Selected Highlights from Recent Conferences

Ritonavir plus Indinavir is a Promising Regimen

Twice daily ritonavir plus indinavir, 400 mg of each, is a promising regimen.

• Combination of ritonair plus indinavir, 400 mg each twice daily, leads to lower peak levels and 3-6- fold higher trough levels of indinavir than standard dose indinavir (800 mg every 8 hours)
• Indinavir exposure ("area under curve") is similar to that of standard monotherapy dose
• Indinavir half-life increased from 2 to 5.8 hours
• No effect seen on levels of ritonavir, when compared to standard dose
• Adherence is likely to be higher with twice-daily versus 3-times-daily dosing of indinavir.

Hsu A and others. Evaluation of potential ritonavir and indinavir combination BID regimens. ICAAC. Abstract A-57.

Nelfinavir plus Saquinavir is an Effective Combination

Study 1 (SPICE study)

• Study of 157 patients (10% women) in randomized open-label 48-week study
• Participants used 2-4 drugs; 54% had no previous HIV therapy
• Entry viral load was greater than or equal to 5,000 copies/mL
• 54% were treatment-naive; all were able to start at least 1 new nucleoside analog drug
• 4 regimens were used: nelfinavir 750 mg every 8 hours plus saquinavir soft-gel 800 mg every 8 hours with or without 2 nucleoside analogs; 2 nucleoside analogs with nelfinavir or saquinavir soft-gel capsule (11% of treatment-experienced patients in nucleoside analog groups started 2 new nucleoside analogs)
• Mean baseline CD4 cell count was 307 cells/mm³ and mean HIV viral load was 4.8 log copies/mL

• At 16 weeks in 133 patients, mean CD4 cell count increase 90-110 cells/mm³ mean decrease in viral load using a test with a limit of detection of 400 copies was 1.6-1.9 log (1.9 log in 4-drug group); mean decrease in viral load using a test with a limit of detection of 50 copies was 2.0-2.6 log (2.6 log in 4-drug group)
• Viral load became undetectable (limit of detection 400 copies) in 84% in 4-drug group, in greater than 90% of 4-drug group participants with no prior HIV therapy, in 76% of the saquinavir plus 2 nucleoside analog group, in 57% of the nelfinavir play saquinavir group, and in 50% of the nelfinavir plus saquinavir group)
• Viral load became undetectable (limit of detection 50 cop) in 57% of saquinavir plus 2 nucleoside analog group, in 49% of the 4-drug group, in 32% of the nelfinavir plus 2 nucleoside analog group, and in 28% of the nelfinavir plus saquinavir group
• Side effects experienced inlcuded diarrhea (19-46%), nausea (8-19%), abdominal pain (2-8%), vomitting (2-8%), fatigue (0-6%), weakness (0-8%), joint aches (2-8%)
• 6-15% of each group discontinued or crossed-over into another group
• Study is continuing to 48 weeks
• The authors concluded that a 4-drug combination including nelfinavir plus saquinavir-soft gel shows a potent initial viral load suppression and is reasonably well tolerated

Study 2 (Ottawa, Ontario)

• 14 patients (7% women) in open-label study for 12 months
• Participants used 2-4 drugs; no previous protease inhibitor use
• Nelfinavir used at standard dose of 750 mg every 8 hours plus saquinavir soft-gel capsule at reduced dose of 800 mg every 8 hours with or without 1 or 2 nucleoside analog drugs (AZT or 3TC or d4T)
• Entry criteria included a CD4 cell count of 25-500 cells/mm³ and an HIV viral load greater than 20,000 copies/mL. Participants had no previous protease inhibitor therapy, were on a stable nucleoside analog regimen or had a "washout period"
• Median baseline CD4 cell count was 327 cells/mm³ and mean viral load was 39,917 copies/mL. 11 of 14 had taken prior nucleoside drugs while 3 had not
• After 11 months (in 10 patients), viral load became undetectable (limit of detection 500 copies/mL) in 90%
• Median viral load decreased by 2.1 log copies/mL
• Median CD4 cell count increased by 175 cells/mm³
• After 20-35 weeks (in 12 patients), the common nelfinavir mutation D30N was not detected, and the common saquinavir mutations L90M or G48V were found in 4 of 13 and was associated with an increase in HIV viral load
• Side effects were moderate and included diarrhea in 43% (83% of these were found to have intestinal parasites), headaches (21%), rectal gas (14%), and heartburn, abdominal pain, abdominal cramps, weakness and pain in legs (7% each)
• No serious treatment-related side effects and no clinically significant abnormal laboratory abnormalities were found.

Kravcik S and others. Protease gene mutations and long-term follow-up of HIV-infected patients treated with Viracept (nelfinavir mesylate) plus saquinavir-soft gel capsule. ICAAC. Abstract I-191

Posniak A and others. NV15436 study of protease inhibitors in combination in Europe (SPICE); (saquinavir [soft gel] plus nelfinavir). ECCATHI. Abstract and oral presentation 209.

Ritonavir plus Saquinavir Leads to Undetectable Viral Load in Cerebrospinal Fluid

Study 1

• Open-label, randomized study of 141 patients no protease inhibitor drug use and nucleoside analog use discontinued, at several North American locations; cerebrospinal fluid (CSF) data was available for 13 patients
• Participants received ritonavir plus saquinavir, 400-600 mg each twice daily or 400 mg of each 3 times daily, for 60 weeks; nucleoside analog drugs were discontinued at the start of therapy
• Median baseline CD4 cell count was 264 cells/mm³ and viral load was 57,000 copies/mL in the 13 patients in CSF substudy
• After 48-60 weeks, blood plasma viral load was undetectable in 90% of 109 patients after 48 weeks of follow-up
• CSF viral load was undetectable (limit of detection 400 copies) in 12 of 13 (92%); 13th patient (with drug doses 600 mg each) had CSF viral load of 650 copies/mL and plasma level less than 200 copies/mL
• Of 109 patients completing 48 weeks, the fewest discontinuations due to drug adverse events was in the 400 mg-400 mg group
• Drug levels in CSF are still being evaluated; CSF white cell count data were not presented
• The authors concluded that for HIV positive patients without protease inhibitor experience, the double protease combination of ritonavir plus saquinavir, 400 mg each every 12 hours, is the best tolerated. It leads to significant rates of undetectable viral load within 1 year in both blood plasma and CSF

Study 2

• A case report from London described the detection of a CSF viral load of 13,800 copies/mL and a plasma viral load of 1,800 copies/mL in a patient taking ritonavir plus saquinavir for at least 2 weeks. The patient did not have meningitis.
• The authors concluded that a combination of 2 protease inhibitors alone may not provide sufficient antiviral effect in the brain to prevent HIV dementia. They continued that the CSF may "function as a sanctuary site and source of drug-resistant escape mutations."
• While the plasma viral load was reasonably low, the patient may not have been taking therapy long enough to achieve undetectable levels in either body compartment.

Farthing C and others. Cerebrospinal fluid (CSF) and plasma HIV RNA suppression with ritonavir-saquinavir in protease inhibitor naive patients. ICAAC. Abstract LB-3.

Moyle GJ and others. Pharmacokinetics of saquinavir at steady state in CSF and plasma: correlation between plasma and CSF viral load in patients on saquinavir containing regimens. ICAAC. Abstract 235.

4-Drug Combination Twice Daily Leads to 100% Undetectable Viral Load

• All participants had never taken protease inhibitor drugs or 3TC, 80% had never taken any antiretroviral drugs at all.
• 12 patients at Aaron Diamond Center in New York City with early to chronic HIV infection; 80% had never taken any anti-HIV therapy and 100% had never taken protease inhibitors or 3TC; duration of HIV infection ranged from 90 days to 8 years
• Regimen consisted of ritonavir 400 mg every 12 hours (after 21 days, increased to 500 mg for 7 days and then to 600 mg) plus saquinavir 400 mg every 12 hours (after 42 days, saquinavir increased to 600 mg every 12 hours) plus AZT 300 mg every 12 hours (later changed to d4T every 12 hours in 3 patients) plus 3TC 150 mg every 12 hours. AZT/3TC were added on study day 14
• Mean baseline CD4 cell count was 385 cells/mm³ and mean HIV viral load was 5.3 log copies/mL
• At 48 weeks in 10 patients, the median CD4 cell count increase was 86 cells/mm³
• At 16 weeks, median viral load decrease was 3.7 log copies/mL
• At 24 weeks, 100% of patients (10 of 10) had undetectable viral load (limit of detection 50 copies); at 48 weeks, 100% of patients (9 of 9) had undetectable viral load (limit of detection 25 copies)
• At 48 weeks, 7 of 10 had negative lymphoid tissue (lymph node, tonsil or intestinal lymph tissue) cultures for HIV even after CD8 cells were removed in vitro
• At 48 weeks, 4 of 4 patients tested had negative CSF HIV cultures
• 2 of 6 tonsil lymph tissue did have multispliced HIV RNA consistent with RNA of regulatory genes not RNA-associated with active HIV reproduction
• 2 patients withdrew from study due to increased liver enzymes (1 had grade 4, life threatening elevation; 1 of those 2 was replaced in the study)
• Gastrointestinal side effects including nausea and diarrhea were common, leading to the withdrawal of 1 patient
• 2 patients changed from AZT to d4T due to nausea
• The authors concluded that this 4 drug regimen including double protease inhibitor therapy leads to a quick, significant and persistently undetectable reduction of HIV viral load in 100% of patients who can tolerate the drugs.

Talal A and others. Saquinavir in combination with AZT/3TC and ritonavir: a conventional BID regimen. ICAAC.Abstract I-208.

Ritonavir plus Saquinavir Added to AZT plus 3TC (4 Drugs Twice Daily)

• Pilot phase II open-label study of 16 patients in France (ANRS 069 study)
• Regimen included ritonavir 600 mg plus saquinavir 400 mg, every 12 hours
• At entry, patients had been taking AZT/3TC for greater than 3 months (no previous protease inhibitors) and had a CD4 cell count less than 200 cells/mm³ and HIV viral load greater than 20,000 copies/mL
• Mean baseline CD4 cell count was 103 cells/mm³ and mean HIV viral load was 4.86 log copies/mL; mean prior antiretroviral therapy was 49 months (i.e., extensive prior nucleoside treatment)
• After 24 weeks, mean CD4 cell count increase was 93 cells/mm³
• Median viral load decrease was 3.0 log copies/mL
• Viral load became undetectable (limit of detection 200 copies) in 62% (10 of 16)
• Side effects included elevated blood triglycerides (94%), diarrhea (69%), numbness around the mouth (31%), hot flushes (25%), taste impairment (25%) and increased liver enzymes (19%)
• 56% (9 of 16) had ritonavir dose reductions due to adverse events (6 patients reduced to 500 mg twice daily and 3 patients to 400 mg twice daily)
• The authors concluded that ritonavir plus saquinavir added to a regimen of AZT/3TC in patients without prior protease inhibitor experience leads to impressive surrogate marker data.

Michelet C and others. Safety and efficacy of a combination of ritonavir and saquinavir added to AZT plus 3TC in HIV-infected patients. ICAAC. Abstract I-202.

4-Drug Therapy in People with Advanced AIDS

• 58 patients were included in observational study for 48 weeks; 69% had prior protease inhibitor therapy and 90% had prior therapy with nucleoside analog drugs
• Median baseline CD4 cell count was 175 cells/mm³ and HIV viral load was 5.0 log copies/mL
• 69% had prior protease inhibitor experience and 90% had prior therapy with nucleoside analogs
• Regimen consisted of ritonavir plus saquinavir plus 3TC plus either AZT or d4T
• After a mean follow-up of 25 weeks, the maximal CD4 cell count increase was 141 cells/mm³
• Maximal viral load reduction was 2.2 log copies/mL
• Viral load was undetectable in 63%
• Therapy failed in 41%, defined as failure to achieve undetectable viral load
• Patients without prior protease inhibitor therapy were more likely to respond to quadruple therapy (55%) than patients with protease inhibitor experience (40%)
• Side effects were similar to those already reported for the drugs, including diarrhea (36%), nausea (12%) and rash (2%)
• 10% stopped treatment due to adverse events.

Kaufmann G and others. Efficacy of a 4-drug combination therapy including 2 protease inhibitors in patients with advanced HIV-1 illness. ICAAC. Abstract I-200.

Ritonavir plus Saquinavir plus 2 Nucleoside Analogs in Treatment-Experienced Patients

• Retrospective analysis of all 58 patients in Vancouver taking ritonavir 600 mg plus saquinavir 600 mg, both every 12 hours for 2 months or longer, plus currently prescribed nucleoside analog drugs
• 38% had prior protease inhibitor therapy and most had prior nucleoside analog therapy
• Median baseline CD4 cell count was 130 cells/mm³ and HIV viral load was 4.8 log copies/mL
• After a median 5.4 months, median CD4 cell count increase was 80 cells/mm³
• Median viral load decrease was 1.85 log copies/mL
• Viral load became undetectable (limit of detection 500 copies) in 49%
• Those with no prior protease inhibitor therapy were 4.5 times more likely to achieve undetectable viral load than those with prior protease inhibitor experience
• Adverse drug events included nausea, vomiting and diarrhea (41% each) and insomnia and rash (3% each)
• 12% discontinued therapy, including 5% due to nausea, vomiting or diarrhea and 3% due to increasing HIV viral load (3% lost to death unrelated to therapy)
• The authors concluded that ritonavir plus saquinavir is effective in suppressing HIV viral load in patients previously treated with nucleoside analog drugs, although prior protease inhibitor therapy limits these benefits markedly
• Surrogate marker benefits may have been even better if one or more of baseline nucleoside analog drugs had been changed.

Rhone SA and others. The antiviral effect of ritonavir and saquinavir among HIV infected adults: preliminary results from a community based study. ICAAC. Abstract I-207.

Drugs Combinations After Failing Nelfinavir

Study 1 (St. Paul, MN)

• 19 patients rolled over from studies 506 (11 patients), 511 (1 patient) and 525 (7 patients)
• Regimen consisted of ritonavir 400 mg plus saquinavir 400 mg plus d4T 40 mg plus 3TC 150 mg, all taken every 12 hours
• Mean baseline CD4 cell count was 109-226 cells/mm³ and mean viral load was 60,948-233,667 copies/mL
• Nelfinavir had been used for a mean of 30-41 weeks
• At baseline, 13 of 16 (81%) had D30N resistance mutations (associated with nelfinavir resistance), 2 of 16 (13%) had L90M mutation (saquinavir resistance), 7 of 11 (64%) had M184V mutation (3TC resistance) and 8 of 11 (73%) had other nucleoside analog drug resistance mutations
• At week 16 in 7 patients from studies 506 and 511, mean CD4 cell count increase was 80 cells/mm³ , mean viral load decrease was 1.4 log copies/mL, and viral load was undetectable (limit of detection 500 copies) in 6 of 7, though viral load level increased after week 8; at week 24, viral load was undetectable in 5 of 7 (71%)
• At 16 weeks in 4 patients from Study 525, mean viral load decrease was 0.6 log copies/mL and viral load was undetectable in 43%

Study 2 (New York City)

• Open-label pilot retrospective study of 12 patients
• Nelfinavir had been taken for 3 months or longer (median 11 months) with a loss of HIV viral "containment"
• Participants were switched to ritonavir/saquinavir plus 1-2 nucleoside analogs or to indinavir plus 2 nucleoside analogs (AZT/3TC or d4T/ddI)
• Median baseline CD4 cell count at time of switch was 289 cells/mm³ and viral load was 4.5 log copies/mL
• After 8 weeks, the median viral load reduction was 0.46 log (0.55 log if switch was to ritonavir/saquinavir regimen, 0.21 log if switch was to indinavir regimen)
• Viral load was undetectable in 3 of 12 (25%) (2 in the indinavir group and 1 in the ritonavir/saquinavir group)
• 3 viral load response patterns were noted after 8 weeks: durable response (3 of 12), transient response (4 of 12) and no response (5 of 12)
• The authors concluded that in patients without prior protease inhibitor experience who are failing nelfinavir combination therapy, a switch to a new single or double protease inhibitor 3- or 4-drug combination leads to a smaller than expected reduction in HIV viral load or none at all. However, a minority do reach an undetectable viral load in the short run. Drug resistance correlation might help predict those who will respond.

Henry K and others. Experience with a ritonavir/saquinavir based regimen for the treatment of HIV-infection in subjects developing increased viral loads while receiving nelfinavir. ICAAC. Abstract I-204.

Sampson MS and others (presentation by Barr M). Viral load changes in nelfinavir treated patients switched to a second protease inhibitor after loss of viral suppression. ICAAC. Abstract LB-5.

Ritonavir plus Saquinavir after Failing Indinavir or Other Protease Inhibitors

Study 1 (San Francisco)

• Open-label study with 19 patients (5% women)
• Regimen included ritonavir 400 mg plus saquinavir 400 mg, both every 12 hours and nucleoside analog drug modification if possible (6 of 19 had brief prior ritonavir experience; mean prior nucleoside analog therapy was 53 months)
• Median baseline CD4 cell count was 169 cells/mm³ and HIV viral load was 4.5 log copies/mL
• 11 of 19 (58%) had their nucleoside analog therapy changed at the time of the switch to ritonavir/saquinavir, mostly from AZT/3TC to d4T/3TC
• Viral load became undetectable (limit of detection 500 copies) in 7 of 19 at week 4, in 3 of 19 at week 12 and in 2 of 15 (13%) at week 24
• 9 of 12 who failed on therapy developed L90M saquinavir resistance mutation, compared to durable responders who did not develop the mutation
• The authors concluded that a ritonavir/saquinavir-containing 4-drug combination in patients who failed prior indinavir therapy lead to a potent but transient decrease in HIV viral load.

Study 2 (Spain)

• Study of 11 patients who had failed indinavir monotherapy (4) or different combination therapies (7)
• Regimen included ritonavir 400 mg plus saquinavir every 12 hours
• Mean baseline CD4 cell count 50 of cells/mm³ and HIV viral load of 4.9 log copies/mL
• Results for 8 of 11 patients who completed 24 weeks showed a ean CD4 cell count increase of 60 cells/mm³ and a mean viral load decreases of 1.3 log copies/mL
• 2 of 8 had the saquinavir resistance mutations L90M and G48V at baseline; saquinavir resistance mutations were present in 2 of 3 non-responders
• The authors concluded that patients who have failed indinavir therapy who did not have saquinavir mutations may be more likely to respond to ritonavir plus saquinavir

Study 3 (Albany, NY)

• Retrospective evaluation of 33 patients
• 23 of 33 had previously taken indinavir, 11 of 33 had taken ritonavir and 5 of 33 had taken saquinavir (some had taken more than 1 protease inhibitor); all had previously used nucleoside analog drugs
• Median baseline CD4 cell count was 61 cells/mm³ and HIV viral load was 197,273 copies/mL
• Results after 5 weeks in 33 patients showed a median CD4 cell count increase of 28 cells/mm³ and median decrease in viral load of 97,764 copies/mL to 99,509 copies/mL (percentage undetectable was not in abstract)
• Results after 22 weeks in 11 patients showed median CD4 cell count increase of 47 cells/mm³ and median decrease in viral load of 80,689 copies/mL (from 116,090 to 35,401) (percentage undetectable was not in abstract)
• 15 patients discontinued double protease inhibitor therapy due to drug toxicity (20%), elevated or increased HIV viral load (40%) or both (40%)
• No data were presented regarding type of prior protease inhibitor therapy and outcome, and no data was given on baseline resistance mutations
• The authors concluded that ritonavir plus saquinavir is of limited value in people with AIDS who have extensive previous treatment

Deeks S and others. Virologic effect of ritonavir plus saquinavir in subjects who have failed indinavir. ICAAC. Abstract I-205.

Piliero P and others. A retrospective evaluation of the combination of ritonavir and saquinavir in protease inhibitor experienced patients. IDSA. Abstract 230.

Puig T and others. Usefulness of ritonavir and saquinavir combination therapy for HIV-advanced patients failing on indinavir. ICAAC. Abstract I-201.

Ritonavir plus Saquinavir plus d4T is a Good Combination

• Open-label phase II study of approximately 60 patients (5% women) from Switzerland
• Regimen consisted of ritonavir 400-600 mg every 12 hours plus saquinavir 600 mg every 12 hours plus d4T 30-40 mg every 12 hours
• Entry criteria included a CD4 cell count less than 250 cells/mm³, HIV viral load greater than or equal to 10,000 copies/mL (subsequently increased to greater than 25,000 copies/mL), no or stable nucleoside analog therapy for 2 months or longer and no prior d4T or protease inhibitor therapy
• Mean baseline CD4 cell count 84 was cells/mm³ and HIV viral load was 5.2 log copies/mL
• After 9 weeks in 49 patients, mean CD4 cell count increase was 102 cells/mm³ and mean HIV viral load decrease was 2.5 log copies/mL
• Viral load became undetectable (limit of detection 500 copies) in 67% (33 of 49)
• 7 patients discontinued before week 9
• Side effects included fatigue (2), MAC infection (1), increased liver enzymes (1); 1 patient discontinued due to a kidney infection, and 2 patient discontinued by request
• Ritonavir levels were found to be therapeutic in 15 of 16 patients in which levels were measured, with corresponding 10-100-fold elevated levels of saquinavir; all 15 had significant viral load reductions and CD4 cell count increases.

Battegay M and others. A pilot study of saquinavir in combination with ritonavir and d4T in patients with advanced HIV disease. ICAAC. Abstract I-203.

Vernazza PL and others. Virologic assessment of a 9-week phase II combination study of saquinavir, ritonavir and d4T. ICAAC. Abstract I-209.

Ritonavir Added to Prolonged Saquinavir Monotherapy

• Mutation at codon 90 may predict a poor response
• Lack of mutations l90M or G48V indicated a more favorable response
• Study included 12 patients previously treated with saquinavir monotherapy for median 4.9 years
• New regimen included ritonavir 500 mg plus saquinavir 400 mg, each twice daily
• Median baseline CD4 cell count was 250 cells/mm³ and HIV viral load was 4.8 log copies/mL
• After 16 weeks in 11 patients, the median increase in CD4 cell count was 30 cells/mm³ and viral load decreased by 0.03 log copies/mL
• Results yielded 3 patterns, based on saquinavir mutations

* If no saquinavir mutations were present at baseline (3 of 11 patients), median increase in CD4 cell count was 80 cells/mm³ and viral load decrease was 2.0 log copies/mL

* If saquinavir mutation L90M was present at baseline (7 of 11 patients), median increase in CD4 cell count was 20 cells/mm³ and viral load increase was 0.22 log copies/mL (these patients did have a transient viral load decrease response at week 2)

* If both saquinavir mutations L90M and G48V were present at baseline (1 patient), CD4 cell count decreased by 50 cells/mm³ and viral load increased by 0.21 log copies/mL (no viral load response was seen, even initially)

• Mutation at codon 90 may predict a poor response
• Lack of mutations L90M and G48V indicates a more favorable response
• The authors concluded that a lack of saquinavir mutations may indicate a favorable response to combined double protease inhibitor therapy with ritonavir plus saquinavir
• Although this study is small, the results add more evidence for the benefits of drug resistance testing, particularly regarding which drugs to exclude from a regimen due to the presence of resistance mutations.

Pym AS and others. Presence of mutation at codon 90 may predict response to ritonavir-saquinavir combination therapy in HIV infected patients pre-treated with saquinavir monotherapy. ICAAC. Abstract I-193.

Ritonavir plus Saquinavir in Protease Inhibitor-Experienced Patients

• Open-label prospective study of 54 patients from St. Vincent’s Hospital in New York City
• Ritonavir was added to saquinavir-containing regimen, or saquinavir was added to ritonavir-containing regimen, or ritonavir plus saquinavir were added after a failing indiavir-containing combination was stopped
• Reason for changing of therapy was clinical failure (7%), virologic failure (increasing HIV viral load in 52%) or intolerance of drug (34% due to gastrointestinal symptoms)
• Mean baseline CD4 cell count was 166 cells/mm³ and HIV viral load was 4.65 log copies/mL
• At 12 weeks, mean viral load reduction was 0.55 log copies/mL (all 3 groups), 1.0 log (in ritonavir added group), 0.11 log (in saquinavir added group), and 0.34 log (in ritonavir and saquinavir added group)
• A greater than 0.5 log reduction in viral load was achieved by 29% (in ritonavir added group), 4% (in saquinavir added group) and 10% (in ritonavir and saquinavir added group)
• Results underscore the need to change 2 or more drugs when a patient is failing a regimen (although some patients in this study changed due to drug intolerance)
• Patients experienced with protease inhibitors in combination are less likely to respond to other protease inhibitor(s) in combination.

Sampson M and others. Ritonavir-saquinavir combination treatment in protease inhibitor experienced patients with advanced HIV disease. ICAAC. Abstract I-104.

Ritonavir plus Saquinavir After Failing Indinavir or Ritonavir Combinations

• Open-label prospective study in France of 24 patients (25% women)
• Reason for changing therapy was virologic failure (87%) or drug intolerance (12%)
• Prior protease inhibitors used were indinavir (75%) and ritonavir (25%), for a mean 7.3 months; prior nucleoside analog therapy duration was a mean 43 months
• Regimen included ritonavir 400-600 mg twice daily and saquinavir 400-600 mg twice daily
• Mean baseline CD4 cell count 107 was cells/mm³ and HIV viral load 5.06 log copies/mL
• After 4 months, mean CD4 cell count increase was 35 cells/mm3 and mean viral load decrease 0.45 log copies/mL
• Viral load undetectable (limit of detection 500 copies) 2 of 19 (11%)
• Adverse events include gastrointestinal distress (13%) and elevated liver enzymes (4%)
• The authors concludes that there is a lack of efficacy in ritonavir plus saquinavir combination in patients who have failed or are intolerant to either a ritonavir or an indinavir combination, with a limited but transient decrease in HIV viral load and an insignificant increase in CD4 cell count.

Batisse D and others. Efficacy and safety of ritonavir and saquinavir in combination in protease inhibitors-experienced patients. ICAAC. Abstract I-206.

ABT-378 plus Ritonavir

• ABT-378 (an experimental protease inhibitor from Abbott Laboratories) plus ritonavir is the most potent double protease inhibitor combination to date
• ABT-378 is 10 times more potent than ritonavir in vitro
• A single dose each of ABT-378 400 mg plus ritonavir 50 mg leads to a concentration of ABT-378 that is 32 times higher than the IC50 (concentration that inhibits 50% of HIV) in vivo 12 hours after dosing
• Single dose co-administration was well tolerated without serious side effects
• Blood concentrations of ABT-378 was not affected by food
• ABT-378 has low levels of cross-resistance with either indinavir or saquinavir.

Lal R and others. Single-dose pharmacokinetics of ABT-378 in combination with ritonavir. ICAAC. Abstract I-194.

Sun E. Targetting the flexible pit second-generation HIV protease inhibitors. IDSA. Abstract S60.

PNU-140690 plus Ritonavir is Effective

• PNU is an experimental non-peptide protease inhibitor
• In vitro synergy (enhanced effect of combining 2 drugs) was demonstrated for ritonavir-resistant HIV isolates.

Chong K and others. In vitro combination of HIV-1 protease inhibitor PNU-140690 with ritonavir against ritonavir sensitive and resistant clinical isolates. ICAAC. Abstract I-197.

KNI-272 Double Protease Combinations Studied in Rats

• Combining the experimental protease inhibitor KNI-272 and indinavir leads to a 6-fold increase of KNI-272 and a 2.6-fold increase of indinavir
• Combining KNI-272 and ritonavir leads to a 21-fold increase of KNI-272 (effect on ritonavir was not stated)
• KNI-272 plus saquinavir does not lead to a change in KNI-272 level (effect on saquinavir was not stated)
• All data are "area under the curve" concentration measurements.

Sato H and others. Altered pharmacokinetics of KNI-272 when co-administered with other protease inhibitors. ECCATHI. Abstract 334.

Nelfinavir After Previous Protease Inhibitor Failure

Study 1 (San Diego)

• After failing or not tolerating an indinavir- or ritonavir-containing regimen, a nelfinavir-containing combination was tried as alternate therapy
• 23 patients were in nelfinavir expanded access program after a median 29 days
• 92% had failed prior protease inhibitor therapy, while 8% were intolerant
• Median baseline CD4 cell count was 37 cells/mm³ and HIV viral load 5 log copies/mL
• After 1 month, the median CD4 cell count increase was 25 cells/mm³ (some decreased while others increased) and median viral load increase was 0.05 log copies/mL (some increased while others decreased)
• 52% had discordant CD4 and viral load responses, e.g., an increase in one and a decrease in the other
• Genotypic resistance mutations were not reported in the abstract
• No changes in quality of life measurements
• No apparent benefits in short term follow-up after 1 month

Study 2 (Denver, CO)

• After failing or not tolerating indinavir-, ritonavir-, or saquinavir-containing combinations, patients were given a nelfinavir-combination
• 16 patients were in nelfinavir expanded access program after 1 month
• The percentage failing versus not tolerating protease inhibitors was not stated
• Mean baseline CD4 cell count was 62 cells/mm³ (viral load not stated in abstract)
• 9 of 16 (56%) were still taking nelfinavir after a mean of 109 days
• All had a greater than 0.3 log copies/mL decrease in HIV viral load
• 8 of those 9 had a mean viral load decrease greater than 0.7 log copes/mL and a CD4 cell count increase of 28 cells/mm³
• 6 of those 8 were taking triple therapy, while 2 of the 8 were taking double therapy
• 7 of 16 (43%) no longer taking nelfinavir after taking the drug for a mean 78 days
• 4 of those 7 stopped nelfinavir due to failure to respond or HIV progression; 2 stopped due to adverse events
• A greater than 0.7 log copies/mL decrease in HIV viral load occurred among 7 patients taking nelfinavir-triple combination therapy compared to a 0.1 log copies/mL increase in HIV viral load among the 7 patients taking nelfinavir double combinations
• Nelfinavir genotypic resistance mutations were not reported in the abstract
• Adverse drug reaction occurred in 75%, most commonly diarrhea
• The authors conclude that nelfinavir-containing triple combinations may provide benefits to some patients who have failed or are intolerant to other protease inhibitor combinations

The results of the Denver study differ from those of the San Diego study, although the Denver report did not indicate in their abstract baseline viral load nor the percentages of patients failing versus intolerant to prior protease inhibitors. Also, the Denver patients who responded may have been those who were intolerant to (rather than failing) previous protease inhibitors and who had not developed protease inhibitor cross-resistance mutations.

Ballard C and others. Early CD4, viral load, and quality of life response to salvage treatment with nelfinavir: the UCSD Owen Clinic nelfinavir expanded access experience. ICAAC. Abstract I-192.

McNicholl IR and others. A descriptive report on 16 protease inhibitor experienced HIV positive patients receiving nelfinavir. ICAAC. Abstract I-196.

New Therapies and Combinations