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January 1998 Volume 1, Number 3-4, Section 2

Protease Inhibitor Update

    Treatment Options After Failing a Protease Inhibitor
    Monthly Monitoring of Viral Load
    Commentary on Steve Deeks Data

    Nadir of Viral Load Response, Baseline Viral Load, How Low Should Viral Load Be?
    Indinavir (Crixivan)
    Ritonavir (Norvir)
    4 Drug Study
    Nelfinavir (Viracept)
    Fortovase: New Saquinavir

The following article reviews the latest updates of data from numerous studies of protease inhibitor therapies reported at recent conferences extending out as far as we now have data, from 1 to 2 years varying by the specific therapy. In general, 80% or more of the study participants were undetectable (by the standard viral load tests, less than 400 or 500 copies/ml). Success with the treatments is associated with continuing to take the regimen, compliance, tolerability of the drugs, and adequate drug blood levels. Also discussed here is the latest treatment strategy information.

Two years is a relatively short period of time. We need to follow individuals taking these treatments for many more years, to monitor how long benefits will last; to evaluate how long viral load reductions and CD4 increases extend life and sustain good health, and to evaluate the tolerability and safety over the long term.

Treatment Options After Failing a Protease Inhibitor. Many individuals have developed resistance to a protease inhibitor therapy. If your viral load is stable you may want to not make any changes until more therapies are available. A more durable benefit will occur if you can assemble a potent regimen consisting of 3 drugs each of which can offer you as much antiviral activity as possible. You may want to consider 4 or more drugs for a regimen. Inside this issue is a report by Dr Cassy Workman who used a 6-drug regimen. Failure of any drug in a specific class can reduce the benefit you may receive from a drug in the same class, so a drug may not really be totally new if you’ve become resistant to a drug in its class. See the Resistance Supplement which includes a review of the latest data on 1592U89 resistance and cross-resistance.

Inside this issue we discuss data and information for all the new drugs expected to be available in 1998, as well as information and data on some of the new combinations in research. Combining two protease inhibitors or a protease with a NNRTI can offer potency. Delavirdine is the only NNRTI that significantly increases protease inhibitor blood levels. Inside this issue is a report on the preliminary effects of delavirdine on the blood levels of certain protease inhibitors. Hydroxyurea in combination with ddI or ddI+d4T can offer a potentially beneficial treatment option.

At this point, most studies attempting salvage therapy after protease failure have produced a small percentage of success. However, usually the regimens used in these studies have not been as potent as they could be. To design a good regimen you will have to use your intuition and knowledge about available treatments. The information in this issue about double protease combinations and NNRTI-protease combinations can be useful. However, I’ve heard anecdotal reports of 4, 5 or 6 drug regimens being successful in suppressing protease resistant virus. Success may depend upon the specific protease drug you’ve failed and the level of resistance developed.

The Resistance Supplement and the NATAP web site review the studies that have been conducted attempting salvage therapy. There are two studies that offer potential exceptions to the disappointing results from others. At ICAAC, Dr Keith Henry reported preliminary data on a small study of individual who failed nelfinavir+AZT/3TC, had limited nucleoside experience, and were switched to a 4-drug regimen of ritonavir+ saquinavir+d4T/3TC. Initially, 12/12 individuals were <500 copies/ml, and at week 16 6/7 were less than 500 copies/ml. The key is the durability. 16 weeks is too soon to make conclusions. An update will be reported at the ’98 Human Retrovirus Conference. In ACTG 347, individuals who failed 141W94 monotherapy were switched within two weeks of failure (which maybe a key) to indinavir+nevirapine+d4T/3TC. In the first few months, the group (n=33) has responded well as 29 individuals are less than 500 copies/ml, and 4 persons had viral loads under 2200 copies/ml. It appears as though viral load is trending down. Again this is preliminary as durability is the key. Updates will be reported.

The ICC (Inter Company Collaboration) is a coalition of drug companies that manufacture antiretroviral drugs for HIV. They are planning to start a 6 site study in early ‘98 for individuals who have failed a protease inhibitor. They have designed a variety of numerous and unique combinations of experimental and approved drugs to use in this study. The study, the combinations, and the sites should be in place by February ‘98. It’s expected that there will be a site in New York City and other major cities. This might be a good opportunity to access a drug combination that you might otherwise not be able to put together. The studies will include new experimental drugs that are not generally available, such as 141W94, adefovir (PMEA) 1592U89, DMP-266, MKC-442 (a new NNRTI). Look for the announcement for the start of the study.

Monthly Monitoring of Viral Load and Immediately Switching to a Potent Regimen Upon Rebound in Viral Load. This might be a key factor in potentially avoiding protease inhibitor cross-resistance. In recent months, an increasing number of leading HIV researchers have been supportive of this approach. But at this point it is just a theory because studies have not yet officially addressed the approach. If you monitor your viral load monthly, that would allow you to detect a rebound in viral load quickly. After a second test to confirm that failure, you could immediately change your therapy. By discontinuing the protease inhibitor to which you may now be resistant, you may avoid any further resistance or mutations from further developing in your protease enzyme. By remaining on a protease after resistance starts and continues to develop, you may be allowing further resistance to develop. If you switch the protease before much resistance has had a chance to develop, you may have a better opportunity to be sensitive to the second protease inhibitor. Thus, you may limit or avoid cross-resistance.

However, this is not black and white. Some individual’s viral load can plateau at a detectable level of for example 2,000, 10,000, or 30,000 copies/ml; and their viral load may remain at that level for a period of time. One study suggests that if you can keep viral load below 5,000 copies/ml progression of disease can be maintained. This opinion offers a different approach than full viral load suppression. You should consider the risks and benefits of switching therapy or remaining on the same therapy. Of course, it is difficult to predict whether an individual’s viral load will plateau or skyrocket. If a person’s viral load appears to be plateauing, it is difficult to predict whether or when it may increase. If a person has few or no adequate treatment options currently available, it may be preferable to closely monitor your viral load and wait until they can start a new regimen consisting preferably of 3 new drugs that will offer adequate potency. Some individuals in this position are considering hydroxyurea therapy as an alternative. See the hydroxyurea section for extensive discussion about its use.

The Real Deal on the ICAAC Report by Steven Deeks of 53% Protease Inhibitors Failure Rate. The mainstream press irresponsibly reported a mischaracterization of the information reported by Dr. Deeks. He received a lot of publicity when he reported at ICAAC that patients in his clinic had about a 53% failure rate when using protease inhibitors when he took a look back at their records. In fact, his purpose of reporting this information was to show what happens when protease inhibitors are used incorrectly:

• Many of the patients merely added a protease inhibitor onto current therapy without changing underlying nucleosides, after extensive prior nucleoside experience.
• The compliance rate was not good among these patients.
• Some of the patients had prior saquinavir resistance leading to a measure of cross-resistance to their next protease inhibitor.
• Some individuals had advanced HIV and therefore waited too long to begin therapy; their CD4 was low and/or their viral load was >100,000 copies/ml.
• Because of extensive prior nucleoside treatment, improved regimens could have been designed for some of the individuals including a combination of a protease with a NNRTI or a double protease regimen such as ritonavir+saquinavir with nucleosides.
• For the purposes of the study, failure was defined as <500 copies/ml, or above detection. This means that individuals who may have had a viral load of 1,000 or 800 or 3,000 were defined as failures when in fact that may be a mischaracterization.
• Deeks reported a high success rate of about 80-90% for individuals using protease inhibitors properly.

Deeks study highlights that (1) It is vital to individualize therapy. Every person has a different CD4 count, viral load level, a different background of prior treatment experience, etc. You cannot merely use a single therapy approach for every person such as a protease inhibitor plus two nucleosides. (2) Early aggressive treatment strategies should be considered. Initiating therapy too late in an individual’s course of disease (when their CD4 may be too low or their viral load too high) can cause failure.

Baseline Viral Load, Nadir of Response, How low should my viral load be? Many studies have now shown that an individual’s viral load before starting therapy predicts how well they will respond to therapy and possibly how durable the response may be. If you begin HAART or for that matter any therapy with a high viral load it is less likely that you may reach undetectable or lower. For example, if your viral load prior to starting therapy is 1,000,000 copies/ml, you are less likely to reach undetectable with HAART. If your viral load is 15,000 copies/ml you are very likely to reach a low viral load and to sustain the viral load suppression. Being more aggressive and starting therapy when your viral load is lower may be beneficial to you. Evaluate your options. If your viral load is high, an extra potent regimen may be necessary.

Some data has been reported by Dale Kempf, PhD of Abbott Labs, suggesting that the nadir of your viral load response will predict the durability of effect from therapy or how long you will sustain your response to therapy. The nadir is the lowest level your viral load reaches from therapy. The lower you can reduce your viral load, the more durable your response will be.

Based on this and other information, a number of researchers have stated their opinion that reducing viral load to <50 copies/ml will probably result in a more durable suppression of viral load than lowering viral load to only 200 or 400 copies/ml. They have said that lowering viral load to as low a level as possible should produce better durability of response. Dr. Doug Richman said recently that the goal of therapy should be to lower viral load to <1 copy/ml. However, actual data supporting this thinking is important (and may be reported at the ‘98 Human Retroviruses Conference;) Because many individuals may not be able to reach so low, we need to know how crucial it may be. Some individuals may not be able to reach such a low level of viral load without expending several treatment options rather than saving them.

How important is full suppression of viral load to stopping virus replication in the lymph tissue as well as in other potentially protected compartments such as the CSF or brain? The answers to these questions are not yet available. Preliminary research indicates that viral load reduction in plasma causes similar reductions in lymph tissue viral load. But the relationship between plasma viral load reduction and the viral load in the CSF and the effect on the brian is not yet well defined. Considerable additional research to understand these issues well enough to base definitive treatment decisions is required. Partial suppression due to partial penetration may lead to premature resistance in the brain and subsequently in the blood.

Indinavir. Dr. Roy Gulick of New York University Medical Center and Bellevue Hospital reported 100 week data for individuals taking indinavir+AZT/3TC in Merck study #035. This was a blinded and randomized study of 97 individuals comparing the triple regimen to AZT/3TC alone, and indinavir monotherapy. Participants were 3TC and protease inhibitor naive, and AZT experienced (average 2.4 years). 80% of participants had taken other nucleosides prior to the study including ddI, ddC or d4T. The median baseline CD4 and viral load were 144 cells and 43,190 copies/ml. See Table 1

Table 1. Week 100 Median CD4 and Viral Load changes from Baseline


CD4 inc.

HIV RNA dec.

%<500 copies/ml

%<50 copies/ml



-2.12 log

79% (22/28)

64% (n=25)

IDV mono*


-1.2 log

40% (n=25)




-1.0 log

30% (n=29)


* It is important to remember that those randomized to indinavir monotherapy added AZT/3TC and those who started with AZT/3TC added indinavir after 6 months on the medications they were originally assigned to. Some of the data in the table are approximations made from visual observations of graph line charts.

Dr Doug Richman, an ACTG investigator in this study, made the following observations about 035 at the recent December ACTG meeting:

    • The only reason for failure past 9-12 months should be non-compliance.
    • Reconstitution of the immune system appears to be gradually and persistently occurring as CD4 increases from baseline were 225 at week 100.
    • Virus in plasma is a product of virus in lymph tissue.
    • A couple of weeks after discontinuing therapy lymph node viral load comes back towards baseline.
    • Viral RNA nadir predicts duration of maximal response.
    • If you can see HIV RNA copies in the blood that means replication is occurring in the lymph tissue.
    • The goal of therapy should <1 copy/ml.

ACTG 320. This was a randomized and blinded trial of indinavir in combination with 2 nucleosides vs 2 nucleosides alone in 1156 individuals who were AZT-experienced, but 3TC and protease inhibitor naive, with CD4 <200. Most study participants used AZT/3TC but a small percentage used d4T/3TC. The median prior AZT experience was 21 months. This is called a clinical endpoint study and its purpose was to evaluate the effect of indinavir therapy on disease progression and survival. The FDA has declared during this past year that viral load improvements caused by therapy correlate with slowing of disease progression, clinical endpoint studies such as this are no longer required.

The risk of progression to AIDS or death was reduced by about 50% for those receiving indinavir+2 nucleosides compared to those receiving only 2 nucleosides.

The viral load reductions at 6 months from baseline for those receiving the triple regimen were as expected: -2.2 log in the <50 CD4 group, and 3.1 log in the 51-200 CD4 group. However, the preliminary viral load data after 6 months of treatment with the triple regimen showed that only 47% in the <50 CD4 group were <500 copies/ml; and, only 62% in the 51-200 CD4 group were <500 copies/ml. In study 035, 80% at week 100 were <500 copies/ml. At baseline, the individuals in 320 had lower CD4s and higher viral loads than those in 035; although indinavir is a potent protease, this suggests that individuals with more advanced HIV may need more potent regimens than they received in 320 which could be nucleosides in combination with a double protease regimen or with a protease+NNRTI. Resistance testing is planned to try to better understand the results.

Ritonavir. In this open-label, non-randomized french study conducted by J. Leibowitz and others, 32 treatment naive participants were initially enrolled to receive ritonavir (600 mg bid) for 14 days followed by the addition of AZT (200 mg tid) plus ddC (0.75 mg tid). The participants’ baseline CD4 was between 50 and 250, had a drop of 200 cells to a level of less than 350 over a recent 6 month period, or they had a CD4 count of 250 to 350 with symptoms. The mean baseline CD4 count was 160. Median baseline viral load was about 63,000 copies/ml (4.8 log).

During the first 6 months, 11 participants dropped off the study. Investigators reported 6 of these discontinuations were due to the distasteful solution (liquid) form of ritonavir. When this study started, the ritonavir solution (liquid) formulation was used because the capsule formulation was not yet available. Investigators believed compliance was a problem because of that. After 52 weeks, the capsules were substituted for the liquid formulation, and it appeared as if compliance improved. At about the same time, the mean viral load reduction appeared to improve. In Hamburg, HIV RNA data was reported to 96 weeks. See Table 2

Table 2. Ritonavir+AZT/ddC: Approximate Mean Changes in CD4 and Viral Load from Baseline


CD4 inc.

HIV RNA decrease

28 weeks (n=17)

+110 (n=17)

-2.0 log

52 weeks (n=17)

+165 (n=17)

-1.6 log

72 weeks (n=17)

+155 (n=17)

-1.9 log

96 weeks (n=9)


-2.1 log

na = not available

Ritonavir+AZT/3TC, Naive. This was an open-label two-armed study where 33 treatment naive individuals were randomized to begin the triple regimen of ritonavir+AZT/3TC simultaneously or to the delayed group where ritonavir was initiated alone followed by the addition of AZT/3TC three weeks later. The immediate vs delayed comparison was undertaken to detect if there is a difference in antiviral effect (or the development of resistance) due to the 3 week delay in adding AZT/3TC. The immediate group (A) had median baseline CD4 and viral load of 177 cells and 5.27 log (about 187,000 copies/ml). The delayed group (B) had a median baseline CD4 and viral load of 134 cells and 5.37 log (about 235,000 copies/ml). See Table 3

Table 3. Ritonavir+AZT/3TC: Changes from Baseline in CD4, viral load & % undetectable


CD4 inc.

HIV RNA dec.

% undetectable*


Group A B A B A B A B
week 16 +105 +80 -2.8 -2.8 100% 72% 14 16
week 32 +180 +110 -2.9 -2.9 100% 81% 12 13
week 40 +190 +125 -3.2 -3.0 80% 81% 9 11
week 52 +200 +180 -3.1 -3.1 91% 100% 11 9

* Undetectable was <230 copies/ml
Values are approximations based on visual observation of graph lines

We know from the results of several studies that side effects from ritonavir can include- elevated liver function tests, elevated triglycerides, asthenia (fatigue), diarrhea, nausea, and parasthesia (numbness around mouth or other areas). The dose escalation method and eating hi-fat, hi-calorie meals may help reduce side effects. Over time side effects tend to diminish.

As part of this study, baseline and subsequent tonsil lymph tissue biopsies were conducted. Significant reductions in lymph tissue viral load have been reported. For an extensive discussion of the data published in the May 9 ‘97, Science, see the NATAP report on our web site - "Virus Activity in the Lymph Tissue; Reservoirs of virus: provirus DNA and Memory CD4 lymphocytes."

4-Drug Therapy: Ritonavir+Saquinavir and AZT/3TC. At ICAAC, Andrew Talal of The Aaron Diamond AIDS Research Center in New York City reported interim findings of a small open label study of 10 chronically infected individuals receiving a 4-drug double protease therapy.

8/10 were treatment naive, 1/10 had prior AZT experience, and 1/10 had AZT and ddC experience. The baseline mean HIV RNA was 5.33 log (215,986 copies/ml) with a range of 8,011-585,068 copies/ml. The baseline mean CD4 count was 385 with a range of 179-673. The Roche Amplicor and Ultrasensitive tests were used to evaluate plasma HIV RNA. Lymph tissue and CSF samples were evaluated, and results are posted to NATAP’s website.

Results. After 48 weeks, 10 individuals remain on study treatment: the median increase in CD4 from baseline was 105; the median reduction in plasma HIV RNA from baseline was about 3.40 log (using the lower limit of detection of 200 copies/ml); 10/10 have <25 copies/ml; at week 32, the CD8 count decreased about 360 and there was a trend towards normalization of the CD4/CD8 ratio. The study is ongoing and further data will be reported.

Ritonavir+Saquinavir. During the Spring of ‘97, 48 weeks of data were reported for this combination. Study #462 was an open label study of several dose regimens for this combination. The study investigators reported that 400 mg ritonavir every 12 hrs + 400 mg saquinavir every 12 hrs produced similar CD4 increases and reductions in viral load at week 48 as the regimen of 600 mg every 12 hrs of ritonavir + 400 mg saquinavir every 12 hrs. They observed a 3.0 to 3.3 log reduction (using a more sensitive measure of HIV RNA reduction) in viral load from baseline, 90% remaining on study drugs were <200 copies/ml, and CD4s increased more than 100 cells. Some participants added d4T+3TC because they had not reached undetectable. After adding d4T/3TC all but one person reached <200 copies/ml and remained there from 4-16 weeks later. Some persons added d4T/3TC just to assure their viral load suppression. An update to 60 or more weeks will be reported at the ‘98 Human Retroviruses Conference in Chicago in early February.

Nelfinavir. Protocol #511 was a randomized and blinded study where 297 treatment naive individuals received either AZT/3TC, nelfinavir 500 mg tid + AZT/3TC, or 750 mg nelfinavir tid + AZT/3TC. About 100 persons were randomized to each arm. After 6 months all individuals were permitted to receive nelfinavir. The mean baseline CD4 and viral load were 288 cells and 153,044 copies/ml. The 750 mg dose was found to be superior in this study and is the only FDA approved dose. See Table 4

Table 4. Mean Changes at Month 12 from baseline in CD4 & Viral Load, and % Undetectable


6 months


12 months



750 mg nlf

750 mg nlf

CD4 increase




HIV RNA decrease

-1 to 1.3 log

-2 log

-2 log

Vldec. 50 copy test*

-1.28 log

-2.79 log


%<500 copies/ml

25% (n=84)

82% (n=81)

80% (n=69)

* The Roche Ultrasensitive test with a lower limit of 50 copies/ml was used. The data from this test was not available at month 12.

Some of the numbers in this table were approximated from visual observation of a graph line chart. At month 12 it appeared on the graph as though CD4 was trending upward.

In this study, a 20% rate of diarrhea was reported at 6 months for those taking the 750 mg dose. At month 12, the rate reported was 12%. The reduction may have been due in part to the use of an over-the-counter antidiarrheal medication which appears to be helpful. Other side effects noted at month 12 were- nausea (7%), abdominal pain (4%), flatulence (2%), rash (4%), asthenia (1%). Nelfinavir is to be taken with food. Without an adequate meal, its absorption and benefit can be significantly reduced.

Saquinavir SGC (Fortovase), EOF, New Formulation. The new soft gelatin capsule formulation of (SGC) saquinavir received full FDA approval on Friday November 7, 1997. Invirase is the old formulation of saquinavir (HGC-hard gelatin capsule). Due to the limited bioavailability of HGC saquinavir, the antiviral effect and its durability had limitations. Fortovase is the new formulation and it provides increased exposure (amount) of saquinavir, 8-10 times those that were seen with the HGC saquinavir at its standard dose of 600 mg three times per day. The new SGC saquinavir is prescribed at 1200 mg three times per day.

Roche has explained Fortovase delivers more drug through the body than does Invirase. The HGC took too long to dissolve in the digestive tract and be absorbed, so enzymes had a chance to degrade it, leaving less in the bloodstream. The new formula combines the drug with an oil like substance that is more rapidly digested and allows more drug to reach the bloodstream. The new formulation is more quickly absorbed because small micron sized droplets of medium chain mono- and di-glycerides contain dissolved saquinavir. You now have an oil comprised of these small saquinavir containing droplets which allow for a wider dispersion of the drug which enables it to be absorbed more quickly before degradation from the enzymes.

Roche Labs is transitioning the old formulation of saquinavir off the market. For only 6 months the old version of saquinavir (Invirase) will be available in your pharmacy. If you have been using Invirase and want to continue, Fortovase will be available after 6 months for individuals currently using it in combination with ritonavir or for those patients who through consultation with their doctors have decided to continue taking Invirase.

Refrigeration. Your pharmacist will refrigerate saquinavir upon receipt. You can store saquinavir in your fridge. But if you don’t refrigerate it, or if you take it out, or in and out of your fridge, you have a total of 3 months of unrefrigerated time. The new saquinavir can be kept out of refrigeration and at room temperature for a total of 3 months.

Ritonavir+Saquinavir. Both Roche and Abbott have explained that if you are currently taking the double protease combination of ritonavir+saquinavir it doesn’t matter if you use Invirase or Fortovase. The dose will be the same, 400 mg every 12 hours. The drug blood levels of saquinavir hit a maximum peak with ritonavir. Ritonavir increases saquinavir blood levels 20-50 fold. Whether you use Invirase or Fortovase saquinavir, blood levels cannot be higher. Both Abbott and Roche have stated side effects should not be any different.

Food Effect. Taking Fortovase with a full meal is recommended because it greatly increases drug levels in studies compared to taking Fortovase without eating and increases drug absorption more than with a light meal.

Taking Fortovase with a light low fat meal is preferable to not eating. Preliminary results from an ongoing study indicated that blood levels of Fortovase are reduced by about 40% when the drug is taken following a low fat meal compared to it being taken with a high fat meal.

Sun Study: Fortovase+AZT/3TC.

This is an open-label non-comparative examination of the triple regimen of saquinavir SGC (soft-gel capsule, Forto-vase) plus AZT and 3TC. 42 treatment-naive individuals were enrolled with mean baseline and HIV RNA and CD4 of 4.8 log (about 63,000 copies/ml, range 8,951-1,193,168) and 419 cells, respectively. The study is ongoing and the following data is preliminary.

The investigators reported that after 20 weeks:

• The reduction in viral load for 23 evaluable study participants was 3.34 log (range: -4.5 to 2.2 log). However, the investigators used a more sensitive viral load test (20 copies/ml), which can report (accuracy of results using 20 copy test can be inconsistent) viral load reductions down to a lower level than you’ll get from using the 400 copy test.
• 91% were <400 copies/ml (undetectable)
• 60% were <20 copies/ml.
• 259 CD4 increase from baseline of 419 cells.
• 19/42 participants had withdrawn from the study by week 20 and were not included in the analysis: 2 due to adverse events, 3 due to non-compliance, 4 due to refusal of treatment, 6 lost to follow-up, 1 missed week 16 visit.

Safety. Investigators characterized the triple combination as well-tolerated. The most frequent side effects related to study drug were (>5%): nausea, vomiting, diarrhea, and headaches.

Lab abnormalities: 1 person had a grade III AST/ALT (liver function tests) at week 2 which resolved after discontinuing study treatment. 1 person had a grade IV AST/ALT at week 12 associated with acute hepatitis A. 1 person had a Grade III AST/Grade IV ALT at week 20 associated with acute hepatitis A. An approximate 20% incidence of diarrhea has been reported associated with saquinavir SGC in a different study.

Cheese Study: SGC Saquinavir vs Indinavir. In Hamburg, JCC Borleffs of University Hospital Utrecht, and others reported preliminary findings from this 48 week study comparing Fortovase+ AZT/3TC to Crixivan+AZT/3TC. Study participants were protease inhibitor and 3TC naive. They were permitted to be AZT naive or with <12 months AZT experience. Two receiving Fortovase and one receiving Crixivan had <12 months AZT experience. Those with = Grade 3 lab abnormalities were excluded.

At week 8, both groups experienced about a 2 log reduction in viral load. At week 12, viral load was reduced to below detection (400 copies/ml.) using the Amplicor viral load test. Gastrointestinal side effects were the most commonly reported by individuals taking the Fortovase regimen were: diarrhea (6), nausea (2)

Click here to link up to additional Fortovase studies and safety profile data. See Table 5

Table 5. Fortovase (saquinavir): CD4 and Viral Load Changes

  Baseline Week 4 Week 12 Week 24
SGC SQV+AZT/3TC CD4 (mean) 310 398 434 (n-16) 563 (253 increase ) n-3
HIV RNA (median) 4.87 log* 3.16 log 2.60 log 2.60 log (decrease 2.27 log)
IDV+AZT/3TC CD4 (median) 296 351 345 (n-14) 505 (209 increase) n-3
CD4 (median) 4.92* 3.12 2.60 2.60 log (dec. 2.32 log)

4.87 log is equal to about 74,000 copies/ml; 4.92 log equals about 83,000 copies/ml.

The number of evaluable participants at week 24 is small (3), so the data could be different after more individuals reach 24 weeks.

Phase II Dose Ranging Study of 141W94 in combination with AZT/3TC. Investigators have reported preliminary 12 week data but the study is continuing for 48 weeks. The purpose of this study is to assess safety and tolerability of this triple combination, CD4 and plasma viral load responses; and to make dose selection for studies.

Although participants were required to be 3TC and protease inhibitor naive, they had prior nucleoside experience. The nucleoside experience of the individuals in the different treatment arms of this study varied, and this could confuse trying to discern differences in treatment effect between study arms. Prior nucleoside experience for any given individual in this study may limit the antiviral effect of receiving AZT/3TC in this study.

There are 4 arms in the study: AZT/3TC, and 3 different doses of 141 each with AZT/3TC 900 mg bid (twice daily) 141, 1050 mg bid 141, and 1200 mg bid 141.

It appears as if the 1200 mg dose is the one selected for development. After the first 12 weeks, the CD4 increases were about 100 for those receiving the 1200 mg dose of 141. Their viral load reduction was -2.65 log.

Additional information on 141W94 is available on website- safety and antiviral activity of other doses. See Table 6

Table 6. 141W94: Drug Related Adverse Events in >10% of Patients up to Week 12



900 mg bid

1050 mg bid

1200 mg bid






Nausea± vomiting




13 (2)






Gaseous Symptoms










Malaise & Fatigue










Skin Rashes

2 (1)

1 (1)


9 (4)

Any Grade 3 or 4 Event





( ) no. inside parenthesis indicates # of patients who discontinued 141.
* paresthesis includes a numbness and/or tingling

Resistance. Early in vitro research identified a relatively different resistance profile for 141 compared to other available protease inhibitors. 50 was identified as the main mutation. The same in vitro research suggested that saquinavir may resensitize 141 resistant virus to 141. These possibilities remain to be confirmed, although we can be hopeful that protease inhibitor resistant virus may be sensitive to 141. Some expert researchers preliminarily do not believe that 141’s resistance profile will be unique enough to suppress protease resistance virus. Essentially, some researchers believe all protease inhibitors will be problematically cross-resistant. Additional information on the resistance profile (mutations) should be available in early 1998. The use of a double protease regimen including 141 with either saquinavir, indinavir, ritonavir or nelfinavir may offer some hope to the potential for suppressing protease inhibitor resistant virus. But, that application has yet to be explored. An initial study of the safety, pharmacokinetics, tolerability and potency of these double protease combinations is ongoing. Data from the study should be available at February ‘98 Human Anti-retroviral Conference.

Glaxo Wellcome is conductng pediatric studies along side with adult studies. It is expected that FDA approval will be sought at the same time for both adult and pediatric use.

4-drug Therapy: 141W94 + 1592U89 + AZT/3TC in 24 individuals- 13 acutely infected and 11 chronically infected. Dr David Ho briefly summarized the preliminary data from a small study conducted at the Aaron Diamond AIDS Research Center in New York. They used a bid regimen, all drugs were taken twice daily. The acutely infected group were within 90 days of infection. All participants received:

• 141W94 1200 mg bid
• 1592U89 300 mg bid
• AZT/3TC 300 mg/150 mg bid

The purpose of the study is to test the antiviral potency of this regimen in blood, CSF and gut-associated lymph tissue. RT and DNA PCR in PBMCs (peripheral blood mononuclear cells), tissues and semen will be conducted. Although a measure of drug activity in the CSF does not necessarily reflect the activity in the brain, AZT and 1592 were selected for their CSF penetration.

Withdrawals. 1 person withdrew from the acute group due to GI side effects; additional persons are experiencing nausea. 1 person from the chronic group was lost to follow-up. 22 persons have been treated for 5 to 25 weeks.

HIV-RNA. The line graph of the reduction in plasma viral load for the acutely-infected individuals showed a decline of about 3 log by about 10 to 18 weeks. For the chronically-infected individuals, the line graph of the reduction in plasma viral load appeared to be about 2.5 log by week 6 and approached 3 log by about week 20.

At week 8, 8/10 chronically-infected individuals were <100 copies/ml, and 5/6 were <100 copies/ml at week 12. At week 16, 5/5 acutely-infected individuals were <100 copies/ml.

CD4 cell counts. The mean baseline CD4 count was about 550 for the acute group. By about 20-26 weeks, the mean increase appeared to be about 100 CD4. In the chronic group, they started off with a mean CD4 count of about 300, and by about week 22 the increase was about 200 CD4.

CSF. The antiviral activity in the CSF has been observed in only 6 persons in this study. Additional persons are being studied along with ongoing follow-up for these 6 participants. By measuring free virus in the CSF at baseline and at 1 month on therapy, there is a consistent decrease in HIV-RNA in the CSF for all 6 persons, but only a few have so far reached undetectable.

GI associated lymph tissue. The viral load in lymph tissue was generally declining.

The data reported is preliminary as the study is ongoing. Ho preliminarily concluded that the therapy was reasonably well tolerated, and shows potent antiviral activity in both chronic and acutely infected individuals particularly in the blood and lymph tissue of GALT. The CSF is being assessed.

PNU 140690 (protease inhibitor)

Upjohn conducted and reported at ICAAC preclinical data from studies of their protease inhibitor, PNU 140690 Safety, tolerance and pharmacokinetics were studied in healthy volunteers (n=48) in escalating single doses at doses of 100, 300, 500, 700, 900, 1200, 1600, and 2000 mg.

Investigators characterized PNU 140690 as generally well tolerated for up to the 10 days of study. Gastrointestinal related side effects were the most commonly observed (nausea, diarrhea, vomiting and abdominal cramping). They were mostly mild and occasionally moderate. No serious medical events were reported and no clinically significant lab abnormalities were reported. 140690 showed a modest 30% bioavailability in the dog and rat and was attributed to limited drug absorption. The AUC of various doses suggest dosing at 3 times per day.

Preclinical studies showed a synergy when 140690 was combined with ritonavir vs ritonavir resistant virus. 140690 was active against ritonavir resistant virus. Combining PNU 140690 with ritonavir might improve dosing of PNU to twice daily. Upjohn thinks the resistance profile of 140690 may be sufficiently unique to be effective against protease inhibitor resistant virus. In first quarter of 1998 they plan to explore this potential by initiating a trial treating individuals who’ve failed indinavir with PNU 140690. Subsequent trials are expected treating individuals who’ve failed other protease inhibitors.

ABT-378 is a new protease inhibitor being developed by Abbott Labs. See the Double Protease Section for a discussion of this drug.

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