/200 indinavir/ritonavir. The patients were had extensive previous treatment experience. The study design is a multi-center (6 site) retrospective chart review study of individuals who had failed at least 1 PI containing regimen. 95% of the patients had prior exposure to indinavir or ritonavir. The patients had a mean number of 6 prior antiretroviral (ART) regimens, and a mean number of 3 prior PI regimens. The average number of NRTIs in the new RTV/IDV regimen was 2 (range 1-4). 7/29 patients were NNRTI naÔve at baseline, and 29/41 patients had a NNRTI in their IDV/RTV regimen. After 12 (n=41), 24 (n=30), and 36 (N=16)weeks, the median viral load reduction from baseline was -1.65 log, -1.46 log, and -1.66 log, respectively. The median CD4 increase was about 75 at week 24.

Grossman reported there were no cases of kidney stones, and there were 2 discontinuations. 19 of 41 patients reported side effects. There were 7 cases of nausea & vomiting, 2 cases of diarrhea, 5 cases of rash & dry skin, and 1 case of paresthesia.

Rafael Campo, from the University of Miami, reported on his retrospective analysis of 27 patient's medical charts, who started salvage regimens consisting of 800 mg IDV twice daily and 200 mg of RTV twice daily, with at least one NRTI and/or a NNRTI. Patients had at least one PI containing regimen which they failed. Failure was defined as a rebound in viral load to >1000 copies/ml after having a VL <400 on at least one occasion or as failure to achieve VL <400 after >6 months on the original PI regimen. Rsponders were defined as patients with a viral load <400 on at least one occasion after starting the RTV/IDV regimen. Non-responders were defined as patients who never reached <400 regardless of how much their viral load decreased.

Campo reported that despite the presence of IDV and RTV genotypic and phenotypic resistance prior to starting the 800/200 mg twice daily IDV/RTV regimen, viral suppression <400 copies/ml is achieved. 4/4 with baseline phenotypic resistance, and 10/13 with baseline genotypic resistance achieved viral suppression. He associates failure to achieve viral suppression to non-adherence. Grossman's report did not address adherence of his patients.

Camp reported that by reviewing patient's charts he found 15 responders and 12 non-responders followed for a mean of 32 and 31 weeks, respectively. Among the responders, 6 were African-Americans and 9 were Hispanic. Among the non-responders, 4 were African-Americans, 4 Hispanic, 3 Haitian, and 1 was non-Hispanic white.

At initiation of IDV/RTV regimen CD4 counts were 283 and 150, and viral load was 156,000 copies/ml and 228,000 copies/ml for responders and non-responders, respectively. The patients treatment experience folows. Both groups had previously used 6-7 HIV ART drugs. Both groups had 2.8 mean prior HAART regimens. Their mean duration of prior therapy was 117-137 weeks. Both groups had received a mean of about 2.5 protease inhibitors, and 2.5 protease inhibitor regimens. The responder group had 101 weeks mean duration of PI therapy and the non-responders 86 weeks.

Interestingly, Campo reported that having genotypic and phenotypic baseline resistance to IDV and RTV was associated with a more favorable response to the RTV/IDV regimen rather than with therapeutic failure. Campo concluded that since this was a marker for better adherence. The individuals with baseline resistance may have had so because they were more adherent to their previous failing regimens. In patients with genotypic resistance to IDV and RTV, 10/13 (77%) achieved viral suppression. In patients without genotypic resistance at baseline, 5/14 (36%) had achieved viral suppression. In patients with phenotypic resistance at baseline, for whom testing was done and available („ 4X fold resistance), 4/4 had viral suppression. In patients with <4X phenotypic resistance, 5/15 achieved viral suppression. All patients showing resistance to IDV or RTV were resistant to both. IDV phenotypic resistance at baseline ranged from 4- to 35-fold, and RTV phenotypic resistance was 11- to 72-fold.

Campo reported that 83% (5/6) responders had at least 2 new drugs as part of their IDV/RTV regimen, while only 17% (1/6) of the non-responders had 2 new drugs. He also reported that 5/8 (63%) of the responders were NNRTI naÔve and used a NNRTI in their new regimen, while 3/8 (37%) of the non-responders were NNRTI naÔve and used a NNRTI in the new regimen.

8 of the 15 responders (53%) have maintained VL <400 copies/ml and 3 (20%) have <50 copies/ml. 5 patients (33%) had transient VL rebounds to >400 but it was associated with non-adherence. Campo reported they returned to <400 upon re-initiation of IDV/RTV regimen. 2 patients have had viral load rebounds to 151,000 and 2696 copies/ml, respectively, reportedly due to non-adherence. Their viral loads decreased to 451 and 873 copies/ml, respectively (6 and 14 weeks later, respectively) upon re-starting the regimen.

Larger prospective clinical trials are needed to confirm these results and to better characterize safety, tolerability, and viral responses in both dosing regimens (800/200 and 400/400).