Contents
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DMP-266 (efavirenz) may act as P450 Inducer: Significant efavirenz - saquinavir interaction
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DOUBLE PROTEASE INHIBITOR COMBINATIONS
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Ritonavir/saquinavir
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Nelfinavir/saquinavir
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Ritonavir/nelfinavir
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Ritonavir/indinavir
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Indinavir/nelfinavir
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Indinavir/saquinavir
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Amprenavir + other PI's
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ABT-378/ritonavir
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The Great Salvage Therapy Drug Juggle
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TREATMENT ALERT
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DMP-266 (efavirenz) may act as P450 Inducer: Significant efavirenz - saquinavir interaction
DuPont Merck, the developers of the NNRTI efavirenz, has issued a warning on pharmacokinetic
interactions with saquinavir. Efavirenz is not yet licensed for use as an antiretroviral
agent, but is available across Europe in various compassionate use programmes. The text of the alerting letter to investigators is set out below for your information.
May 12, 1998
Dear efavirenz Clinical Investigator,
This letter contains important drug-drug interaction information for physicians prescribing
the investigational agent efavirenz (SustivaTM, DMP-266)
and may require you to change antiretroviral regimens for certain patients taking efavirenz and saquinavir together
. DuPont Merck recently completed sample analyses from an interaction study which evaluated the concomitant use of efavirenz and the soft gel (SGC) formulation of saquinavir (FortovaseTM). Preliminary findings of this multiple dose healthy volunteer study indicate that the concomitant administration of efavirenz 600mg daily and SGC saquinavir 1200mg q8h results in a decline in plasma efavirenz concentrations of about 10%, an amount not believed to be clinically significant. Plasma saquinavir concentrations declined by about 60% which is anticipated to be clinically significant.Currently eight percent of patients in the efavirenz expanded access programme are receiving SGC saquinavir as the only protease inhibitor in combination regimens. Until further information is available, DuPont Merck strongly recommends that clinicians not use SGC saquinavir as the only protease inhibitor in combination regimens unless no other regimen is possible. All other saquinavir-containing double protease regimens are strongly discouraged with the possible exception of ritonavir/saquinavir (see below).
Ritonavir (NorvirTM) is well documented to increase saquinavir levels and AUC. The combination of ritonavir and saquinavir is clinically a common double protease inhibitor regimen in antiretroviral experienced patients. This combination is part of the regimen being prescribed for 21% of patients in the efavirenz Expanded Access programme. Assuming appropriate plasma levels of each of the three drugs can be achieved, efavirenz/ritonavir/saquinavir may be a reasonable salvage option for those without other therapeutic options. No data are yet available to guide clinicians on appropriate dosing of the combination of efavirenz/ritonavir/saquinavir. Although getting underway, no completed clinical trials have yet evaluated pharmacokinetics, safety or efficacy for this combination.
The outcome on saquinavir levels of a triple drug-interaction study including an inhibitor and an inducer of cytochrome p450 is particularly difficult to predict.
Therefore when selecting a dose of saquinavir to be used with ritonavir and efavirenz clinicians must balance the risk of potential under-dosing of saquinavir against possible increased side effects from higher doses of saquinavir.
The most common doses used clinically with the ritonavir/SGC saquinavir dual protease inhibitor combination appear to be ritonavir 400mg b.i.d. and SGC saquinavir 400mg b.i.d. The combination of ritonavir 400mg b.i.d. with SGC saquinavir 800mg b.i.d. has recently been tested in a very limited number of normal volunteers without a noticeable increase in side effects*.The use of efavirenz with ritonavir and SGC saquinavir is not recommended pending data on the drug-drug interactions. There are no data to support any dosing recommendation or even the use of these drugs together. If another regimen is not available, clinicians should strongly consider the potential that may exist for underdosing of SGC saquinavir when given 400mg b.i.d. in combination with ritonavir and efavirenz. DuPont Merck will generate interaction data on the triple combination of efavirenz/ritonavir/saquinavir and will make this available as soon as possible.
As required by local and country-specific regulations, please share this new information about efavirenz with your IRB / ERC. Should you have any further questions about these findings, please call the Program Monitor.
Sincerely,
Nancy Ruiz, M.D.
Clinical Development, Virology, DuPont Merck.
* Personal communication with Roche Laboratories Inc. Data on file at Roche.
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ANTIRETROVIRALS
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DOUBLE PROTEASE INHIBITOR COMBINATIONS
There is growing evidence to support the use of dual protease inhibitor regimens for
the treatment of HIV disease. These regimens are most effective when taken in combination
with reverse transcriptase inhibitors by patients who are treatment naive, or at
least naive to protease inhibitors. Of the dual-PI regimens, RTV/SQV is the best studied
combination, with excellent potency and durability, and it is the only one to be
listed as a preferred regimen in the DHHS guidelines. Although far from perfect,
RTV/SQV (with new RT inhibitors) may still be the best "salvage regimen" for people failing
regimens with single protease inhibitors. Initiating salvage therapy early, while
the viral load is low, may increase the chances of a successful response. The only
other dual-PI regimen with established clinical efficacy in PI-naive patients is NFV/SQV.
There is less support for use of NFV/SQV following failure of other PIs. All other
dual-PI regimens are under study, and should be used with caution, if at all, until
further data are available on safety, pharmacokinetics, and efficacy. Dual-PI regimens
may be capable of profound and extremely durable suppression of viral replication.
RTV/SQV may, in fact, be the most potent antiretroviral regimen currently available.
However, dual-PI regimens should be used with caution in patients who may have trouble
adhering to antiretroviral therapy. Resistance to dual-PI combinations is likely
to lead to extensive cross-resistance within the PI class. The choice to initiate
therapy with two protease inhibitors may involve a decision to sacrifice "salvageability" for
the sake of potency and durability. Patients who make this choice must do everything
they can to make the regimen last.
Ritonavir/saquinavir (RTV/SQV)
This is the most extensively studied and most widely used dual protease inhibitor
combination. Sixty-week data are now available from a trial involving over 100 patients,
and in that trial 89% of patients continue to have undetectable viral loads (<200
copies/ml). Because the lower dose regimen (400/400 mg bid) was better tolerated and
equally efficacious, all participants were allowed to switch to that regimen at 48
weeks. The results of this trial led the DHHS guidelines committee to add RTV/SQV
to the list of preferred protease inhibitors for initial therapy. The reduced dose of ritonavir
is better tolerated than full-dose ritonavir (600 mg bid). This regimen is also more
convenient than other saquinavir-containing regimens, which now require that the
patient take six capsules of saquinavir three times daily. RTV/SQV is also the most
widely used "salvage" regimen for patients failing therapy with other protease inhibitors.
Several small retrospective studies looking at indinavir (IDV) failure suggest that RTV/SQV is rarely effective once IDV resistance has developed, a finding consistent
with what is known about resistance patterns associated with IDV therapy. However,
there are some data suggesting that RTV/SQV may be effective in patients who switch
from IDV to RTV/SQV early. Switching when the viral load is low may minimise the number
of mutations that lead to cross-resistance. The experience with RTV/SQV after nelfinavir
(NFV) failure has been somewhat more positive. In one study prolonged suppression of viral load was reported in up to two-thirds of patients failing NFV and switching
to RTV-SQV containing regimens. These findings are consistent with what is known
about genotypic patterns of NFV resistance, which is typically heralded by the development of the D30N mutation, a mutation which by itself does not lead to decreased susceptibility
to other protease inhibitors. RTV/SQV also appears to be effective in a number of
patients who fail therapy with SQV alone. In one study, switching from SQV to RTV/SQV was more effective than switching to either IDV or RTV alone. In another study,
both RTV/SQV and IDV were effective following SQV failure. However, both studies
involved failure of the hard-gel formulation of SQV (Invirase), for which drug failure
may sometimes be due to low drug levels rather than resistance. These findings may not
apply as well to failure of the soft-gel formulation (Fortovase). When the soft-gel
capsule formulation of SQV (Fortovase) is used in combination with RTV, the same
dose (400 mg bid) leads to equivalent plasma concentrations as seen with the hard-gel formulation
(Invirase) and costs significantly less.
Nelfinavir/saquinavir (NFV/SQV)
NFV increases the AUC of SQV by 5-fold, while SQV has no effect on NFV levels. In
the European SPICE trial, more patients randomised to receive SQV (soft-gel formulation)
800 mg tid plus NFV 750 mg tid plus two nucleoside analogues had undetectable viral
loads than those receiving the NFV/SQV alone or either of the two protease inhibitors
plus two nucleosides. For salvage therapy, there is less experience with this combination
than with RTV/SQV. Because NFV has a more modest effect on SQV metabolism than RTV, the reduction in pill burden is minimal: the regimen used in the SPICE trial requires
patients to take seven capsules three times daily, not including nucleoside analogues.
Ritonavir/nelfinavir (RTV/NFV)
In a single-dose pharmacokinetic trial, RTV increased the AUC of NFV by 2.5-fold.
RTV may also accentuate the M8 metabolite of NFV, possibly resulting in increased
antiviral activity. Data from a pilot trial involving RTV (400 mg bid) plus either
500 mg or 750 mg bid of NFV suggest that this combination has potent activity, but like NFV/SQV,
may require supplemental reverse transcriptase inhibitors for optimal activity. Pharmacokinetic
studies are in progress.
Ritonavir/indinavir (RTV/IDV)
A multidose pharmacokinetic study of this combination demonstrated that IDV clearance
is reduced by RTV, which leads to less variability in pharmacokinetics and increased
trough levels. At the 400/400 mg bid dose, the AUC of IDV approximates that of the
standard dose of IDV (800 mg q8h), thus making IDV a bid medication. RTV may also reduce
the effect of food on IDV. Efficacy data are not available for this combination.
Indinavir/nelfinavir (IDV/NFV)
In a single dose study, NFV increased the AUC of IDV by 50%, and IDV increased the
AUC of NFV by 80%. Clinical trials of IDV/NFV are in progress, but the right dose
combination hasn't been worked out yet. Doses of 1000 mg and 750 mg bid of IDV and
NFV, respectively, led to adequate trough levels of IDV but inadequate trough levels of NFV.
The same was true when the dose of NFV was increased to 1000 mg bid. Efficacy was
disappointing, perhaps because of inadequate drug levels. Until appropriate dosing
can be worked out, this combination should probably be avoided in clinical practice.
Indinavir/Saquinavir (IDV/SQV)
Despite a potentially favourable pharmacokinetic interaction, this combination has
not been studied because of the demonstration of in vitro antagonism. It is not clear
whether this antagonism is clinically relevant, but until this has been determined,
the combination probably should not be used.
Amprenavir in Dual-PI Combinations
Amprenavir, the new Glaxo-Wellcome PI formerly known as 141W94, has been combined
with SQV, IDV, and NFV in a small pilot study. All combinations were well-tolerated
and associated with significant viral suppression.
ABT-378/ritonavir
The new protease inhibitor from Abbott Laboratories, ABT-378, has in vitro potency
ten times greater than that of RTV, and like RTV, is metabolised by the CYP3A pathway.
In a placebo-controlled, multiple-dose study of ABT-378 plus RTV, high drug levels
of ABT-378 were achieved when 200 to 600 mg bid were combined with 50 or 100 mg of RTV.
Similar levels were also achievable with once daily dosing.
Source: The Hopkins HIV Report (May 1998
Author:
Joel E. Gallant, M.D., M.P.H.
Dual PI's in first line combo's look more potent, they can be easier to take (bd)
thereby encouraging compliance, and their pharmacokinetic and antiretroviral profile
suggests improved durability of response may be obtained. With wide cross resistance
amongst current PI's becoming apparent might it be better to maximise your chance of success
with a PI by combining it with another to ensure good blood-levels, more rapid viral
suppression? Some clinicians cry of jeopardising sequencing, but have we yet had
this seductive concept demonstrated to work with PI's? |
The Great Salvage Therapy Drug Juggle
Estimates of the number of people on protease inhibitors who fail to achieve stable
viral loads below quantifiable limits (less than 400 copies/ml by PCR) range as high
as 70% in pre-treated populations. Those who do not reach this plateau face the daunting prospect of either continuing on a regimen that allows viral breakthrough or putting
together some backup or "salvage" therapy. The chances of successfully switching
therapies are dimmed by the realities of HIV's capability of developing simultaneous
cross-resistance to groups of drugs as well as each individual drug's side effects, which
make them intolerable for many people.
When to Switch
Deciding when to switch therapy is a largely unsettled issue. The Public Health Service Guidelines for the Use of Antiretroviral Agents (U.S.) devotes several sections to this topic. The PHS document recommends switching if less than a 0.5 to 0.75 log (68% to 82%) reduction in viral load occurs four weeks after initiating therapy - or less than a 1 log (90%) reduction by eight weeks. The eventual goal is to achieve levels below the limit of quantification (BLQ) of the standard PCR assay (400 copies/ml) within four to six months. If viral loads do not go that low or eventually rebound above that level, the Guidelines again advise altering therapy. (The Guidelines recognise that people with very high initial viral loads may never go below 400 copies/ml. Also, some people who rebound may stabilise, at least for a time, at modest viral loads of a few thousand. For such individuals, continued monitoring may be acceptable until their HIV rebounds to a level greater than three times the lowest stable viral load measurement.)
The Guidelines do not endorse the clinical use of the unapproved ultrasensitive PCR viral load assay, with its lower limit of detection of 20 to 40 copies/ml. Yet some studies (e.g., the INCAS trial of AZT/ddI/nevirapine and Merck 035, which tested AZT/3TC/indinavir) report that a viral load below 40 copies is strongly associated with long-term antiviral effect.
Driving viral loads below 400 copies/ml is frequently problematic. Many people whose viral loads have been reduced to below 400 copies really have no way to modify or intensify their antiviral regimes to restrict HIV still further because of the absence of effective treatment options.
At the International Workshop on Salvage Therapy for HIV Infection held in New Orleans on April 17-18, many of the researchers and physicians felt that switching early from a partially suppressive regimen (one that allows a low but detectable viral load) to a maximally suppressive regimen is likely to provide a better long-term outcome. The longer an individual stays on a treatment that allows some viral replication, the more likely that additional resistance mutations will accumulate. The correlation between baseline mutations and treatment response is not yet fully understood, but it does appear that the more resistance mutations present, the more likely subsequent drugs will fail.
Some workshop participants felt that an early switch strategy did not always pay off in their experience. Speaking after the workshop, Judith Falloon, M.D., of the National Institute of Allergy and Infectious Diseases (NIAID), stated that about a year ago she was very aggressive in changing treatments immediately but results were mixed. She said, "I switched a lot of people for a relatively limited benefit set." Although a viral load of 1,000 copies/ml used to be enough to trigger a change in regimen, she now waits to see if there is a definite upward trend in viral load or downward trend in CD4 count. A stable viral load in the 1,000 to 5,000 range may not warrant a change, especially if the patient does not have three new drugs available.
In addition, there have been cases of continued benefit even after viral breakthrough. At the 5th Conference on Retroviruses and Opportunistic Infections last winter, Steven Deeks, M.D., reported on 143 San Francisco General Hospital patients with CD4 count rises of 50 to 100 cells and viral loads below baseline a median of 18 months after initiation of therapy and a median of 12 months after clear evidence of virologic failure (see abstract 419 and ATP's Doctor Fax 40 & 43).
Since this improvement probably will prove transitory in the end, Dr. Deeks stated that continuing on therapy after viral breakthrough should really only apply to people who do not have the option of switching to a maximally suppressive regimen. "If there is a salvage regimen that might achieve durable suppression, then it makes sense to switch early. If in all likelihood, you're only going to get transient viral suppression, then it may not be a good idea to switch because that would limit the ability to get durable suppression down the line, by burning up drugs now. This argument, in my mind, pertains mainly to the use of NNRTIs [non-nucleoside reverse transcriptase inhibitors, such as nevirapine] in salvage regimens. If someone has not been on an NNRTI, then they still have a chance of getting a very potent response to drugs in that class. However, this response will only be durable if the NNRTI is used in combination with other drugs that are effective. Often those drugs are not yet available." A similar cross-resistance issue may apply to protease inhibitors.
Data regarding the efficacy of salvage protocols are beginning to emerge from small clinical trials. Several such studies presented at recent conferences reported mixed results. Most salvage regimens seem to provide initial high-level viral suppression, but the antiviral effect does not last long in a large percentage of cases. Some studies have attempted to determine predictors of response, so that strategies with the best chance of success can be developed.
Backup for Nelfinavir Failure
Finding a backup therapy for nelfinavir failure has been touted by nelfinavir's manufacturer (Agouron Pharmaceuticals) as comparatively easy. The key HIV mutation conferring nelfinavir resistance (at codon 30 on the protease gene) does not confer cross-resistance to other protease inhibitors. But the appearance of codon 30 is often accompanied or shortly followed by secondary mutations that do reduce response to protease inhibitors as a group.
At the Retrovirus Conference, Pablo Tebas, M.D., from Washington University in St. Louis, Missouri, gave an update on a small cohort of volunteers who had failed nelfinavir treatment in three phase II clinical trials (abstract 510). The participants were switched to a combination of d4T/3TC/ritonavir/saquinavir after two consecutive viral load tests above 5,000 copies/ml by Chiron's bDNA assay. All participants had taken nelfinavir for a median of 55 weeks.
Twenty-four volunteers in the substudy had little or no antiretroviral experience prior to enrolling. Dr. Tebas had 24-week data on 19 of these participants. All 19 achieved viral loads BLQ (less than 500 copies/ml by bDNA) after switching to the salvage protocol. This decrease was sustained at week 24 in 13 of the 19 (68%), five of whom were BLQ by the ultrasensitive assay (40 copies/ml by PCR). At the Salvage Therapy Workshop, Keith Henry, M.D., of Regions Hospital in St. Paul, recounted that the remaining five participants had also reached 24 weeks. According to the most recent viral load data, 17 out of 24 participants (71%) were still BLQ of the standard assay.
An additional seven participants in the crossover substudy had extensive prior antiretroviral therapy. They also had higher mean viral loads and lower mean CD4 counts than the less experienced group. Only three of the seven (43%) in this more advanced group achieved viral loads BLQ.
The crossover substudy design could not employ an early switch strategy because viral load results of the participants in the original studies were blinded (unknown to the investigators and participants). After unblinding the study results, it was determined that the median time on nelfinavir with detectable viral load was 48 weeks. An earlier change in therapies might have prevented the gradual accumulation of multiple resistance mutations.
The most frequent baseline mutations in the HIV protease gene prior to switching to ritonavir/saquinavir were at codon 30, found in 17 of 25 participants. Five of 25 participants harboured HIV with a mutation at codon 90 that sometimes appears after exposure to nelfinavir and is commonly associated with resistance to saquinavir. However, in this small cohort, the presence or absence of these mutations was not predictive of a short-term virologic response. The most significant predictor of failure was a higher baseline viral load.
The Mysteries of Saquinavir Failure
Second-line therapy in the case of saquinavir failure has always been controversial because the key codon 90 resistance mutation does not by itself cause indinavir to fail. In concert with other mutations, it does contribute to indinavir resistance, though. It also may affect nelfinavir (see above). In addition, most salvage therapy studies have been conducted using the old formulation of saquinavir (Invirase). It is not possible to extrapolate these results to the new formulation of saquinavir, Fortovase, which achieves much higher blood levels of saquinavir. The low saquinavir levels resulting from Invirase may have been insufficient to cause saquinavir-resistant HIV to develop in many patients (although small undetectable subpopulations of resistant virus may have arisen). Last year, ACTG trial 333 found that switching to indinavir or Fortovase after lengthy Invirase use are not feasible salvage therapies (see ATP's Doctor Fax 20).
At the recent Retrovirus Conference, Jody Lawrence, M.D., of Stanford University, and colleagues described the sequential use of nelfinavir and indinavir/nevirapine in 16 participants who had received at least six months of treatment with a saquinavir-containing regimen and had viral loads above 5,000 copies/ml (abstract 422). Median baseline CD4 count was 156 cells and viral load was 16,716 copies/ml. Because all participants had received extensive antiretroviral therapy (an average of four prior agents), only 6 of 16 (38%) received one or two new reverse transcriptase inhibitors when switching to the new protease inhibitor-containing regimens.
Eleven participants experienced only a transient benefit after switching to nelfinavir. At two weeks they had a median viral load drop of 0.59 log (74%), with most participants' viral loads returning to baseline by week 12. The group then switched to indinavir plus nevirapine in combination with two reverse transcriptase inhibitors. This change decreased viral load by a median of 1.58 log (97%) after four weeks. Six of the 11 (55%) taking this third sequential protease inhibitor containing regimen achieved a viral load below 400 copies/ml. However, only 3 (27%) maintained maximum viral suppression beyond week 20.
Dr. Lawrence stated that the total number of mutations at baseline was correlated with decreased durability of treatment response. Specifically, the AZT-associated resistance mutations at codons 67, 70 and 219 along with the saquinavir-associated codon mutation 90 were quite highly associated with rapid failure.
Indinavir Failure Rule: Switch Early
Finding a backup therapy for those experiencing viral load rebound on indinavir is the most difficult problem of all. Indinavir regimens that fail to completely suppress HIV trigger the emergence of a series of mutations conferring broad cross-resistance to other protease inhibitors. Still, there is some hope.
Joel Gallant, M.D., and colleagues from Johns Hopkins in Baltimore, conducted a retrospective analysis of patients taking ritonavir/ saquinavir (plus new reverse transcriptase inhibitors in most cases) soon after re-emergence of detectable HIV on an initially successful regimen (Retrovirus Conference abstract 427). Seventeen study subjects had failed indinavir-containing regimens. Twelve of the 17 (70.5%) achieved viral loads below the limit of quantification (400 copies/ml) at a median of 33 weeks (with some participants out to 50 weeks) after switching to the ritonavir/ saquinavir combination.
Four participants in this study had failed nelfinavir-containing combinations. Three of the four still had viral loads below 400 copies/ml at a median of 33 weeks after starting the salvage regimen.
Dr. Gallant feels that these participants experienced a better antiviral response than those in other studies did because they switched fairly early with a relatively low median viral load of 13,507 copies/ml. They thus avoided the accumulation of resistance mutations in their HIV and the resulting cross-resistance to new protease inhibitors. He stated, "I think that unless you make an early switch, you may be guaranteeing that patients will never get another protease inhibitor that works. In my experience, this is the only way that you maybe get a second round of protease inhibitors." Although the availability of new reverse transcriptase inhibitors for most trial participants may have helped too, Dr. Gallant feels that this was not enough to account for the durable response.
Saquinavir/Nelfinavir Gets Mixed Reviews
Nelfinavir inhibits the liver's breakdown of saquinavir in a manner similar to ritonavir. Administering nelfinavir at the standard dose along with reduced doses of saquinavir yields saquinavir levels equivalent to those achieved with a standard Fortovase regimen. Nelfinavir/saquinavir may be a better salvage therapy for indinavir failure than most current possibilities because of reduced cross-resistance issues.
Stephen Kravcik, M.D., of Ottawa General Hospital in Canada, presented results of a 14-person pilot study at the Salvage Therapy Workshop. Participants had previous protease inhibitor treatment with indinavir, ritonavir and/or saquinavir. Median viral load was 84,500 prior to switching to nelfinavir/saquinavir. None of the participants were able to add two new reverse transcriptase inhibitors. This regimen did not work well as salvage therapy: there were only transient improvements in viral load and CD4 count. The three participants who experienced a good response (two had viral loads below 500 copies/ml and one had a sustained 1 log [90%] decrease in viral load) were all saquinavir-naïve. Dr. Kravcik believes this combination only has a limited role as salvage therapy.
At the 6th European Conference on Clinical Aspects and Treatment of HIV Infection held in Hamburg last fall, a German group presented a poster on nelfinavir/saquinavir salvage therapy with better results (late breaker 925). Jürgen Lohmeyer and colleagues designed a salvage protocol using 1,000 mg of saquinavir (Invirase) and 1,250 mg of nelfinavir twice a day in conjunction with two reverse transcriptase inhibitors. The 25 participants had at baseline a mean CD4 cell count of 118 and a median viral load of 20,000. All had been previously treated with protease inhibitors. Seventeen participants completed eight weeks of treatment and experienced a mean viral load decrease of 1.8 logs (98%) and a mean increase of CD4 cells of 113. Viral load decreased to below 500 copies/ml in 10 of the 17.
Combining Three Hot Drugs is not so Hot
One possible way to improve salvage therapy's chances is to administer potent new drugs that have not yet been approved and will therefore be completely new to patients regardless of treatment history. Dr. Falloon presented data at the Salvage Therapy Workshop on two salvage therapy protocols with one such combination using the three experimental drugs: efavirenz (DuPont Merck's new NNRTI), amprenavir (Glaxo Wellcome's new protease inhibitor) and abacavir (Glaxo Wellcome's new nucleoside analogue).
The first trial was a small NIH pilot study of 11 participants who had failed on indinavir-containing regimens. In the initial part of the study, abacavir (300 mg) and amprenavir (1200 mg) were given twice a day. Efavirenz was added later (600 mg once a day). While using the abacavir/amprenavir combination, three of the 11 participants experienced a 1.5 to 2 log (97% to 99%) drop in viral load from baseline. The response lasted for only six and eight weeks in two of the three but went on for more than 28 weeks in the third. After efavirenz was added, there was a better response, with five of nine participants achieving at least a 1 log (90%) drop from baseline (two of the five had a short duration of response). Efavirenz also activated liver metabolism, decreasing the peak levels of amprenavir by 46% and the trough level by 59% in eight participants. When efavirenz and amprenavir were dosed together, the efavirenz levels were not significantly different than expected.
Despite this effect, the amprenavir dose was not increased for the larger salvage study, known as protocol 2007, because of the already high amprenavir pill burden (eight large pills twice a day). The open-label 2007 trial enrolled 101 participants who had detectable viral load after at least 20 weeks of protease inhibitor treatment. At baseline, median viral load was 122,851 copies/ml and median CD4 count was 160. Participants were categorised as NNRTI-naïve or -experienced. Highly preliminary eight-week data are available for some of the participants. In the NNRTI-naïve group, a 0.5 log (68%) viral load decrease was achieved in 81% at week two and 58% at week eight. In the experienced group, a 0.5 log decrease occurred in 53% at week two and 30% at week eight. Using a more stringent measure of benefit, a 1.5 log (96.8%) decrease or a decrease in viral load to less than 400 copies/ml occurred in 45% of the NNRTI- naïve group at week two and in 42% at week eight. In the NNRTI-experienced group, fewer participants achieved this decrease, 18% at week two and 17% at week eight.
Only 5% of NNRTI-experienced participants versus 24% of NNRTI-naïve participants went below 400 copies/ml at any time in the study's first eight weeks. Many of the NNRTI-experienced volunteers probably had developed NNRTI cross-resistance that affected efavirenz, which appeared to be central to the triple combination's effect. For all the participants, previously developed cross-resistance apparently presented a major challenge to both the abacavir and amprenavir. And whether efavirenz was effective or not in a patient, it lowered amprenavir levels, making this protease inhibitor still more problematic.
This regimen was also complicated by the three drugs' overlapping side effects: 47% of participants suffered skin rash or irritation, 59% had digestive complaints and central nervous system side effects were evident in 67%. Such side effects could cover up a relatively rare systemic syndrome that leads to a potentially life-threatening hypersensitivity to abacavir. However, Dr. Falloon stressed that this syndrome has only occurred upon discontinuing and then reintroducing the drug (see ATP's Doctor Fax 38).
Mega-HAART
There have been several accounts of salvage therapy using six or seven agents. Cassy Workman, M.D., of Australia, presented a report on 12 heavily pre-treated study subjects at the Retrovirus Conference (abstract 426). Participants had failed ritonavir, saquinavir (Invirase) and indinavir as well as all the nucleoside analogues. Mean viral load at baseline was 170,065 copies/ml. Salvage therapy consisted of six drugs: d4T (40 mg twice a day), ddI (400 mg once a day), 3TC (150 mg twice a day), nevirapine (200 mg twice a day), nelfinavir (at an elevated 1,000 mg - 750 mg is standard - thrice daily) and saquinavir (Invirase, at the standard 600 mg three times a day). Nine of the 12 were able to stay on this onerous combination and achieved viral loads BLQ (400 copies/ml) at week 12. CD4 counts increased between 30 and 370 cells.
It is not too surprising that this combination should be effective, at least initially. The nevirapine and the extra-strength nelfinavir were both new, and the nelfinavir boosted the saquinavir (taken as Invirase) blood levels enough so that it was now an effective drug. Some of Dr. Workman's patients also may have still been sensitive to d4T and ddI since HIV resistance to these two is comparatively infrequent. At the Salvage Therapy Workshop, Schlomo Staszewski, M.D., of Goethe University in Frankfurt, proposed a similar strategy that he termed "mega-HAART." He has combined six to eight drugs in 37 failing patients to strategically increase antiviral activity and plasma drug levels. Dr. Staszewski used at least three nucleoside analogues, one or two NNRTIs and two to three protease inhibitors. Thirty-two patients experienced a viral load reduction of over 2 logs (90%), 26 of 37 achieved viral loads BLQ on the standard assay at least once and 11 of 37 went BLQ on the ultrasensitive assay at least once. Dr. Staszewski is now testing maintenance therapies with a reduced number of drugs in patients whose response goes below quantification on the ultrasensitive assay.
"Henry's Best Shot at It"
Meanwhile, in Minnesota, Dr. Henry is conducting an exploratory salvage strategy study in his clinic that combines information from resistance assays, viral load tests, treatment history and analysis of the protease inhibitor levels in the blood. Dr. Henry uses a computer program to devise a flow chart for each individual. He determines the major mutations and the categories of drugs that are most likely to be ineffective. He recycles d4T and ddI, adds hydroxyurea to boost the ddI and prescribes the best-looking protease inhibitor at the best possible dose. If the results are promising Dr. Henry supplements the combination early with efavirenz or another NNRTI. He has used this strategy in about ten patients for only a short period to date, and so far, responses have been good.
He cautions that, "short-term virologic responses in the overall scheme of things is not something to brag about. If patients are suppressed and then rebound, I'm not sure what you've accomplished exactly other than burning more bridges." Dr. Henry stressed that an individual approach taking such factors as clinical status and adherence into consideration is extremely important. He added, "I'm tolerating people with less than total suppression because I think that in a year or two I will be able to offer more potent, sound regimens that will work if I don't burn through everything now. I think I have time to wait in some types of patients and don't have time to wait in others."
Ongoing and Developing Trials
Obviously, there is a great need for larger clinical studies and more hard data. Several such studies are either ongoing or in development. The most advanced is ACTG 359, which is a 24-week safety and efficacy study (with a 24-week extension), in 300 indinavir failures. Salvage regimens for this protocol include Fortovase plus ritonavir or nelfinavir in combination with delavirdine and/or adefovir. A unique feature of this study is that it involves no FDA-approved nucleoside analogues. An interim analysis is underway on preliminary data.
Two other large ACTG salvage protocols are expected to open for enrolment by July of this year. ACTG 398 is a phase II trial of amprenavir with or without another protease inhibitor in combination with abacavir, efavirenz and adefovir in 460 volunteers with protease inhibitor failure. Subjects will be allowed to have prior exposure to up to three protease inhibitors and one-third will be allowed prior use of nevirapine or delavirdine.
ACTG 400 is a phase II open-label salvage therapy trial for 300 nelfinavir failures. Participants must be naïve to at least two nucleoside analogues and all of the NNRTIs. Treatment regimens will include combinations of the other protease inhibitors (including amprenavir) with efavirenz and two new nucleoside analogues.
Two small pilot studies are also in the works through the Intercompany Collaboration for AIDS Drug Development (ICC) looking at salvage regimens with double NNRTI combinations, including Triangle's new compound MKC422 and delavirdine or nevirapine, plus ddI/d4T with or without hydroxyurea. The first few regimens are expected to begin enrolment in early June. The study will enrol 25 persons in each regimen at 7 different sites. The 3 regimens for protease failures are:
adefovir+efavirenz+141W94+1592U89
MKC-442+delavirdine+ddI+d4T
MKC-442+nevirapine+ddI+d4T
MKC-442 is a NNRTI in early development which has shown a -1.30 log reduction in viral load in a 15 day study. This trial is the first to study the combination of two NNRTIs.
Author: Jill Cadman
Source: GMHC Treatment Issues, Vol. 12, No. 4; April, 1998
Treatment Issues is published twelve times yearly by GMHC, Inc. Subscription lists are kept confidential. GMHC Treatment Issues, The Tisch Building, 119 West 24 Street, New York, NY 10011 Fax: 212/367-1528; e-mail: daveg@gmhc.org
Salvage therapy may be the most misused and confused term when talking about antiretroviral
treatment. "Real" salvage might be considered as the heavily pretreated patient (PI's,
NRTI's and NNRTI's) with a falling CD4 <200 and a rising viral load >100,000! Are those that fall outside this hard-line definition also "salvage" cases or just
patients sequentially failing their planned antiretroviral sequencing strategy?
(eg. 2NA ( 2NA + NNRTI ( 2NA + PI ( 2NA (any left!) + 2PI's ( recycled NA's + hydroxyurea
+ recycled PI's + recycled NNRTI's (= SALVAGE + organ failure!). |