Protease Inhibitor Update

Saquinavir (Fortovase) Update to Week 32

Fortovase is the new formulation for saquinavir (Invirase). In studies, Fortovase resulted in increased plasma drug concentrations that are 10-fold higher than that of the 600mg dose of Invirase. Further details about this are available in NATAP Reports January ‘98 issue. C Farthing, M Sension and H Chang reported on 42 treatment naive individuals receiving Fortovase+AZT/3TC in this open label study. The study was designed to be 24 weeks but its been extended to 48 weeks.

Patients Not Included in Analysis. Investigators noted that patients enrolled at the Florida site included transient patients. This study was conducted at only two sites, one in Ft Lauderdale and another in Los Angeles. Of the 42 enrolled patients, 22 were not included in this analysis. Two patients were lost due to adverse events, 7 patients due to non-cooperation or non-compliance with study medication, and 4 patients due to refusal of treatment. Five patients lost to follow-up, 2 patients had treatment interruption at week 24, one patient with less than 4 weeks on study and 1 patient withdrew due to insufficient therapeutic response.

Changes in Viral Load and CD4. Participants received Fortovase 1200mg (3x/log) tid with AZT/3TC. Mean baseline CD4 was 419. Mean baseline plasma viral load was 4.8 log or 63,757 copies/ml. At week 32, 20 evaluable patients had a mean reduction in viral load of -3.35 log, 90% (18/20) had <400 copies/ml using the Roche Amplicor test, 70% (14/20) had <20 copies/ml using the Roche Ultrasensitive test, and the mean CD4 increase was 209 cells. The mean CD8 count decreased 150 from baseline.

Adverse Events. Adverse events were moderate to severe in > 5% of patients at week 32: nausea (6), vomiting (4), diarrhea (4), headache (5).

Lab Abnormalities (week 32):

• 1 grade III AST/ALT at week 4 resolved upon treatment

discontinuation

• 1 grade IV AST/ALT at week 12 associated with hepatitis A

• 1 grade III AST/grade IV ALT, grade III alkaline phospatase,

grade III bilirubin at week 20, associated with acute hepatitis A

• 1 grade III neutropenia at week 16 resolved upon replacement

of AZT with d4T

• 1 grade III triglycerides at week 2 associated with patient

having discontinued cholesterol reduction medication

Comparison of Invirase and Fortovase in Treatment Naive Individuals at Week 24

This is a preliminary 24-week analysis of participants who were initially randomized to the new soft gel capsule saquinavir (SGC-SQV) because the majority initially randomized to Invirase hard gel capsule (HGC) switched at week 16 to the SGC-SQV. Analysis of crossovers at week 24 is not yet available because some didn’t switch until week 24.

Participants were randomized to open-label 1200mg tid SGC-SQV plus two NRTIs of choice or 600 mg tid Invirase plus 2 NRTIs of choice. Baseline CD4 and viral load for Fortovase and Invirase were 448 and 408, respectively, and 4.8 log (63,000 copies/ml) for both. Approximate ethnic demographics of participants: 68% Caucasian, 19% African American, 10% Latino, 1% other, about 8% female. See Table 11

Safety and Tolerability. Investigators reported that most adverse events were related to the gastrointestinal (GI) tract, were relatively mild in severity, and were slightly more common with Fortovase. Through 16 weeks, a total of 10 patients (1 patient on Invirase and 9 on Fortovase) withdrew prematurely from the study due to clinical AEs/intercurrent illnesses. In 8/10 patients, withdrawal was due to GI intolerance. But most GI intolerance did not prevent ongoing therapy. There was no major difference reported between the two groups regarding lab abnormalities. 4% reported abnormalities for elevated glucose. Reported adverse events for those taking Fortovase included: nausea (18%), diarrhea (17%), flatulence (11%), abdominal discomfort (11%), and headache (9%).

Fortovase (saquinavir) vs Indinavir: 24 weeks

63 individuals were enrolled in this open label randomized pilot study comparing 1200 mg tid Fortovase plus AZT/3TC (n=30) to 800 mg indinavir every 8 hours plus AZT/3TC (n=33). This is a preliminary 24-week analysis of a 48-week study to evaluate the antiviral activity of Fortovase.

Change in Viral Load and CD4. The baseline CD4 and viral load for the Fortovase group was 301 CD4 cells and 4.95 log (89,100 copies/ml). The baseline CD4 and viral load for the indinavir group was 4.93 log (85,000 copies/ml) and 337 cells. Two individuals in the Fortovase group had <12 months prior AZT use and 1 person in the indinavir group had <12 months prior AZT use. At week 24, both the saquinavir (n=14) and indinavir (n=12) groups had achieved a 2.5 log reduction from baseline to <400 copies/ml (Roche Amplicor). At week 24, the CD4 increase for the Fortovase group was about 300 from baseline while the CD4 increase for the indinavir group was about 70 cells. The number of evaluable patients at this point may be too small to draw conclusions on the difference in CD4 increases.

Moderate and Severe Adverse Events. There were 6 reported gastrointestinal related complaints in the Fortovase arm vs 1 in the indinavir arm. In the indinavir arm, there was 1 grade 2 kidney failure reported and one case of nephrolithiasis (kidney stones).

Nelfinavir Update to 21 Months

Agouron reported a 21-month update on data from study #511 comparing nelfinavir (NFV) 750mg tid plus AZT/3TC to AZT/3TC alone or 500 mg NFV tid with AZT/3TC. About 300 treatment naive individuals were enrolled in the study. They were evenly divided between the 3 treatment groups. At 6 months, individuals receiving AZT/ 3TC alone were permitted to add nelfinavir. In the Salvage Therapy Study Section below is a review of the K Henry study where a small number of individuals who failed nelfinavir in this study received RTV/SQV +d4T/3TC.

Changes in Viral Load and CD4. Mean baseline CD4 and HIV RNA were 283 and 153,000 copies/ml (geometric mean- 4.9 log), respectively. They were not different for all three treatment groups. See Table 12

20 Month Update of 12 Treatment Naive Persons on Nelfinavir+AZT/3TC

M. Markowitz and others, at the Aaron Diamond Research Center, reported data at 20 months for 12 individuals with chronic HIV infection but who were treatment naive. They all initiated treatment with nelfinavir 750 mg tid, AZT 200 mg tid and 3TC 150 bid in February 1996. Mean baseline plasma HIV RNA was 5.32 log (about 208,000 copies/ml) and mean baseline CD4 was 258. The study was intended to assess antiviral potency and durability, and the immunological effects of prolonged suppression of viral replication.

One person was switched to d4T/3TC/indinavir at week 4 due to intolerance and was experiencing diarrhea, abdominal pain, and grade 4 CPK. All 12 persons achieved <500 copies/ml (bDNA) by week 12. Three persons had viral load rebound (bDNA) at months 7, 15, and 17, respectively. Viral rebound was based on 2 consecutive viral load tests above the level of detection. 8/12 patients remain on original nelfinavir regimen. 4/8 remain suppressed below 25 RNA copies/ml. The other 4 patients have intermittent low level detectable HIV RNA when using the ultrasensitive test. Sometimes they are <25 copies/ml but other times they can be detected at between 25 and 200 copies/ml.

The 3 individuals whose viral load rebounded received a regimen containing d4T/ddI/RTV/SQV. One person was switched to that regimen at month 18 after viral load rebounded to 4,232 copies/ml, and suppressed viral load to undetectable. Four months later the patient had to interrupt therapy due to acute hepatitis B infection, and their viral load rebounded to 100,000 copies/ml. The second person experienced a rebound in viral load at month 7 to 10,000 copies/ml. Their viral load went undetectable after starting new regimen but rebounded to 2,330 copies/ml in 2 months. They intensified the regimen by adding delavirdine and went to undetectable where they remain to date. The third person experienced a brief initial viral load rebound to what appeared to be several thousand copies at month 13 but went back to undetectable at month 15. At month 17 they had a second rebound to what appeared to be about 2,000 copies, whereupon the new regimen was started. This person failed to return for follow-up but appeared to be salvaged with the new regimen.

Investigators concluded that the nelfinavir median trough levels during the first 12 months of therapy did not predict subsequent treatment failure. The median trough levels for the 3 treatment failures were 2.21, 1.49 and 1.04 ug/ml. The mean trough level for the entire group was 1.43 .49 ug/ml. The actual PK data is available on the NATAP web site.

Investigators reported that the mean number of naive t-cells in 10 evaluable patients increased from 63 at baseline to 120 at 18 months. The 3TC M184V mutation was observed in all 3 treatment failures; 2/3 treatment failures had the nelfinavir mutation D30N; and, 1/3 had the L90M, which has been observed associated with nelfinavir and other protease inhibitors.

141W94

(Amprenavir) is taken with or without food. It is taken twice a day. It is expected that a liquid dosing formulation will be available for adults after FDA approval as well as a capsule formulation. Simultaneous FDA reviews for both pediatric and adult approval is expected in the Fall of ‘98. Preliminary data from several studies of protease inhibitor naive individuals are reviewed below. Studies of 141 in combination with other drugs for individuals who’ve failed protease inhibitors are beginning. In an early monotherapy study of different doses, 9 individuals achieved a median maximum -1.69 log reduction from a median baseline of about 120,000 copies/ml at the 1200mg bid dose regimen. The estimated oral bioavailability is 70%. The half-life has been reported ranging from 7 to 9.5 hours. An expanded access program is expected to begin in July that may offer participants a variety of treatment regimens to choose from. A study of 141W94 in double protease combinations is described in the Double Protease Section.

Preliminary Interaction Data for 141W94 with Indinavir or Efavirenz

Preliminary pharmacokinetics (PK) data has been reported for the combination of indinavir+141. Investigators have characterized a preliminary range for increases in Cmax of 16-31% and in AUC of 22-64% for 141 when used with indinavir. They reported no appreciable change in indinavir blood levels when used with 141. These increases, if confirmed in further studies, may contribute to the potency and effectiveness of the combination of 141+indinavir. Interaction data with other protease inhibitors should be available soon.

In the efavirenz section of this newsletter we describe preliminary PK data in which efavirenz reduced 141 Cmax, AUC, and Cmin by 39%, 36%, and 43%, respectively. However, the clinical relevance of this effect is uncertain. 141 increased efavirenz AUC by 15%.

Pharmacokinetics (PK)

Pk is the term used to describe measures of drug levels in blood: Cmax, Cmin, and AUC. The Cmax is the peak level of drug reached in the blood during a dosing period. For example, indinavir is taken every 8 hours. During that 8-hour dosing period the Cmax is the highest level of drug reached in the blood. The AUC (area under the curve) is the total drug concentration in the blood during that 8-hour period. These are standard methods used to measure blood levels of a drug. Frequently, the Cmin is considered to have the most important measure. It is key to maintaining a drug’s blood concentration level (Cmin) above the point where it will fall below the level necessary to adequately suppress virus replication. Dosing schedules should be prescribed by drug manufacturers to prevent blood levels of a particular drug from falling below the level needed to adequately suppress viral replication. Since viral replication causes resistance, not adhering to a well-designed recommended dose schedule may be an invitation for resistance.

Additional studies, described in this newsletter, are starting which will explore 141 in a variety of different combinations as a salvage therapy for individuals who have failed single or multiple protease inhibitors. You may want to be cautious about using 141 as part of a salvage regimen until successful regimens have been identified. You don’t want to lose the potential benefit of this drug by developing resistance unnecessarily. Unless, if you feel unable to wait and want to begin a 141 containing salvage regimen soon.

141W94+AZT/3TC (ACTG 347) Salvage Therapy - NVP+IDV+d4T+3TC

Dr Robert Murphy reported preliminary findings from this study at the Retrovirus meeting. This study was designed to investigate if 141 monotherapy would be adequate treatment. Investigators felt it possible that 141 might be potent enough due to its unique characteristics to be adequate as a monotherapy in suppressing viral load. The drug did not perform well enough in this study as monotherapy. The most beneficial information to come out of this study is from the resistance data being generated, the side effect profile, and the data from the salvage regimen used for those in the monotherapy arm.

92 study participants were randomized to 141 1200mg bid+AZT/3TC or to 141 monotherapy. Participants were stratified by treatment naive or experienced, and by baseline viral load of over or below 50,000 copies/ml. Because we don’t yet have the differences of effect between the treatment naive and experienced groups, it is difficult to interpret the antiviral effect of 141 in this study. Resistance analysis and CSF substudies are ongoing. Phenotypic resistance tests will be conducted for 141 and other PIs.

Participants were 3TC and protease naive, and have no clinical history of AIDS. The study group had a wide range in CD4 and viral load at baseline, which also makes the data a little more difficult to interpret. Median baseline CD4 was 304 and median baseline VL was 30,707. 52% were treatment naive and 48% were treatment experienced.

After 9 or 10 patients reached an endpoint, the monotherapy study was stopped. After a median of 88 days on therapy, 15/41 monotherapy patients and 1/40 on triple therapy reached a study endpoint. The 3 endpoints for stopping were tightly defined as a rise in viral load above baseline, a 1 log increase from the nadir of decline in viral load, or >500 copies/ml after 16 weeks of therapy.

Preliminary CD4 and Viral Load Changes. With an on treatment analysis, by weeek 4 the median viral load reduction was to below 500 copies/ml. 68% (n=27) were <500 copies/ml at week 24, but study investigators said the intent to treat analysis was about the same. The CD4 increase was approximately 60 at week 24. Investigators characterized 141 as well tolerated.

Signs-Symptoms. (grade 1+2/3+4). Murphy said only 3 patients discontinued due to drug related side effects: rash (1), nausea (2). See Table 13

Lab Abnormalities. Murphy said no one came off study due to lab abnormalities. See Table 14

Salvage Therapy. 36 patients from the monotherapy arm decided to enroll in a salvage rollover protocol (ACTG 373) consisting of indinavir (800mgq8h)
+nevirapine+3TC+d4T. Murphy reported that the group receiving the 4-drug salvage regimen went to <500 copies/ml within a short period of time. It is important to note that the individuals who were switched to the salvage regimen had their viral load rebound detected quickly and switched therapy quickly. This is in line with the suggestion, outlined in this newsletter, that individuals monitor viral load monthly, immediately stop a failing protease regimen to limit resistance, and immediately switch to a new protease therapy.

 

We reported in the Jan ‘98 issue of NATAP Reports that 29/33 receiving the 4-drug salvage regimen were <500 copies at about 4 months after starting therapy. There has not been an update since then. The 4 others had viral load under 2,200 copies/ml and were trending down. It is too preliminary at month 4 to conclude that the salvage regimen was successful because durability is the key, but the data are encouraging and need to be followed.

Preliminary Resistance Analysis for 141W94

From previous in vitro resistance research it appears as though I50V is the dominant mutation arising from use of 141. The I50V mutation has not been reported to be associated with resistance to indinavir, ritonavir, saquinavir or nelfinavir. In vitro, the I50V mutation alone was reported to cause only low level resistance (3 fold) to 141. Upon continued passage in vitro a second mutation M46I emerges producing a double mutant (I50V, M46I/L) with a 3 to 7 fold reduction in sensitivity to 141, and a third mutation of I47V produces a triple mutant (I50V, M46I, I47V). This triple mutation resulted in a 20-fold resistance to 141. Mutations in vivo have not been reported prior to the data from ACTG 347.

It’s been reported from an in vitro study that saquinavir passage re-sensitized 141 resistant virus to 141 again. Margaret Tisdale, of Glaxo Wellcome, took a 141 resistant virus (46I, 47V, 50V). After culturing this virus with SQV, initially the virus was susceptible to SQV. After passaging this virus through many cycles of replication, the virus developed resistance to SQV. She then retreated this virus with 141 and found it was susceptible to 141. The SQV associated mutations remained (48, 84) and the two 141 associated mutations (46,50) remained. The double 141 mutant (50,46) may not cause high level resistance as the triple mutant would. The 46 mutation appears to be one of the compensatory mutations that may not do much to 141 (1). In another in vitro experiment, 141 were passaged to produce a virus with resistance mutations (10F, 46L, 47V, 50V) which was not cross-resistant to saquinavir. This same virus was 3 fold resistant to indinavir (2, 3).

GW researchers reported that using in vitro lab strains of HIV, 141 was active against a nelfinavir mutant with the nelfinavir D30N mutation, and in vitro nelfinavir was 2-3 fold resistant to a 141 triple mutant. Ritonavir was 5 fold resistant to a 141 mutant.

It is important to bear in mind that in vitro resistance data does not necessarily predict human response. Although a fair amount of the previous protease inhibitor in vitro data has reasonably predicted human response and played a role in predicting protease inhibitor cross-resistance, in vitro research can be biased by the lab methods and conditions used by the researcher. Based on in vitro data there is reason to think that saquinavir and 141 may have a special relationship.

(1) Fourth Resistance Workshop, Sardinia, July 6-9 1995

(2) Partaledis et al, Jnl of Virology, Sept 1995, p 5228-5235

(3) Fifth Resistance Workshop, Whistler, July 3-6 1996

At the Retrovirus Conference, R D’Aquilla, MP De Pasquale and others reported preliminary resistance data for 141 from ACTG 347:

• The preliminary data shows resistant virus of two types appeared, those that had the I50V mutation and those that didn’t have the I50V mutation

• Those who had the I50V mutation also had other protease mutations (46, 47, 54, 84) and often a gag p1/p6 cleavage site mutation (which may not be relevant). Investigators reported that the I50V mutation appears to be always linked with other mutations suggesting it impairs fitness for viral replication and requires compensatory mutations for resistance to develop

• When no I50V mutation appears other mutations appeared in gag and protease (10, 20, 54, 82, 84 and others)

• Although the I50V has not been reported to be associated with other protease inhibitors, other mutations that are associated with resistance to the other PIs were observed associated with 141 (10, 20, 36, 46, 54, 82, 84)

Data is available on 4 individuals who rebounded during triple therapy with 141+AZT/3TC. 3/4 developed the 3TC M184V mutation. Only 1/3 had protease and gag cleavage site mutations (84, 50, P1/p6, also with M184V). The 4th person had no mutations in gag, protease or RT.

One of the major questions surrounding 141 is, can virus resistant to other PIs is susceptible to 141? That is, can 141 be successfully used as salvage therapy for those who’ve failed one or multiple PIs? The answer to that question is uncertain. The data available so far indicates 141 will have to be part of a potent regimen if it is to suppress protease resistant virus. The ACTG 398 and 400 studies are addressing this issue.

The resistance substudy of ACTG 347 is ongoing. Additional resistance data will be reported from 347 including the results of phenotypic resistance testing of HIV isolates to 141 and other PIs. It appears as if by the time the FDA reviews it for accelerated approval we should have a good amount of resistance data.

4 Drugs- 1592U89 + 141W94 + AZT/3TC in Acute and Chronic Infection

R Kost from the Aaron Diamond Research Center reported data from this study of individuals with both acute infection and individuals with chronic infection treated with a potent 4-drug regimen. The study objective, as stated by the investigators, included determining the safety and efficacy of 141W94 (amprenavir) and 1592U89 (abacavir) when used in combination with AZT/3TC (Combivir). Other study objectives include: the changes in plasma viral load; the dynamics of HIV in gut-associated lymphoid tissue; and the decay of HIV in cerebrospinal fluid (CSF) in subjects with detectable HIV in CSF at baseline. Secondarily, the study is looking at adherence and factors affecting adherence to a 4-drug regimen. This 4-drug regimen is all dosed bid, twice daily.

The study is an open label pilot study of 16 newly infected and 11 chronically infected individuals. The newly infected group (NI) was defined by negative western blot (WB) and positive RT-PCR, evolving WB, or pos. WB with neg WB within past 90 days. The chronically infected group (CI) was defined by pos WB >90 days, or unknown date of seroconversion. Individuals were excluded if they had abnormal LFTs, were pregnant, or had active opportunistic infections. Participants had to be protease and 3TC naive, and had to have a viral load >5,000 copies/ml. The regimen they received was 1592 300mg bid, 141 1200 mg bid, and AZT/3TC (Combivir) 300mg/150mg bid. See Table 15

Subjects Reaching Undetectable (<100 copies/ml). There has been some non-compliance in this study (see adherence study below). Individuals who are being compliant to the study drugs remain <100 copies/ml. See Table 16

CSF. Lumbar puncture was performed at baseline and between week 3 and 8 in 5 CI and 1 NI subjects. The mean CSF viral load at baseline was 1,644 copies/ml for the NI group (n= 7), and 8,093 copies/ml for the CI group (n=7). The mean reduction in CSF viral load was -1.42 log after 3-8 weeks of therapy for the 6 subjects who underwent serial sampling. Follow-up was limited by an unusually high incidence of post lumbar puncture headache.

Viral Load in Lymph Tissue. The authors reported that HIV productively infected cells and virions trapped in gut associated lymph tissue (GALT) decayed rapidly similar to decay rates found in peri-pheral blood. Additional data is available on the NATAP web site.

In 5 persons in whom multiply spliced mRNA was detectable at baseline, the MS mRNA decreased to below detectable (<50 copies/ug tRNA) by weeks 3-6, confirming the rapid decay of productively infected cells.

Infectious virus was culturable at baseline in 3/8 persons; after 3-6 weeks of therapy, none was positive (<0.1 TCID 50/104 mononuclear cells).

Changes in CD4 and CD8 Cells. The mean CD4+ counts rose from 560 to 793 (+233) in the newly infected group at week 28 and from 315 to 520 in the chronically infected group at week 28. The number of naive CD4+ cells increased from 202 at baseline to 230 at week 28 in the NI group, and from 97 to 140 in the CI group.

The mean CD8+ counts declined in the NI group from 1163 to 740 at week 28, and in the CI group from 830 to 601. Mean naive CD8+ cell counts rose from 212 to 242 in the NI group at week 28, and from 124 to 186 in the CI group.

The increases in naive cells appear modest. But, at this time, the significance of increased naive CD4 cells due to HAART is uncertain. Individual responses to HAART with regards to naive cells appear to be variable. It is uncertain why certain individuals are capable of producing a larger increase in naive cells than others. Some individuals may be able to charge up their thymus to make new naive cells while other individuals may not. The relationship of the thymus to increases in CD4 due to HAART remains uncertain (see Immune Restoration Report).

Activation markers on CD4+ and CD8+ cells were measured. CD38+ and DR+ markers appear on both CD4+ and CD8+ as markers of activation. The fraction of CD8+ cells expressing CD38+ and DR+ decreased comparably in both NI and CI groups. No trends were evident in the CD4+ cells expressing activation markers. Virus antigen stimulates activation markers.

Toxicity. No grade 3 or 4 toxicities have occurred. Mild to moderate (grade 1 or 2) rash have been seen in 2 CI and 5 NI individuals during week 2 of therapy. 6 persons remained on therapy. 1 person discontinued therapy and restarted without recurrence of rash. Gastrointestinal toxicity was common (nausea with or without vomiting, flatulence, and diarrhea). Paresthesia (numbness, tingling) and fatigue were common but mild. Adverse events significantly diminish after several weeks of therapy.

141W94 + 1592 in Treatment Naive Individuals

35 treatment naive individuals with CD4 >400 and viral load >5,000 received open-label 141 1200 mg bid and 1592 300 mg bid. The baseline HIV RNA was 4.43 log or about 27,000 copies/ml. Investigators reported that plasma viral load declined rapidly, 80% (n=28) were <500 copies/ml by week 4. Of the 28 evaluable patients at week 4, there were two patients who dropped out from the study due to adverse events and one who temporarily interrupted therapy due to personal reasons. The viral load decline at week 2 appeared to be 3 log from baseline.

Week 20 and 24 Individual Viral Load Levels*

Week 20 and 24 viral load levels were measured with a boosted Amplicor Roche test (limit of detection 5 copies.ml) in the 11 patients who reached 24 weeks of follow-up. Plasma virus was negative in 3/11, below 5 copies/ml in 6/11, and <50 copies/ml in 9/11. At weeks 20 and 24 viral load was <500 copies/ml in 11/11. A negative value does not mean virus is not present; only that it wasn’t found. Actual viral load data for each person is on the NATAP web site.

Safety. Side effects experienced by study participants included nausea, vomiting, diarrhea, paresthesia (numbness & tingling), headache, epigastralgia, and fatigue. Rash, either erythematous or masculopapular, was the only serious reported adverse event. Five patients experienced rash that appeared after 6 to 9 days of treatment. In 2 out of 5 patients therapy was not interrupted and the rash resolved. In one patient therapy was interrupted and then successfully rechallenged after 9 days along with prophylactic administration of cetirizine for 2 weeks. In the remaining two patients, who had developed fever and constitutional symptoms along with the rash, the rechallenge caused a more severe re-exacerbation of rash and constitutional symptoms after one dose of either 1592 or 141, compatible with a hypersensitivity reaction. These two patients withdrew from study.

A hypersensitivity reaction has been reported by Glaxo Wellcome due to taking 1592 at an incidence rate of about 3% (reported range 2-5%). Details explained in the NRTI Report (See 1592) of this issue.

Salvage Therapy

Potential for Limiting or Preventing Protease Inhibitor Cross Resistance by Switching Protease Inhibitors Immediately After Viral Load Rebound; RTV/SQV as Salvage Therapy after Failure of Initial Protease Inhibitor Regimen

Joel Gallant and others reported preliminary data from a study of individuals who failed either nelfinavir or indinavir regimens. This study has potential importance. The study was conducted to determine whether early switches in therapy after failure would be more likely to lead to viral suppression. Although the data is preliminary, the results suggest that quickly detecting failure to your initial protease inhibitor and then immediately switching to a second protease inhibitor may be crucial to responding well to the second protease inhibitor regimen. This issue is discussed on page 4.

Salvage therapy studies using RTV/SQV or any other regimen have shown mostly disappointing results. The percent of individuals who experience sustained viral load responses is usually small (most of these studies only extend to 6 months). Gallant said in most studies RTV/SQV has been initiated only after significant time and viral load rebound on the failing regimen -- after greater cross-resistance may have developed. The two studies showing potential exceptional salvage responses are discussed herein: ACTG 347 and Keith Henry nelfinavir study.

The data for this study was collected retrospectively from chart review of 29 clinic patients at Johns Hopkins Hospital. Failure of the initial regimen was defined as any detectable viral load after 16 weeks of therapy confirmed on two occasions. 12/17 (70.5%) failing indinavir responded (HIV RNA <400 copies/ml) with persistence to a median of 33 weeks. The median viral load for the responders at the time of switching therapy was 13,507 copies/ml. The median viral load at the time of switch for the non-responders was 17,600 copies/ml. NRTIs were switched in all but one of the responders and two of the non-responders.

Among the 4 patients reported to have failed nelfinavir, 3 responded (HIV RNA <400 copies/ml) with persistence to a median of 33 weeks. The median viral load at the time of switching therapy for the responders was 9,150 copies/ml. The one non-responder had a median viral load of 40,150 copies/ml at the time of switching therapy. NRTIs were switched in all patients.

Dr Gallant feels the longer you stay on therapy after resistance develops more mutations develop and more cross-resistance develops. The lower your viral load at the time of switching therapy the more likely you are to respond well. Although the data reported here is not statistically significant, the preliminary results are consistent with what we know about protease inhibitor resistance and cross-resistance.

Viral Load Responses to RTV/SQV Regimen in Persons Who Previously Failed Nelfinavir (NFV) Regimen

P Tebas and others reported follow-up data from a previous report at ICAAC in September ‘97. 26 patients who failed a nelfinavir regimen in nelfinavir study #511 or #506 were enrolled in this study and received RTV/SQV/d4T/3TC. Study #511 was for treatment naive individuals and they received NFV+AZT/3TC. Participants in study #506 received d4T+NFV, and had prior NRTI and delavirdine experience. Of the 26 enrollees in this study, 21 were from 506 and 5 were from 511. They had been exposed to a median of prior nelfinavir treatment of 55 weeks (23-82) before enrolling in this salvage trial. The mean time spent on nelfinavir with detectable viral load is 48 weeks, and this may be key. Obviously, individuals remained on nelfinavir despite failure for a prolonged period allowing resistance to build up. The investigators reported that baseline viral load for the non-responders was 80,692 copies/ml while it was 42,230 copies/ml for the responders to the salvage therapy, and they said a higher baseline viral load may increase the risk of failure to this regimen. The mean CD4 count at baseline was 222 (range 82-448).

The authors said that NFV failure was associated with the following mutations: D30N in conjunction with M36I, A71V, and N88D. Other mutations can be detected using a more sensitive assay. Following is a table reported by the investigators summarizing the protease changes at entry to this study. See Table 17

Viral Load Changes. Two patients quit the study during the first two weeks due to GI intolerance. 24 continue in the study and 19 reached 6 months at the time of this report. It was previously reported that 6/7 had <500 copies/ml at week 16, and 2 of those 6 had <40 copies/ml (Ultrasensitive PCR). At week 24, 68% (13/19) had <500 copies/ml. The investigators also reported subsequent to the Retrovirus Conference that at weeks 32 and 40, 5/8 (62.5%) and 2/3 (66%) had <500 copies/ml, respectively. Although its not statistically significant, they said there was no apparent relationship between failure due to resistance and the presence of L90M. The investigators said they still need to establish the durability of this regimen beyond 24 weeks.

Table 11. Fortovase Changes in Viral Load and CD4 from Baseline

Table 12. Nelfinavir+AZT/3TC: Viral Load and CD4 Changes at Month 21

(*) Study analysis used in this intent to treat approach included only patients who responded to therapy. A treatment "responder" was defined as achieving two consecutive HIV RNA measurements at or below 400 copies/ml (limit of detection of test). Individuals who started study treatment but did not "respond" to therapy as defined were not included in analysis.

Table 13. 141W94: Side Effects (grade 1-2/grade 3-4)

Table 14. 141W94: Lab Abnormalities

Table 15. 4 Drugs- 141W94+1592U89+AZT/3TC Baseline CD4 and Plasma Viral Load

Table 16. <100 copies/ml, 4 Drugs- 141W94+1592U89+AZT/3TC

Table 17. Mutation Changes Following Nelfinavir Therapy