Part 1. Reducing VL to <50 copies/ml

NATAP reported a year ago that at the January 1997 Retrovirus Conference Dale Kempf, PhD, a researcher at Abbott Labs, reported that the lower your nadir (lowest level reached) of viral load drop the greater your durability should be. Increasingly since then, additional leading researchers have said that lowering viral load <50 copies/ml should create more durable responses. There appears to be mounting evidence supporting this thinking.

A French research group reported at the Retrovirus Conference their study findings that individuals with <20 copies/ml had greater durability of viral load suppression than those that had <200 copies/ml but did not have <20 copies/ml. The French research group studied 349 individuals who started a 3 drug protease inhibitor containing regimen between April ‘96 and October ‘96. They were followed for a median of 15 months. 53% were on an indinavir regimen and 47% were on a different protease regimen. The median baseline CD4 and viral load were 97 cells and 100,000 copies/ml. 92% were treatment experienced while 8% were naive. At month 3, 37% (n=129) had <200 copies/ml (Roche Amplicor assay), and 10.3% (n=36) had <20 copies/ml (Ultrasensitive RT-PCR). Viral escape among virological responders was defined as after having HIV RNA <200 copies/ml, and a person’s viral load was >1000 copies/ml on two consecutive tests, despite continued therapy. After a median follow-up period of 15 months, viral escape occurred after 3 months in 7.1% (2/28) of those who had reached <20 copies/ml, while 34.1% (27/79) of those who had viral load >20 copies/ml had viral escape after 3 months (p<0.01); median follow-up was 15 months.

In efavirenz studies participants with undetectable viral load by a sensitive measure are more likely to remain suppressed during the course of the studies extending out to as much as about 12 months. As well, participants in nevirapine study 1046 did not remain under 200 copies/ml unless they were <20 copies/ml. These data are from NNRTI 3-drug combination studies. Except for the French study reported above similar data have not yet been reported from protease studies. But, at the International Geneva AIDS Conference in July 1998, it is expected that Agouron will report data from their 511 study of nelfinavir+AZT+3TC on the durability of antiviral effect when a person goes below 50copies/ml as oppoosed to not going below 50 copies/ml.

The researchers found baseline HIV RNA and previous antiretroviral therapy influenced HIV RNA being <20 copies/ml after 3 months (median 15 months follow-up). Of study participants with baseline HIV RNA <100,000 copies/ml, 14.3% (25/175) had viral load <20 copies/ml after 3 months; 6.4% (11/174) of individuals having >100,000 copies/ml had viral load <20 copies/ml after 3 months (p<0.05). 21.4% (6/28) of treatment naive individuals had <20 copies/ml after 3 months of treatment, while 9.3% (30/321) of treatment experienced had viral load <20 copies/ml (p=<0.05). When they analyzed baseline CD4 stratified to <97 cells or >97 cells, they did not find any correlation with durability of viral load response.

A research group from Amsterdam reported preliminary data from a study they initiated because they feel that lowering viral load to as low as possible as quickly as possible may be associated with better antiviral activity. For a full version of the report on this web site, see "Clearance of HIV Following 3, 4, or 5 drug combinations; and, trying to Maximize Viral Load Suppression with 5 drug Regimen". They compared 3, 4, and 5 drug protease containing regimens in a partially retrospective analysis and found that the 5 drug regimen caused a more rapid decline in viral load. It remains uncertain if more rapid decline in viral load is associated with better clinical effect in the long term, so the investigators will continue to follow the patients for durability of viral load response and long term clinical effect. It is suggested that the more rapid viral load declines or steeper the slope of decline of a person’s viral load the more quickly replication may be stopped or inhibited. Possibly, the more quickly viral load declines and replication stopped the more likely the person may be to reach <50 copies/ml.

The rapid decline of viral load can be influenced by previous antiretroviral drug experience, the potency of a regimen, and baseline viral load. The lower a person’s baseline viral load when they begin a new regimen, I think the more likely they will be to reach <200 or <50 copies/ml. A person who starts a new regimen with a baseline viral load of 15,000 copies/ml is more likely to reach <50 copies/ml more quickly. A more potent regimen may be more likely to help reach undetectable (<200 copies/ml or <50 copies/ml); and, based on the Amsterdam group’s research it may do so more quickly.

The extent of a person’s NRTI experience can effect their response to a new therapy. Prior experience with NRTI(s) can reduce the effectiveness of subsequent use of NRTI(s). We now know that cross-resistance between protease inhibitors is a challenge and can be a problem. The level of cross resistance between protease inhibitors can vary depending on the drugs (see salvage therapy discussion and studies in this report). Although, we have less experience researching NNRTI cross-resistance, it is likely there is at least partial cross-resistance between NNRTIs.

The longer a person has been HIV infected the more HIV replication they have experienced. Replication can cause virus with pre-existing mutations and virus that is less homogenous (see the Resistance Supplement in the January 1998 NATAP Reports for a discussion of this available on the NATAP web site). There are pros and cons to starting therapy during acute infection or in early disease, but one pro for starting therapy early is that your virus has experienced less viral replication and your immune system is more intact.

Therapy should be individualized according to a person’s situation. Baseline viral load and prior treatment experience are key considerations. If your goal is undetectable viral load, a person with a lower baseline viral load may need a less potent regimen than someone with a high baseline VL. For a person with, for example, a viral load of 15,000 copies/ml a 3 -drug regimen may suffice. If your baseline viral load is 180,000 copies/ml you may need a more potent regimen to reach undetectable, which could consist of a 4 or 5 drug regimen. The Public Health Service Treatment Guidelines recommend that a multi-drug regimen should preferentially contain at least one protease inhibitor. They suggest that a regimen could contain a NNRTI instead of a protease inhibitor but they say there is less evidence supporting success with such a regimen. The latest data on nevirapine and efavirenz treatments without protease inhibitors are in the current NNRTI report on this web site. 32 week data on delavirdine plus AZT/3TC is available in a report in the January 1998 issue of NATAP Reports on our web site.

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At the Retrovirus Conference, a research group reported that a triple NRTI regimen, described below, reduced viral load to undetectable in 9/9 acutely infected individuals.

• ACTG 347- 141W94 monotherapy failures
• Development Information on Upjohn protease PNU-140690 for individuals with protease resistance
• Brief Discussion of ABT-378
• Johns Hopkins Study of Salvage Therapy (with RTV/SQV) When Viral Load is Low

It has been well established by now that cross-resistance between protease inhibitors is an obstacle. At the Annual Resistance Conference in St. Petersburg Florida during the Summer of ‘97, several in vitro and in vivo studies reported the that PI cross resistance prevented response after switching to a new PI. At ISAAC in the Fall of ‘97 numerous human studies were reported showing that there was cross resistance between Is. Again, several in vitro and human salvage therapy studies were reported at the ‘98 Retrovirus Conference showing again cross resistance is an obstacle.

One important study reported at the Retrovirus Conference by Jody Lawrence is interesting. She took d failures treated them with a NFV regimen but they failed pretty quickly. The nelfinavir regimens, however, were not well designed to be potent. Nonetheless, the failure indicates some level of cross-resistance. She then treated them with IDV+NVP and their initial response for several months was good and seemed promising. However, by 24 weeks the responses were fading. However, Keith Henry reported preliminary encouraging data. A small group who failed initial PI therapy with NFV received RTV+SQV+d4T/3TC; at week 24, 68% (13/19) remained undetectable (<500 copies/ml). However, at week 12, 90% (6/7) were undetectable. A detailed discussion of this study is below. A possible key factor in this study is that the participants had been on NFV treatment for an average of about one year. If they had switched therapy immediately after failing, the response might have been better. Debilitating cross resistance may be avoidable by switching PI therapy immediately after failing first regimen and this idea is discussed below. Immediately following are reports from Retrovirus of two in vitro studies demonstrating PI cross resistance.

This brief commentary will address some of the treatment options currently available or expected to be available in the near future for individuals who’ve failed protease inhibitor(s). Additional research in earlier stages is ongoing to characterize virus targets for therapy and treatments for those targets. Several new NRTIs and PIs are in development and are reported in these Retrovirus Reports. FddA is a NRTI in early phase I human testing which may be promising because in vitro it suppressed virus resistant to other NRTIs and appears to have a fair amount of antiviral activity (see FddA article in NRTI Report LINKUP).

NATAP Reports January ‘98 issue contains a 12-page Resistance Supplement in which cross-resistance and resistance concerns for NRTIs, NNRTIs and protease inhibitors are discussed at some length. In the protease section of that report is a discussion of the factors involved in protease cross-resistance and why cross resistance is such an obstacle.

Possibly preventing protease cross-resistance

There may be a potential solution for dealing with protease cross-resistance. If you follow your viral load monthly and change protease therapy immediately after detecting and confirming viral load rebound from undetectable, you may be able to limit or prevent cross resistance. The rationale for this approach is that mutations and consequent resistance occur when replication is ongoing. The purpose of "full" suppression of viral load is to prevent replication and consequent mutations. If you discontinue your protease therapy when rebound is detected quickly you may be able to stop further replication and the consequent development of mutations. The initial mutation(s) may emerge but the secondary mutations may not develop. Therefore, theoretically the potential for cross-resistance may be limited, and you may respond to a new potent protease containing regimen. This approach is growing with increasing acceptance by researchers but there is little data from studies supporting it except for studies discussed below. Additionally, you will probably need a potent regimen to suppress virus that could have a low level protease cross resistance.

In ACTG 347, participants failing 141W94 monotherapy switched very soon after detecting viral load rebound to indinavir+nevirapine+2 NRTIs. About 4 months following the switch 29/33 were <500 copies/ml. Of course 4 months is not long enough to declare success but it is encouraging. The participants continue to be followed and data will be reported. There could be several reasons for the preliminary success noted in 347: the quick switch, a unique resistance profile for 141W94, a combination of both, or the nevirapine could be powering the viral load reduction in which case resistance should emerge relatively quickly. A resistance study of these participants is ongoing so we will have resistance data that may help understand the results.

Joel Gallant reported data at Chicago from a salvage therapy study exploring the same concept of switching protease therapy soon after detecting viral load rebound. The results suggest that switching protease when viral load is low and as soon as possible after failure will increase chance for success. After a mean of 28 weeks, 12/17 were <400 copies/ml following failing IDV+ 2 nukes and being treated with a RTV/SQV regimen where NRTIs were also switched for most participants. As well, after a mean of 26 weeks, 3/4 nelfinavir failures were <400 copies/ml following treatment with a RTV/SQV regimen. The study is discussed below in more detail in the salvage therapy section.

There are several protease inhibitors in development that may be more sensitive to protease resistant virus. It appears as though 141’s resistance profile may be different. A mutation at position 50 appears to be the main resistance mutation for 141 and it has not been seen as associated with resistance to any approved protease inhibitor. Mutations at positions 46 and 47 have also been seen as associated with resistance to 141. A more detailed discussion of 141 resistance follows in the 141 data report below. At this point it is uncertain if 141 will be effective after failing another protease but by the time the FDA reviews 141 for approval there should be data from several studies reflecting on this issue.

For those who’ve failed a protease inhibitor(s), if 141 can help towards suppressing protease resistant virus, it will probably have to consist of a potent regimen including additional drugs. An example of such a potent regimen might be: 141+IDV+1592+efaveirenz+(PMEA and/or recycled NRTIs). Preliminary information from a PK study shows IDV significantly increases 141’s drug blood level, thereby possibly making 141+IDV a more potent regimen. If a person has failed IDV or RTV substituting SQV or NFV for IDV may be preferable. The PK studies of the effect of SQV, NFV and RTV on 141 blood levels are ongoing, so the data are not yet available. Shortly, it is expected that a couple of new studies may begin using potent 4-5 drug regimens exploring double protease regimens including 141+ a second protease. These studies should help determine if these combinations can in fact suppress protease resistance virus. Until we identify combinations that are successful at suppressing virus resistant to protease inhibitors, it may be risky for you to experiment with a regimen. If you try a regimen and it fails, you may lose the opportunity to o use the drugs in that combination again because you may develop resistance to them.

Abbott’s second generation protease, ABT-378, is currently in phase II in HIV infected individuals. ABT-378 appears to have a relatively different resistance profile, based on in vitro research done to date. It did not appear to have a mutation at position 82, which is important for RTV resistance, and relevant to IDV resistance. ABT-378 will be used with a small dose of RTV (50 or 100 mg) because the addition of ritonavir greatly enhances the PK profile of ABT-378. In vitro, ABT-378 appears to suppress virus with some limited degree of ritonavir resistance (possibly up to 25 fold RTV resistance ). Dosing is being explored now by Abbott. As soon as possible, Abbott hopes to start trials with ABT-378 for individuals who’ve failed protease therapy.

Upjohn’s new protease, PNU-140690, may offer some effectiveness against protease resistant virus. Upjohn has just started recruiting for a small study evaluating the effectiveness of PNU140690 in individuals who have failed protease therapy. In one arm, indinavir or ritonavir failures will receive PNU140690. A second arm is for individuals who have experience with multiple protease inhibitors. Participants will receive PNU140690 if they’ve failed their current protease therapy and had previous protease therapy. The objective is to make a preliminary observation if individuals who’ve failed protease inhibitors will be sensitive to PNU140690. If all goes well, the hope is that by this Summer a larger study will begin exploring PNU140690’s effectiveness for individuals who have failed protease therapy. Again it may be less risky until research identifies combinations successful at suppressing protease resistant virus.

At the recent Chicago Retrovirus Conference, preliminary data from Gilead Science’s new drug called PMPA showed a -1.22 log reduction over the course of a 30 day study in HIV infected. Higher doses than used in the 30 day study are expected to be explored. PMPA is from a class of drugs called nucleotides. It is not expected that PMPA would be at all cross-resistant with protease inhibitors. Phase II studies in HIV infected individuals are being planned. A series of studies are expected to begin soon exploring PMPA’s antiviral activitiy, its role in combination therapy, its utility for individuals in different situations, proper dosing, and safety. See more detailed PMPA Report on this web site.

Several other drugs are in earlier stages of development. Historically, drugs are dropped from development with increasing frequency during preclinical stages compared to when they reach human testing in HIV infected individuals. T-20 is the first fusion inhibitor to show antiviral activity in HIV infected individuals. Administration was by IV in an early 14 day phase I study. A subcutaneous pump system similar to those used by diabetics is expected to be explored in a combination salvage therapy with EFV and 2 protease inhibitors for IDV failures. The study is expected to begin in May ‘98. See T-20 report on this web site.

Two Parke Davis protease inhibitors, and 2 NRTIs, FDDA and BCH-10652, are in early development. The data reported at Chicago was interesting. A report on Parke Davis PIs is being prepared. The 2 NRTIs are reported on in the NRTI section.

In NATAP’s January 1998 newsletter, NATAP Reports, we reported the findings of Dr Cassy Workman from Australia. She explored the concept of recycling previously used NRTIs for 12 individuals. She used a 6-drug regimen for individuals who failed protease inhibitors. The 12 persons had previously used all available nucleosides and 3 protease inhibitors (indinavir, ritonavir and saquinavir). But, they were naive to nevirapine and nelfinavir. The 6-drug regimen was: d4T, 3TC, ddI, NVP, NFV, and SQV. 3 individuals were intolerant to components of the therapy that they had previously been intolerant to. But, 9/9 individuals remained on therapy and had undetectable viral load (<400 copies/ml) at week 12. 12 weeks is too soon to draw conclusions but follow-up information will be reported.

Hydroxyurea (HU) is a potential option for therapy. Studies have shown that in combination with ddI, reductions in viral load can be significant. HU has been studied with ddI, ddI+d4T, and with ddI+a protease inhibitor. The actual results of these studies were reported in the January NATAP Reports. An update on HU+a protease+ddI was reported at the Retrovirus Conference and is reported on this web site (LINKUP). There is no cross-resistance between HU and protease inhibitors. There are 3 concerns attached to using HU therapy: (1) HU can lower the WBC (neutropenia), (2) it may also have a negative effect on platelet count, and (3) although viral load may be reduced, proportionate increases in CD4 do not occur; CD4 increases may be blunted; for a discussion of this see the HU reports on the web site. So far, as far as I know there is no data from any study on HU used for protease failure. A potential regimen could include HU+ddI+adefovir (PMEA)+a NNRTI. A small pilot study with this regimen is expected to begin soon for individuals who’ve failed protease inhibitors. As well, a number of other studies are planned exploring HU regimens for individuals with resistance to protease inhibitors.

The ACTG will be exploring "treatment strategy trials" where protease therapy will only be part of a long term treatment approach comprised of several different regimens some of which won’t be containing protease inhibitors. For example, individuals could first receive a regimen consisting of a NNRTI+2 nukes, after failing a person would switch to a regimen with a protease+2 different nukes, after failing the second regimen they could receive a double protease regimen+HU+ddI, or a more potent protease regimen. Additional treatment strategies trials will likely follow. The goal is to discover a sequence of regimens that will succeed in adequate suppression of viral load and delay of disease progression for the long term.

According to Franco Lori, the researcher pioneering the research into HU application in treating HIV, neutropenia may be a concern only for individuals who already have a problems regarding their WBC. The same may be true for platelets. If your CD4 is already low, the HU component to a therapy may not raise your CD4 count. But, using HU in conjunction with other drugs may have the effect of raising your CD4 count. Consult with a knowledgeable physician before making treatment decisions. Within the next few months several studies will start for individuals who’ve failed protease inhibitors.

There are additional potential virus targets for anti-HIV therapy which are in early stages of research. It is always difficult to predict the success or failure of such early research but I think there are good reasons to be hopeful that unique and successful therapies will emerge. Additionally, several new NRTIs that are potentially not cross-resistant with currently available NRTIs are in early development. See articles on this web site about FddA, FTC, and BCH-10652. As well, a report is being prepared on the 2 Parke Davis protease inhibitors which are in preclinical development.

Protease Inhibitor Cross Resistance

In Chicago, S Palmer, R Shafer and TC Merigan reported findings of their in vitro research on cross resistance: "Highly Drug Resistant HIV-1 Isolates are Cross Resistant to Many of the Current Anti-HIV Compounds in Clinical Development."

The investigators said: Increased clinical use of combination treatment for HIV has lead to the development of viruses resistant to multiple drugs. Due to that cross resistance, patients with highly resistant viruses may not respond to newly designed anti-HIV drugs in clinical development.

I think it’s important to put the data from this study into a certain perspective. As discussed above in the introductory section, the development of mutations and consequent resistance builds up over time as viral replication continues. In vitro studies such as this one assume that a number of mutations will accumulate over time. The investigators in this study constructed a recombinant virus that has a number of mutations from patient isolates. But, the patient clinical isolates accumulate these mutations probably because they remained on the protease inhibitor after viral load rebound, when continuing replication was ongoing probably for a while, and multiple mutations were allowed to accumulate. If you can limit the development of these mutations by switching protease immediately after detecting viral load rebound you may be able to prevent the development of subsequent mutations. Under such conditions this in vitro data may not apply.

They assessed the activity of drugs recently developed against multi-drug resistant clinical isolates. Bear in mind, another limitation of in vitro resistance testing. Results from these in vitro studies may not necessarily predict responses by humans taking multi-drug combinations. For example, the results obtained in these types of studies can be subject to the variability of testing conditions or methodology used by different investigators; that is, the testing conditions can be variable from one investigator to another.

Investigators tested 3 groups of resistant isolates, each group containing different resistance mutations:

• 75, 77, 116, 151. These isolates are from patients who have used AZT/ddI. Research has shown that about 10% of individuals who have used AZT/ddI may develop resistant mutants containing these mutations, which are called multi-drug resistant mutations. When a virus accumulates these mutations, the virus may be highly resistant to AZT, ddI, ddC, d4T, and perhaps 3TC. The table below refers to this mutant as MNR (multi nucleoside resistant).
• The 2nd group called the MDR group (multi-drug resistant) contained nucleoside mutations and protease inhibitor mutations. These isolates are from heavily pretreated patients sharing 8 RT resistance mutations - 41, 43, 67, 118, 184, 210, 215, 219; and, these protease mutations- 10, 48, 54, 71, 77, 82.
• 10, 46, 84, 90. The 3rd group of patient isolates contained these protease inhibitor mutations.

The 2nd column is the amount of drug required to inhibit viral replication by 50%. That is referred to as the IC50 (inhibitory concentration). The IC50 or the IC90 are standard lab tests to measure phenotypic resistance. The 3rd column contains the amount of drug necessary to inhibit viral replication by 50% of the MNR mutant virus. For example, 4.93 is 123 times greater than 0.04, therefore there is 123 fold resistance. The MDR mutant in 4th column exhibited a 5 fold resistance to d4T. 1592U89 displayed 15 fold resistance to the MNR mutant, and 6 fold resistance to the MDR isolate. This is first suggestion that individuals developing a MNR mutant may have resistance to 1592. For a more detailed discussion of 1592 resistance and cross resistance, see the Resistance Supplement in January 1998 NATAP Reports. The mutations present in the MNR and MDR isolates are listed in table.

IC50 (uM) number in parenthesis is the fold increase in resistance

* New NRTI being developed. See current FDDA report on this web site.

The investigators characterized the MNR isolate as being "partially susceptible to PMEA and PMPA".

The results are expressed as means of 4 to 6 values obtained in 2 or 3 experiments.

* This protease inhibitor is from DuPont Merck and not being developed because I think an oral administration could not be developed. But, it looked very good in vitro evidenced by its lack of cross resistance in this experiment. The point is that this cross resistance data suggests that it may be possible to develop a protease inhibitor without cross resistance. The drug manufacturers should be trying to develop such drugs.

** Based on this and other data it is possible that VX-478 may at least have some activity against protease resistant virus, but we don’t have enough data from clinical studies to evaluate that possibility. As discussed above, the main mutation for VX-478 is at position 50. Mutations at 46 and 47 have also been detected. Theoretically, if you stop taking a protease soon after (within 1 month possibly) detecting viral load rebound your virus may still be sensitive to a new protease inhibitor, and thus it may be possible to limit or prevent cross-resistance. The virus has not had much time to replicate, and so the number and quality of the mutations emerging soon after rebound may be limited. J Gallant reported results in Chicago from a study suggesting the same approach. A review of this report is below. Of course, when you start any new regimen you want to feel confident that the components will be potent enough.

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K Hertogs, J Mellors and others reported results from this study intended to determine the frequency of phenotypic cross resistance using the Virco Antivirogram phenotypic test among approved protease inhibitors in recombinant HIV isolates obtained from patients treated with protease inhibitors. A second purpose was to identify the most common protease mutations associated with broad protease inhibitor resistance.

I would put this data into the same perspective described in the previous report immediately above. This in vitro data may not apply if there is limited opportunity mutations to develop. Probably, the best way to understand protease cross-resistance is to follow individuals on one protease inhibitor who fail and continue to follow their responses after switching to a second protease inhibitor. You want to evaluate viral load and the presence of mutations before and after failure and switching therapy. In vitro resistance studies such as these two described do NOT duplicate these conditions.

828 recombinant isolates with protease and RT sequences taken from sequences in plasma were generated for susceptibility testing. The investigators concluded that when a recombinant virus displayed high level resistance (>10-fold) to IDV, RTV, NFV, or SQV, there was phenotypic cross-resistance (>4 fold) to other approved protease inhibitors 77-95% of the time (see table below). They also said phenotypic analysis is essential to understand the functional implications of genetic mutations.

Compensatory mutations at GAG cleavage sites could be detected 52% of cases. The most common was A>V in the p7/p1 site and L/P in the p1/p6 site.

In patient samples with high level (>10 fold) resistance, the most prevalent mutations (>30%) were at positions: 10, 36, 46, 54, 71, 77, 82 and 90. Also detected at a lower rate of incidence were: 20 (20%), 48 (20%), 73 (15%), 84 (10%), 88 (7%).

Table 3. Percent Cross Resistant.

The number of recombinant isolates with >10 fold resistance to IDV, SQV, RTV, or NFV are listed in column 2. Columns 3 thru 10 list the percentage of cross-resistance (both >4 fold and >10 fold) that occurs to IDV, SQV, RTV, and NFV after there is >10 fold resistance to one of the protease inhibitors as indicated in columns 1 and 2. For example, if there is >10 fold resistance to IDV, 83% of the patient isolates had intermediate (>4 fold) cross-resistance to SQV, and 66% had high (>10 fold) cross-resistance to SQV. 

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Data from studies of several protease sparing regimens have been reported at this Retrovirus Conference: EFV, DLV or NVP plus two NRTIs. This open-label pilot study explores treatment with 3 NRTIs during primary infection using AZT, ddI and 3TC. The 9 study participants consented to discontinue therapy after month 12. The investigators reported that at month 12 during therapy, 9/9 patients were under the threshold of <500 copies/ml (Chiron bDNA) and <5 infective cells/107 cells for virus in PBMC cells in blood. The CD4 counts increased significantly, about 200, and plateaued at month 2-3. After discontinuation of therapy, HIV was detec 4 again in plasma and PBMC in all participants.

How long would the participants have remained undetectable, if they had continued therapy? We don’t know because all 9 consented to discontinue therapy at month 12. However, after treatment discontinuation all 4 who developed a 184 mutation had detectable viral load at a low level during therapy (>50 to 500 copies/ml). The Roche Ultra sensitive test was used. It is possible that viral load would have rebounded for those individuals who had the 184 mutation. For individuals with <50 copies/ml, how long would they have remained undetectable? We don’t know.

The one patient (*) who had the 69+70 after discontinuation developed a 184 mutation in addition. This person also had >50 but <500 copies/ml during therapy.

The baseline viral load was reported as 461.103 copies (461,100 copies/ml); range: (28,100 to 2.715 million). The baseline CD4 was 438 (range 238-707). The baseline value for blood cellular virus in PBMCs was 966 infected cells/107 (range 240-3450).

There were no side effect caused discontinuations. 1/9 discontinued ddI (for personal reason).

The mean follow-up was 18 months (15-33). Plasma viral load became detectable in all patients after a mean time of 3 months (1-9) post discontinuation.

There is a 300 person study ongoing in treatment naive individuals comparing a different triple NRTI regimen of ddI+d4T+3TC to d4T+ddI+IDV and d4T+ddI+NVP. Preliminary data is expected to be available in Geneva in June. Individuals failing the NVP or IDV arms will be offered a rollover regimen which will include AZT/3TC. So, this will be the first study I know of which is evaluating AZT/3TC after failing d4T or ddI. This may answer some of our questions about sequencing NRTIs. As well, in a different study, the triple NRTI combination of AZT/3TC and abacavir (1592) is being explored.

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Fortovase is the new formulation for saquinavir. In studies, Fortovase resulted in increased plasma drug concentrations that are 10-fold higher than that of the approved 600 mg dose of Invirase. Further details about this are available in the NATAP Reports Jan 1998 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 with chronic hepatitis B or C were excluded from the study.

Participants received Fortovase 1200 mg tid with AZT 300 mg bid and 3TC 150 mg bid. Mean baseline CD4 was 419. Mean baseline CD8 was 960. Mean baseline plasma viral load was 4.8 log or 63,757 copies/ml.

Patients who experienced a rebound in viral load to greater than 50% of baseline levels on 2 consecutive determinations after a minimum of 4 weeks are defined as treatment failure.

Patients return all medication bottles to the site at each clinic visit so that the number of capsules returned can be counted to assess compliance. Patients who are found to be less than 80% compliant at two consecutive visits may be terminated from study.

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. 22 of the 42 enrolled patients were not included in this analysis:

• 2 patients due to adverse events
• 7 patients due to non cooperation or non compliance with study medication
• 4 patients due to refusal of treatment
• 5 patients lost to follow u.
• 2 patients had treatment interruption at week 24
• 1 patient with less than 4 weeks on study
• 1 patient withdrew due to insufficient therapeutic response

Moderate to severe in >5% of patients at week 32: nausea (6), vomiting (4), diarrhea (4), headaches (5).

Lab Abnormalities (week 32):

This is a preliminary 24 week analysis of participants who were initially randomized to the new soft gel capsule saquinavir (SGC-SQV) because majority initially randomized to Invirase (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-label1200 mg 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.

Concomitant NRTIs- 68% AZT/3TC; d4T/3TC 13% in SGC arm, 21% in HGC arm; d4T/ddI 13% in SGC, 7% in HGC; about 5% other.

Safety

Investigators reported that most adverse events were related to gastrointestinal (GI) tract, were relatively mild in severity, and slightly more common with SGC SQV. Through 16 weeks, a total of 10 patients (1 patient on HGC and 9 on SGC) 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. Two more HGC group patients withdrew by week 24 after conversion to SGC. Of 21 reported serious AEs only two were considered possibly or probably related to SQV (thrombocytopenia and erthema multifome both experienced by HGC patients). There were no major difference reported between two groups regarding lab abnormalities.

Lab Abnormalities

-------Percent of Patients--------

Clinical Adverse Events

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. 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 SQV (n=14) and IDV (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 Fortovase group was about 70 cells. But the number of evaluable patients at this point is too small to draw conclusions from this difference.

There were 4 reported discontinuations in the Fortovase group: death (1), lost to follow-up (2), noncompliance (1); 7 reported discontinuations in the IDV group: adverse event- AZT intolerance (1), death (2), received wrong med (1), grade 4 anemia (1), grade 2 kidney failure (1), withdrew consent (1).

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Agouron reported a 21 month update on data from study #511 comparing nelfinavir (NFV) 750 mg 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 approximately evenly divided between the 3 treatment groups. At 6 months, individuals receiving AZT/3TC alone were permitted to add NFV. 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 3 treatment groups.

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.

(*) 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.

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 NFV 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/IDV 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 their viral load rebound (bDNA) at months 7, 15, and 17 based on 2 consecutive viral load tests above the level of detection. 8/12 patients remain on original NFV 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. But 4 months later 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 NFV 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.

Group 1 is the 4 individuals who remained suppressed <25 copies/ml. Group 2 are the 4 individuals with intermittent detectable virus between 25 and 200 copies/ml. Group 3 are the "treatment failures". Each trough listed below is for a different study subject.

Investigators reported that the mean number of naive t-cells in 10 evaluable patients increased from 63 at baseline to 120 at 18 months. Immune reconstitution did not appear to be associated with viral load response.

The 3TC M184V mutation was observed in all 3 treatment failures; 2/3 treatment failures had the NFV mutation D30N; and, 1/3 had the L90M, which has been observed associated with NFV and other protease inhibitors.

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141W94 (Amprenavir) is taken with or without food. It is expected that a liquid dosing formulation will be available for adults after FDA approval as well as a capsule formulation. Simultaneous FDA review for both pediatric and adult approval is expected by the end the third quarter of ‘98. Preliminary data from several studies of protease inhibitor naive individuals are reviewed below. A number of pivotol and other studies are ongoing, the results of which will be used by the FDA for review. 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 1200 mg bid dose regimen. The estimated oral bioavailability is 70%. The half-life has been reported ranging from 7 to 9.5 hours.

Additional studies will soon begin exploring 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 immediately begin a 141 containing salvage regimen. 141 will be accessible through these salvage studies taking place at ACTG sites. If you are near an ACTU site, by calling the study coordinator you can receive information about these studies. Alternatively, an expanded access program is expected in the near future.

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, however, 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.

Murphy said--it was felt that 141 had some unique features that would allow it to be administered by itself and achieve significant responses. The pharmacokinetics (PK) of the drug are quite favorable. Its dosed just twice daily, there is no food effect, its a small protease inhibitor (the smallest) and binds tightly into the pocket of the protease enzyme, and the half-life is 7.1 to 9.5 hours. Data from a year ago in a 28 day monotherapy study was good.

92 study participants were randomized to 141w94 1200 mg bid+AZT 300 mg bid and 3TC 150 mg bid 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 had to have >50 CD4, >5000 plasma viral load, be 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 exp.

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 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 Data

By week 4 the median viral load reduction was to <500 copies/ml; by an on treatment analysis, 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 about 60 at week 24.

Safety.

Investigators characterized 141 as well tolerated.

Table 11. Significant Signs and Symptoms (grade 1+2/3+4). Murphy said only 3 patients discontinued due to drug related side effects: rash (1), nausea (2).

X= not recorded

Murphy said no one came off study due to lab abnormalities. There were 2 cases of grade 3 glucose elevations.

NF= non-fasting
x= not reported at grade 2

36 patients from the monotherapy arm decided to enroll in a salvage rollover protocol (ACTG 373) consisting of indinavir (800mg q8h)+nevirapine+3TC+d4T, against advise 4 decided to add 3TC and AZT to the 141 they were already taking. Two monotherapy patients who were undetectable prior to adding AZT/3TC remained undetectable, but two who were detectable remained detectable. Murphy reported that the group receiving the 4-drug salvage regimen went to <500 copies/ml within a short period of time.

NATAP 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.

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 below from ACTG 347.

It’s been reported from an in vitro study that saquinavir passage resensitized 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 thru 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 which may not do much to 141. (See Fourth Resistance Workshop, Sardinia, July 6-9 1995). In another in vitro experiment, 141 was 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 (see Partaledis et al, Jnl of Virology, Sept 1995, p 5228-5235).

It was reported that in vitro combination studies with 141W94 and indinavir or saquinavir resulted in a delay of resistance mutations emerging compared to using the individual inhibitors. Dual resistant mutants emerged more rapidly when 141 was combined with ritonavir (16E, 32I, 45I, 46I, 82I, 84V) or nelfinavir (32I, 46I, 54M, 71V). Based on these in vitro studies, 141 with indinavir was the most effective combination in delaying resistance. With indinavir and ritonavir additional mutations were added into the triple 141 mutant (46, 47, 50) leading to dual resistance. The 46, 47, 50 triple 141 mutant was found to be unstable when passaged with saquinavir, as resistance to saquinavir resensitized the virus to 141 (See the Fifth Resistance Workshop, Whistler July 3-6 1996).

In vitro (lab strains of HIV used), 141 was active against a NFV mutant with the NFV D30N mutation, and that in vitro NFV was 2-3 fold resistant to a 141 triple mutant. RTV 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. Since using indinavir and 141 together in vitro delayed the development of resistance mutations this combination might be additive. This could be a reason why the preliminary data from the recently reported 141 double protease combination studies showed a 3.75 log reduction for 141+IDV combination.

As I’ve been saying in NATAP Reports and on our web site, there may be a way to limit or prevent cross-resistance. Generally, the greater the number of mutations, the greater the level of resistance. In vitro a 46I, 50V 141 double mutant was sensitive to indinavir. (See Tisdale et al, Antimicrobial Agents and Chemotherapy, Aug ‘95, 1704-1710). Resistance to ritonavir, indinavir, saquinavir or 141 does not develop until multiple mutations emerge. With these drugs, mutations emerge sequentially: one or two at a time until 4 mutations or more accumulate and full resistance is results. It’s possible that viral load rebound may come before mutations emerge. If you can detect viral load rebound immediately by measuring viral load monthly, you may be able to prevent cross-resistance by switching protease therapy immediately.

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

• They found viral rebound during 141 therapy was associated with mutations in protease and gag cleavage sites. 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. Although gag cleavage site mutations have been rarely associated with IDV, this development may be uniquely associated with 141. 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.

Investigators reported one monotherapy and one combination therapy patient had only wild type virus detected after viral load rebound.

One of the major questions surrounding 141 is --Can virus resistant to other PIs be susceptible to 141?, that is-- Can 141 be successfully used as salvage therapy for those who’ve failed one or multiple PIs?? To be effective it will likely have to be part of a potent regimen.

The answer to that question is uncertain. Several studies to address this question are planned to begin soon. Additional treatments that might be effective in combining with 141 include hydroxyurea, adefovir, 1592, and a NNRTI. Before combining 141 with a NNRTI you must be familiar with potential interactions. The preliminary interaction with efavirenz is reported in the NNRTI section of this web site. Phenotypic testing before starting 1592 may be useful in to identifying 1592 sensitivity; and a double protease could also be considered consisting 141+NFV, 141/SQV, 141/RTV, or RTV/SQV. The interaction between 141 and DLV, NFV, SQV or RTV have not yet been identified. RTV or DLV could significantly raise 141 blood levels, but proper dosing must be identified before using such a combination to avoid under or over dosing. Preliminary interaction data reported at Retrovirus Conference showed EFV reduces 141 blood levels by 35-43%, but Glaxo says this may not be clinically relevant. Preliminary antiviral activity data for these double PI combinations are available in the Double PI Report on this web site (LINKUP). As well, hopefully the future holds a positive development for PMPA which should not be cross resistant to PIs. Phase II PMPA studies are about to get started. PMPA Report being prepared for web site (LINKUP).

In summary, the resistance information on 141 is preliminary. 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.

Part 8C. 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 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); the changes in plasma viral load; the dynamics of HIV in gut-associated lymphoid tissue; to monitor the decay of HIV in cerebrospinal fluid (CSF) in subjects with detectable HIV in CSF at baseline. Secondarily, 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, had active opportunistic infections, they had to be protease and 3TC naive, and have a viral load >5,000 copies/ml. The regimen they received was 1592 300 mg bid, 141 1200 mg bid, and AZT/3TC (combivir) 300mg/150mg bid.

Changes in Plasma Viral Load

The Chiron bDNA test was used measuring to <100 copies/ml; the Roche Ultrasensitive RT-PCR test was used to confirm values <500 copies/ml by bDNA.

Table 14. 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..

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 reduction in CSF mean 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.

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 peripheral blood. 8 chronically infected study participants received serial rectal biopsies to measure the antiviral effect of the therapy in the GI (gastro-intestinal) tract lymph tissue. As you may know 98-99% of virus is in the lymph tissue while 1-2% is in the blood. So, the effect of therapy in the lymph tissue is important. The biopsies were done at baseline (day 0, 8/8), and 3-6 weeks (7/8), and 6-10 weeks (7/8) after therapy started. The investigators used semiquantitative PCR from duplicate rectal biopsies and cell co-culture for the presence of infectious virus.

At baseline, the mean US/MS copy numbers were 207,288 (range 277 to 1.446 million) and 3,790 (range <50 to 19,379) copies/ug to tRNA, respectively. The high US/MS ratio (55:1) suggests that most of the detected virus (US) is FDC associated trapped virus. The MS form (multiply spliced) is found in cells with actively replicating virus. The US form of virus (unspliced) can be found in those cells and also in the form of virions that may be trapped in the lymph tissue of the GI tract. The lower number of MS mRNA copies indicates less productively infected cells in the lymph tissue.

Within 3-6 weeks, US mRNA declined an average 1.5 log from baseline (n=7), and within another 4 weeks 3/7 became undetectable while the 4/7 who still had detectable US mRNA dropped an additional average 0.4 log.

In 5 persons in whom MS 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 the baseline in 3/8 persons; after 3-6 weeks of therapy, none was positive (<0.1 TCID 50/104 mononuclear cells). Again, investigators reported that these results indicate rapid decay of productively infected cells and virions trapped in gut associated lymph tissue, similar to the decay in peripheral blood.

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 (CD4+CD62L+RA+) 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. There appears to be general agreement that increases in naive cells are a good thing. But, at this time, the significance of increased naive cells due to HAART is uncertain. Individual response 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.

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.

 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.

A review of 3 month interim data for 13 individuals (% NI, 8 CI) indicate that subjects reported missing 141W94 as often as they reported missing NRTIs. Most subjects reported missing 2 or fewer doses of NRTIs (10/13 subjects) or 141W94 (11/13 subjects) over a 4 week period.

The investigators concluded-

• in the limited number of subjects examined, CSF viral load appears to decline with similar kinetics to those observed in plasma
• initiation in combination therapy resulted in steady improvement of total CD4 cell counts in newly infected and chronically infected subjects. Naive CD4 cell recovery was modest by week 28 in this population

 

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 (2 to 4 weeks) as 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 drop in the chart in the poster appeared to be 3 log from baseline at week 2.

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. The number in the columns are copies/ml. For example, at baseline patient #1 had a viral load of 39,260 copies/ml, and at week 24 their viral load was 12 copies/ml. For patient #5, the viral load was negative at week 24, meaning they could not detect virus. That does NOT mean the person does not have virus . The results of these tests are variable. You can detect 50 copies one day and 5 copies the next day.

* When OD (optical density) values are below the limit of detection but greater than the negative control OD value plus 3SD, a <5 is given. When OD values are comparable to the negative control OD value, negative is given. It is not necessary to understand this explanation to interpret the table. A neg (negative) value is the lowest viral load. It means they could not detect any virus. It should be better than a <5 value. And, <5 should be better than higher values. Of course, values are not absolute because test variabilities can be a factor.

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-exacebration of rash and constitutional symptoms after one dose of either 1592 or 141, compatible with a hypersenstivity 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%). If a person has the hypersensitivity reaction to 1592 they are to stop taking the drug, and they cannot take it again. Symptoms resolve rapidly with drug discontinuation. Restarting 1592 after experiencing the hypersenstivity reaction can result in serious effects. As a result of restarting therapy after experiencing hypersensitivity, some individuals have been hospitalized and there is one reported death. It is very important to clearly understand this reaction and to be able to recognize it. It is not dose dependent and is characterized by - a fever first accompanied by one or more of the following- nausea (and/or vomiting), malaise (fatigue or tiredness), rash. Additional effects that can be experienced are swollen lymph glands, diarrhea, and muscle aches. If you think you may be experiencing this reaction please consult with your doctor immediately.

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Joel Gallant and others reported preliminary data from this study of individuals who failed either nelfinavir or indinavir regimens. I think this study is very important. This 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 in the first section of this PI Report.

As you may know, 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.

There are two studies that may offer possible exceptions to failure with salvage although additional follow-up is required to confirm the encouraging results. Both studies are discussed in this report: the Keith Henry study where 68% (13/19) had <500 copies/ml at week 24 of treatment after failing nelfinavir; and, the ACTG 347 regimen of nevirapine/indinavir+2 NRTIs individuals received in that study after failing 141W94 monotherapy. After several months (12 weeks) about 87% remained undetectable when last reported. Study participants who failed 141W94 were quickly detected and switched to the salvage regimen. Study investigators feel that may be a reason for the success to date with the salvage regimen. But, continued follow-up is ongoing and necessary to evaluate the durability of the response in both studies.

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 in the poster 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.

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 individuals in 506 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 NFV treatment of 55 weeks (23-82) before enrolling in this salvage trial. The mean time spent on NFV with detectable viral load is 48 weeks. Obviously, individuals remained on NFV despite failure for a prolonged period. The investigators reported that baseline viral load for the non-responders was 80,692 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.

Table 16. Table Summarizing Protease Changes 

Two patients quit the study during the first two weeks due GI intolerance. 24 continue in the study and 19 reached 6 months at the time of this report. Previously reported was 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 that at weeks 32 and 40, 5/8 (62.5%) and 2/3 (66%) had <500 copies/ml., respectively. They reported that 9/13 did not have a baseline L90M mutation, while 3/5 had the L90M at baseline. 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.

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