Group 1:
Treatment arm A: 400 mg bid RTV + 400 mg bid SQV (n=35), every 12 hours
                      B: 600 mg bid RTV + 400 mg bid SQV (n=35), every 12 hours

Group 2:
                      C: 400 mg tid RTV + 400 mg tid SQV (n=33), every 8 hours
                      D: 600 mg bid RTV + 600 mg bid SQV (n=37), every 12 hours

The median number of antiretroviral drugs previously used was 2 for each of the 4 treatment groups.The median baseline plasma HIV RNA ranged from 4.5 log (31,600 copies/ml) to 4.7 log (50,100 copies/ml) for each of the 4 groups. The baseline median CD4 counts ranged from 266-300 for each of the 4 groups.

The two arms: 400/400 bid and 600/400 bid- were both more tolerable than the other two arms

The week 60 data includes only individuals who remained on study drugs. Study dropouts were not included. It is important to bear in mind that a number of the participants originally randomized to Groups C or D changed their dosing regimens to A or B. The actual number of such changes follow the table. 27 participants added up to 2 NRTIs (usually d4T/3TC) after week 12 (see Table 6). Although data is reported for all 4 arms, the 400/400 and 600/400 are more widely used. The incidence of side effects is higher in arms C and D. Also, arms C and D may not be more efficacious than arms A and B, but noncompliance may have been higher when using doses in arms C & D.

As you can see almost half of participants were randomized or switched to 400/400 bid by week 24. By week 60, 51% of those still on treatment were on 400/400 bid.

All participants who were on study at week 48 and had sufficient stored plasma available had HIV RNA measured by the Roche Ultrasensitive test (lower limit of detection 50 copies/ml). 86% (66/80) who were <200 copies/ml by the standard assay also were <50 copies/ml using the Ultrasensitive test.

15 participants who were <200 copies/ml for at least 8 weeks after about 1 year on ritonavir-saquinavir alone and did not add NRTIs had CSF evaluations. Although this data is encouraging, CSF viral load was taken only once which was after being on therapy for >1 year. There was no CSF evaluation taken prior to study entry. Therefore there was no baseline measure taken to compare to the measure taken during therapy, and to see if there was an actual change and to measure the change. 14/15 (93%) had CSF <400 copies/ml. 1 person on RTV-SQV 600-600 bid had a plasma viral load <200 copies/ml but had a CSF viral load of 650 copies/ml. In the Prometheus Study, both baseline and during therapy CSF measures were taken for individuals on RTV/SQV and RTV/SQV plus nucleosides. That data is below.

The incidence of all side effects including those related to the liver were increased for those receiving the dose regimens in arms C and D. For that reason, the dose regimens in arms A and B are recommended. Abbott prefers to recommend the arm A dose regimen of 400/400 bid because of the lowest incidence of side effects compared to the other dose regimens; and, because the CD4 increases and viral load reductions appear equal to those of the other dose regimens.

The 600/400 bid regimen (Group B) has certain pharmacokinetics characteristics you may want to consider. Because you are taking 50% more ritonavir (vs 400/400 bid regimen), the peak, trough and AUC blood levels for both ritonavir and saquinavir are higher compared to if you were taking 400/400 bid. Is that an advantage? I think it offers some potential benefits. If you were taking ritonavir without saquinavir, 400 mg ritonavir would be suboptimal. However, the 60 week data shows that 400/400 bid was equivalent to 600/400 bid as measured by CD4, viral load reductions and percent below detection. But, having higher trough levels of a drug at the end of a dosing period creates a comfortability or cushion, but tolerability and consideration of long term effects are factors.

Some individuals, soon after starting ritonavir+saquinavir regimen, may develop significant elevations in LFTs to the 500-600 level. Rather than immediately discontinuing therapy over concern about those elevations, trying to work through the elevations while continuing on same regimen with very close monitoring may be successful. The elevations may peak and slowly decrease over time to a manageable level.

• 11% (16/141) of patients developed grade 3 or 4 (1500 mg/dl) elevations in triglycerides levels
• 6/16 were treated with antihyperlipidemic agents (drugs that may lower triglyceride levels)
• No cases of pancreatitis have been observed

At week 48, the mean increase from baseline in triglyceride levels for each of the 4 dose regimens were about: +175 for both Groups A and B (400/400 bid, 600/400 bid); +290 for Group D (600/600 bid); +260 for Group C (400/400 tid). The suggestion is that the regimens in A & B are less likely to cause greater increases in triglycerides.

In the week 24 data report (see the Double Protease Combinations report on the NATAP website) the investigators reported a compliance assessment of participants up to week 24. They concluded compliance is highly correlated with treatment response. At week 24, 90% of those defined as being compliant were <200 copies/ml; 97% of those defined as compliant were <1000 copies/ml. Only 66% defined as noncompliant were <200 copies/ml and only 73% were <1000 copies/ml. See the actual report for the investigators definition of compliance.

This report also was issued at week 24 and is discussed in the above mentioned report on the NATAP website. Investigators showed data that of individuals with <1001 copies/ml at week 12, 98% had <200 copies at week 24; of individuals with >1000 copies/ml at week 12, only 25% had viral load <200 copies/ml. If an individual’s viral load was <201 copies/ml at week 12, 93% were <200 copies/ml at week 24. At the Chicago Retrovirus Conference, Lisa Demeter reported that data from ACTG 320 indinavir clinical endpoint study indicates that early viral load reductions also predict treatment response in that study.

NATAP reported preliminary data from the Prometheus Study that was presented at the Hamburg AIDS Conference. See the report on Double Protease Combinations on this website for details. A 24 week update was reported in Chicago. Investigators reported CSF viral load changes between week 0 and week 12 for 8 individuals receiving RTV/SQV alone and for 9 individuals receiving RTV/SQV+d4T. Unlike the CSF data above, this has a comparison between two time points (weeks 0 and 12).

• 138 participants were randomized in this open label study to receive either RTV/SQV (400 mg bid of both) or RTV/SQV+d4T
• there were 7 discontinuations; adverse events experienced were mild/moderate diarrhea (50%); oral parasthesia (50%)- tingling and numbness around mouth; elevated liver enzymes (28%) - more common in RTV/SQV/d4T arm; elevated triglycerides (25%)
• mean baseline CD4 was 273 and 251 for protease alone and d4T arms, respectively; mean baseline HIV RNA was 4.3 log (about 20,000 copies/ml) for both arms; 54% in protease alone arm had previous NRTI experience while 4& % in d4T arm had revious NRTI experience
• at week 24, 64% taking RTV/SQV alone and 87% taking RTV/SQV/d4T were <400 copies/ml (total # of evaluable patients at week 24 is111)
• if viral load did not reach undetectable by week 18, intensification was permitted; 6 patients in the RTV/SQV arm intensified with d4T/3TC and all 6 were undetectable by week 36
• mean CD4 increase was about +145 for both arms

As you can see, of the patients with detectable VL in serum and CSF at week 0, and undetectable VL in serum at week 12 1/3 on RTV/SQV has an undetectable VL in CSF at week 12, as compared to 4/5 in the RTV/SQV/d4T arm. The results from this study are preliminary; it may be too soon to draw conclusions and too small a number of patients at this point to draw conclusions. Week 12 may be too soon to evaluate the effect of a therapy on CSF viral load. In the CSF evaluation discussed above where 14/15 had undetectable CSF viral load, the CSF viral load levels were assessed after one year of therapy. The authors said that neither ritonavir nor saquinavir was found to penetrate the CSF well in 9 patients as measured by RTV or SQV CSF drug levels. But, ritonavir is 99% protein bound in blood, and if you were looking for unbound ritonavir in blood you may not be able to find it.

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No participants had current opportunistic infections at study entry. The median baseline HIV RNA was 39,917 copies/ml (range 19,496 - 109,065). The median CD4 count was 327 cells (range 19-621).

The investigators reported that from genotypic analysis of isolates drawn from all subjects in weeks 15-22 and weeks 20-35 no occurrence of the D30N mutation was observed. At month 12, the median decrease in HIV RNA was about 2.4 log (n=9) and the median increase in CD4 was about 100 (the increase at month 11 was 172), n=9. The percent <500 copies/ml was 80% at month 12 (n=9) and 90% at month 11. As you can see, the data is based on a small number of individuals.

** patient diagnosed with H. Pylori which may have contributed to dyspepsia

The second study called SPICE was reported by M Opravil and others and is a pilot randomized study enrolling 157 individuals comparing 4 treatment arms; the number randomized to each arm in parenthesis:

• SGC SQV 1200 mg tid + 2 NRTIs (A), (26)
• NFV 750 mg tid + 2 NRTIs (B), (26)
• SQV SGC 800 mg tid + NFV 750 mg tid + 2 NRTIs (C), (51)
• SQV SGC 800 mg tid + NFV 750 mg tid without NRTIs (D), (54)

Crossovers to other arms were permitted for intolerance or virological failure. Participants had to be able to start at least 1 new NRTI. The study investigators said the data should be considered preliminary until formal analysis at week 48.

All crossovers were to NFV+SQV+2 NRTIs.

Of 16 reported serious AEs, 4 were considered possibly treatment related:

• unstable diabetes (SQV+NRTIs)
• renal colic (SQV/NFV+NRTIs)
• diarrhea and cachexia (SQV/NFV no NRTIs)
• fever (SQV/NFV no NRTIs)

By 32 weeks, 24 patients crossed over to NFV+SQV+2 NRTIs (C): 6 for toxicity and 18 for virologic failure (2 from arm A, 5 from arm B, and 11 from arm D). The authors said 11 additional patients were defined as virologic failures but had not yet crossed over at the time of this analysis. The following analysis of data was based on individuals remaining on the therapy to which they were originally randomized (crossovers and discontinations were not included). The number of evaluable patients are in parenthesis.

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21 patients were initially enrolled. They were protease naive, CD4 ( 100, HIV RNA ( 30,000 copies/ml. The median baseline viral load was 50,500 copies/ml (range 9000-316,000); the median baseline CD4 was 259 (range 12-568); 58% had no prior nucleoside experience and the remaining 42% were NRTI experienced.

Group A received NFV 500mg every 12 hrs + IDV 1000 mg every 12 hrs (q12h) for one week. Starting in the second week they received NFV 750 mg q12h + IDV 1000 mg q12h. Group B started with NFV 750 mg q12h + IDV 1000 mg q12h.

Based on the data from Agouron’s single dose studies it was expected by some that those effects seen in that study (increased IDV AUC by 51%-single dose of IDV; increased NFV AUC by 83%-single dose of NFV) would be seen when combining NFV with IDV. The investigators in this study did not observe those PK responses reflected in this study. This indicates that you cannot generally rely upon single or limited dosing studies to predict drug interactions and optimal dosing regimens. To do so is risky. It is safer to wait for additional research identifying adequate dosing regimens.

Investigators in this study found that when combining 1000 mg IDV q12h with 750 mg NFV q12h: indinavir blood levels were similar to indinavir taken at the standard dosing of 800 mg every 8 hours; that indinavir did not increase NFV steady state blood levels, resulting in low NFV trough levels. At week 8, 7/10 study participants were <500 copies/ml, and 9 patients had a mean increase in CD4 of 156 cells. Treatment was discontinued in 1 person for rash; other adverse events included: diarrhea/loose stools (6), bloating (2), and nephrolithiasis (1); nephrolithiasis can lead to kidney stones.

Because of the low NFV trough levels, a higher dose of nelfinavir was investigated. All participants raised their dose of nelfinavir from 750 to 1000 mg q12h while maintaining IDV dosing at 1000 mg q12h.

For an explanation of terms like trough, AUC, Cmax and pharmacokinetics (PK) , see the report titled Primer on PK on the web site. Without understanding these terms it is difficult to understand the considerations that go into selecting dosing, and to understand the following tables and much of the other information in NATAP’s reports.

As you can see the trough and AUC (italics) for the NFV 750 q12h dosing regimen was not increased by the addition of IDV, compared to the trough and AUC values for taking NFV monotherapy every 8 hrs (trough- 0.7 vs 1.5 mg/L, AUC- 50 vs 56 mg hr/L).

The investigators reported the mean percent change resulting from increase in NFV dose of 750 mg q12h to 1000 mg q12h in AUC, Cmax and trough for these 5 patients was 31%, 27%, and 35%, respectively.

10/21 (47%) had undetectable HIV RNA by the Roche Amplicor viral load test (<400 copies/ml). 6 of these10 were undetectable using the Roche ultrasensitive test (<50 copies/ml). Three study participants added NRTIs to their regimen after at least 12 weeks either for virological (viral load) failure or to increase antiviral effect to prevent virological failure. The median increase in CD4 from baseline (12-32 weeks) was 133 cells. There were 5 discontinuations.