Ethics Questioned In AIDS Drug Trials Using Suboptimal Therapy
TREATMENT ALERT
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Pharmacia & Upjohn and Gilead have released the following joint statement on the risk
of opthalmic complications with the use of intravenous cidofovir and suggestions for the management of such adverse events.
Cidofovir, which is produced by Gilead Sciences Inc., has just received marketing authorisation in the European Union where marketing
rights are owned by Pharmacia & Upjohn (see ATPs Doctor Fax Issue 22).
A paper on cidofovir associated uveitis will be published on 1st June in the Archives
of Opthalmology which indicates that ...cidofovir associated iritis occurs in the first days after drug administration
and after few courses.
Iritis or uveitis occurred in 15 (6%) of 247 patients who participated in the multicentre,
controlled, phase II/III clinical trials of VistideÆ (cidofovir injection) (data on file, Gilead Sciences). Additionally, these events
were reported in 16 (4%) of 384 patients who received Vistide through the US Treatment IND Program (Nuessle et al. 1997). Additional
descriptions of uveitis or iritis have been received via spontaneous, post-marketing safety reports. The number of reports
precludes an extensive analysis; however, several comments can be made.
The majority of patients who developed iritis or uveitis while receiving Vistide did
so within the first 3 months of therapy. Association of the occurrence of these events with concomitant medications, such as
rifabutin and protease inhibitors, is currently being analysed An interaction with protease inhibitor therapy, if present, may be
due to reconstitution of the immune system facilitating an inflammatory response to cidofovir. Ophthalmic steroids were prescribed
in the majority of cases of iritis or uveitis; when the effect of therapy was commented upon by the clinician, it appears to
be helpful. Therapy with cidofovir was continued in most patients at the originally prescribed dosage schedule.
Some patients developed reductions in intraocular pressure, or hypotony, in conjunction
with uveitis/iritis. Intraocular pressure should be evaluated in patients with symptoms of uveitis/iritis in order to detect
hypotony. If decreases in intraocular pressure are substantial, an interruption or discontinuance of Vistide therapy should be
considered.
Some drugs used in treating AIDS patients may increase the risk for uveitis. Rifabutin
has been associated with uveitis in AIDS patients (Siegal et al. 1990, Jacobs et al. 1994, Tseng & Walmsley 1995). Certain
drug interactions with rifabutin, for example combinations with macrolide antibiotics, may further increase the risk for developing
uveitis (Griffith et al. 1995). Protease inhibitors may interact with rifabutin leading to increased serum concentrations. Ritonavir
increases the AUC of rifabutin by four-fold and indinavir increases the rifabutin AUC by two-fold (Piscitelli et al. 1996).
The incidence of uveitis in patients treated with ritonavir and rifabutin was reported to be 4.6% vs. 0.6% among patients treated
with ritonavir alone (Sun et al. 1996). Acute iritis felt to be possibly related and at least moderate severity was reported
in < 2% of patients treated with nelfinavir (ViraceptÆ package insert). Gariano & Cooney (1997) described a patient receiving cidofovir
who developed iritis temporally associated with the initiation of indinavir therapy. When evaluating uveitis in patients receiving
Vistide therapy, it is important to consider the potential contribution of other drug combinations as well as infectious aetiologies.
Gilead Sciences is actively investigating other possible risk factors for the development
of uveitis, such as extent of retinal involvement of CMV disease and presence of intercurrent illnesses, such as diabetes
mellitus. Several patients in the clinical trials who developed uveitis also had diabetes.
At present, there is no accurate method to determine which patients are at risk for
developing uveitis during Vistide therapy. However, there are several management strategies that have been either suggested by
study investigators or used by clinicians.
Topical corticosteroid therapy, often with cycloplegics, was commonly utilised by
clinicians reporting post-marketing cases of uveitis/iritis. Some of the investigators who participated in the Vistide clinical
trials recommend the use of topical corticosteroids +/- cycloplegics at the first sign of uveitis/iritis rather than delaying therapy
until the condition worsens. This may include the use of topical ophthalmic prednisolone acetate (1-2 drops bid-qid), and
cycloplegics such as atropine 0.5% or 1% (1-2 drops qd-qid), homatropine 2% or 5% (1-2 drops bid-tid), or scopolamine 0.25% (1-2
drops qd-tid).
Some clinicians have suggested it may be prudent to interrupt Vistide therapy until
improvement of uveitis/iritis is observed. In the majority of cases reported to Gilead, though, cidofovir therapy was continued
while the uveitis/iritis was treated. In a few cases, continuance of the cidofovir was stopped if there was no response to topical
corticosteroids or if the uveitis relapsed or worsened.
Based on the possibility that the uveitis may be caused by high local cidofovir concentrations,
some clinicians have sought to facilitate continued use of Vistide therapeutically by extending the maintenance dosing
interval, e.g. to every 3 weeks. However, clinical efficacy and modification of the risk of uveitis has not been evaluated
when cidofovir is administered in a longer dosing interval.
As noted above, if uveitis is related to high local concentrations of cidofovir, a
reduction in the dose to 3 mg/kg may be a useful management strategy. This approach has not been substantiated, though, by controlled
clinical trials.
An extended regimen of probenecid has been suggested by anecdotal experience for both
the management of uveitis acutely and for prophylaxis. Following the standard 4 gm probenecid dose on the day of Vistide administration,
1 gm bid is given for an additional two days. Experience with this approach is limited to 1 health care provider and
has not been investigated in controlled clinical trials. Therefore we cannot recommend this approach at this time.
Nightly prophylactic use of a mydriatic agent has been suggested. Application may
consist of 1-2 drops qhs of a mydriatic/cycloplegic such as atropine 0.5% or 1% (1-2 qhs), homatropine 2% or 5% (1-2 drops qhs),
or scopolamine 0.25% (1-2 drops qhs) for the duration of Vistide therapy.
Uveitis References:
Gariano RF, Cooney EL. Uveitis following administration of the protease inhibitor
indinavir to a patient with AIDS. Clin. Infect Dis. 1997;24:529.
Girth DE, Brown BA, Girard WM, Wallace RJ. Adverse effect associated with high-dose
rifabutin in macrolide-containing regimens for the treatment of mycobacterium avium complex lung disease. Clin. Infect Dis. 1995;21:594-598.
Jacobs DS, Piliero PJ, Kuperwaser MG, et al. Acute uveitis associated with rifabutin
use in patients with human immunodeficiency virus infection. Am. J. Ophthalmol. 1994;118:716-722.
MycobutinÆ (rifabutin) package insert. Pharmacia Inc., Columbus, OH 1995.
Nuessle SJ, Gathe J, Lieberman RM, et al. The VistideÆ (cidofovir injection) Treatment IND for Relapsing CMV Retinitis. Poster presented
at the 4th Conference on Retroviruses and Opportunistic Infections, Washington DC, January 22-26, 1997. Poster #306.
Piscitelli SC, Flexner C, Minor JR, et al. Drug interactions in patients infected
with human immunodeficiency virus. Clin. Infect Dis. 1996/23:685-693.
Siegal FP, Eilbott D, Burger H, et al. Dose-limiting toxicity of rifabutin in AIDS-related
complex: syndrome of arthralgia/arthritis. AIDS 1990;4:433-441.
Sun E, Heath-Chiozzi M, Cameron DW, et al. Concurrent ritonavir and rifabutin increase
risk of rifabutin-associated adverse event. Abstract No. B171. Presented at the XI International Conference on AIDS. Vancouver,
Canada July 8, 1996.
Tseng AL, Walmsley SL. Rifabutin-associated uveitis. Ann. Pharmacother. 1995;29:1149-1155.
ViraceptÆ (nelfinavir mesylate) package insert. Agouron Pharmaceuticals, La Jolla, CA 1997.
Intravenous cidofovir also carries a risk of serious renal complications - physician
and patient education is therefore critical for the appropriate use of this drug (see DocFax Issue 22).
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ANTIVIRALS
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Results of a study published in The New England Journal of Medicine show that treating
infants with a combination of zidovudine, didanosine and nevirapine has marked and sustained benefits in reducing HIV-1 RNA
levels. The authors report reductions in HIV-1 RNA plasma levels of at least 96% in 7 out of 8 patients after four weeks treatment,
with no clinically significant adverse events.
The study examined 8 infants aged 2-16 months with maternally acquired HIV-1 over
a period of 6 months. Five of the eight patients had been pre-treated with zidovudine. Each patient received the following regimen:
1. Zidovudine 180mg/m2 every 8 hours
2. Didanosine 120mg/m2 every 12 hours
3. Nevirapine 120mg/m2 once daily for 28 days then 200mg/m2 every 12 hours thereafter
Baseline viral loads ranged from approximately 41,000-1.5 million copies/ml. All patients
showed rapid reductions in viral load with reductions of at least 96% in seven of the eight patients within 2-4 weeks of
starting therapy.
The reductions in viral load were also sustained. Plasma HIV-1 RNA levels remained
below baseline throughout the six months of therapy in seven of the eight infants treated. Of those 6 patients who began therapy
at 4 months of age or less, 3 had lasting reductions of at least 96% in the plasma RNA levels over the six months of the trial.
Two infants, who began therapy at 2 months of age, showed repeatedly undetectable levels of HIV-1 RNA. Follow up using
an ultrasensitive test showed that, in one patient, HIV-1 RNA remained undetectable until month 15 of therapy. Therapy was
changed following detection of HIV-1 RNA following influenza vaccination. The second patient has continued with the initial therapy
for 18 months, receiving all childhood vaccinations, and has maintained a viral load below 20 copies/ml.
The data has led the authors to suggest that 'therapy with potent combinations of
antiretroviral drugs should be started as early as possible in infants with maternally acquired infection (probably within the first
two to four weeks), to minimise the likelihood that antiretroviral resistance will emerge and to maximise the opportunity for
long-term control of HIV-1 replication.'
The study (ACTG 180) was conducted by two paediatric Aids Clinical Trial Groups at
centres at the University of Massachussetts Medical School and University of California Medical School, USA.
Studies examining the safety and pharmacokinetics of nevirapine monotherapy in reducing
perinatal transmission are currently underway. Preliminary findings of a recent study which examined the pharmacokinetics
of nevirapine in pregnant women and new born infants showed that a dose of 200mg given to the mother during labour resulted in
a ratio of 82% between cord blood levels of nevirapine and those in the maternal circulation at delivery. Subsequent studies are
also planned to examine the potential for reducing rates of perinatal transmission by administering 200mg to the mother during
labour and 2mg/kg to the infants during the first 48-72 hours of life.
Ref: Luzuriaga K, Bryson Y, et al. Combination treatment with zidovudine, didanosine,
and nevirapine in infants with human immunodeficiency virus type 1 infection. N Engl J Med 1997;336
:1343-1349.
Active and well tolerated treatments for children are urgently needed. The availability
of both nevirapine and nelfinavir for children will substantially improve treatment for children
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Hoffmann-La Roche Inc. have announced that it has submitted a New Drug Application
(NDA) to the Food and Drug Administration in the United States for a new formulation of its HIV protease inhibitor saquinavir mesylate.
At the dose used in clinical trials, the new formulation, a soft gelatin capsule, provides eight to nine times the drug
exposure of the current formulation.
Roche has requested marketing clearance for the soft gelatin capsules in combination
with antiretroviral agents in the treatment of HIV infection when therapy is warranted. This request is based on results of clinical
trials with patients who received the soft gelatin capsule formulation in combination with nucleoside analogues. The soft
gelatin formulation is currently being tested in several clinical studies to evaluate its safety, activity, and pharmacokinetic
profile.
Two key clinical trials with the soft gelatin formulation were submitted with the
new drug application: a dose-ranging study (NV15107), which identified 1200 mg three times daily as the preferred dose, and a safety
study (NV15182) with over 400 patients. The third key filing study (NV15355) is a randomised, parallel arm, open-label trial
designed to compare the activity and safety of the current, hard gelatin formulation of Invirase (saquinavir mesylate, 600 mg
tid) and the new, soft gelatin capsule formulation (saquinavir, 1200 mg tid) with two nucleoside analogues in treatment-naive patients.
Sixteen week activity data from this trial will be available in mid-summer and will be submitted to the FDA during the review
process.
Source: Aegis
AIDS Treatment Project has not received any notification of this new formula of saquinavir
being submitted to the EMEA for licensing in Europe. Will this be another potential treatment arriving by slow train in the UK? It remains to be seen what the place of this formula within clinical practise
will be. ACTG 333 suggests that it will be of little benefit to those already experienced with the previous formula of saquinavir
(see DocFax Issue 20).
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PATHOGENESIS
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Stories in the popular press are once again trumpeting the possibility of eradicating
HIV from the bodies of infected people. For this to be possible, it would be necessary to uproot the virus from all parts (or
"compartments") of the human body, not just from the bloodstream, where it can be measured with the viral load test. Specifically,
new articles published May 7 and 8 in the journals Science and Nature, have launched another flurry of speculation concerning
the ifs and whens of the eradication theory.
The Science article, published by A.T. Haase and his team, presents undoubtedly good
news. They report dramatic drops in the amount of HIV and viral material recovered from the lymph nodes (specifically the tonsils)
of infected adults who had never taken antiretroviral drugs before. After six months of combination therapy with AZT, 3TC
and ritonavir, the team reported that 99.9% of the virus had been cleared from the lymphatic tissue. This study not only demonstrates
that antiretroviral drugs are having a major impact on HIV in parts of the body outside of the blood stream, but suggests
as well that levels of virus have also declined in the follicular dendritic cells (found in the lymph nodes) more quickly then
many researchers had anticipated. Follicular dendritic cells (FDCs) hold HIV and other pathogens on their surface. Because of
this, some researchers fear that FDCs will prove to be a hiding place for the virus during antiretroviral therapy. This study's
findings are hopeful because they reflect the rapid decline of HIV in these pivotal cells.
The second study, published in Nature, is causing a buzz partly because it originates
from the lab of Dr. David Ho, whose ideas about how the virus acts in the body currently dominate the HIV research world. Ho's
paper theorises that another body compartment, namely the white blood cells called macrophages, will become the longest lasting
hiding place of the virus. Based on this assumption, Ho and his colleagues have used a purely mathematical calculation to estimate
that, if antiviral therapy were to stop HIV from replicating completely, it would take 2.3-3.1 years to eliminate the virus
from the body. This is by no means a certainty.
A second paper published in the same issue of Science by T.W. Chun et al. suggests
that HIV may find its most reliable hiding place in a third compartment called "resting CD4 cells". Furthermore, Dr Ho acknowledges
in his paper that HIV may prove to linger in other yet undiscovered areas of the brain or other body compartments. The truth
of the matter will of course not be known for at least another year when people living with HIV may be convinced to stop treatments
which have successfully suppressed their viral load in order to test Dr. Ho's theories. In the meantime, researchers will
continue to play theoretical hide and seek with the virus and the popular press will no doubt continue to speculate about a cure.
Source: CATIE News
Abstracts:
Decay characteristics of HIV-1-infected compartments during combination therapy
Analysis of changes in viral load after initiation of treatment with potent antiretroviral
agents has provided substantial insight into the dynamics of human immunodeficiency virus type 1 (HIV- 1). The concentration
of HIV-1 in plasma drops by ~99% in the first two weeks of treatment owing to the rapid elimination of free virus with a half-life
(t1/2) of less than or equal to 6 hours and loss of productively infected cells with a t1/2 of 1.6 days. Here the authors
show that with combination therapy this initial decrease is followed by a slower second-phase decay of plasma viraemia. Detailed
mathematical analysis shows that the loss of long-lived infected cells (t1/2 of 1--4 weeks) is a major contributor to the second
phase, whereas the activation of latently infected lymphocytes (t1/2 of 0.5--2 weeks) is only a minor source. Based on these
decay characteristics, the authors estimate that 2.3--3.1 years of a completely inhibitory treatment would be required to eliminate
HIV-1 from these compartments. To eradicate HIV-1 completely, even longer treatment may be needed because of the possible
existence of undetected viral compartments or sanctuary sites.
Ref: A S Perelson, P Essunger, Y Cao, M Vesanen, A Hurley, K Saksela, M Markowitz,
D D Ho. (Letter to Nature) Nature 387, 188 (1997)
Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection
The capacity of HIV-1 to establish latent infection of CD4+ T cells may allow viral
persistence despite immune responses and antiretroviral therapy. Measurements of infectious virus, and viral RNA, in plasma and
of infectious virus, viral DNA and viral messenger RNA species in infected cells all suggest that HIV-1 replication continues
throughout the course of infection. Uncertainty remains over what fraction of CD4+ T cells are infected and whether there are latent
reservoirs for the virus. The authors show here that during the asymptomatic phase of infection there is an extremely low total
body load of latently infected resting CD4+ T cells with replication- competent integrated provirus (<107 cells). The most prevalent form of HIV-1 DNA in resting and activated CD4+ T cells
is a full-length, linear, unintegrated form that is not replication competent. The infection progresses even though at any given
time in the lymphoid tissues integrated HIV-1 DNA is present in only a minute fraction of the susceptible populations, including
resting and activated CD4+ T cells and macrophages.
Ref: T-W Chun, L Carruth, D Finzi, X Shen, J A DiGiuseppe, H Taylor, M Hermankova,
K Chadwick, J Margolick, T C Quinn, Y-H Kuo, R Brookmeyer, M A Zeiger, P Barditch-Crovo, R F Siliciano (Letter to Nature) Nature
387, 183 (1997)
Kinetics of Response in Lymphoid Tissues to Antiretroviral Therapy of HIV-1 Infection
In lymphoid tissue, where human immunodeficiency virus-type 1 (HIV-1) is produced
and stored, three-drug treatment with viral protease and reverse transcriptase inhibitors markedly reduced viral burden. This was
shown by in situ hybridisation and computerised quantitative analysis of serial tonsil biopsies from previously untreated adults.
The frequency of productive mononuclear cells (MNCs) initially diminished with a half-life of about 1 day. Surprisingly, the
amount of HIV-1 RNA in virus trapped on follicular dendritic cells (FDCs) decreased almost as quickly. After 24 weeks, MNCs with
very few copies of HIV-1 RNA per cell were still detectable, as was proviral DNA; however, the amount of FDC-associated virus
decreased by 3.4 log units. Thus, 6 months of potent therapy controlled active replication and cleared >99.9 percent of virus from
the secondary lymphoid tissue reservoir.
Ref: Winston Cavert, Daan W. Notermans, Katherine Staskus, Stephen W. Wietgrefe, Mary
Zupancic, Kristin Gebhard, Keith Henry, Zhi-Qiang Zhang, Roger Mills, Hugh McDade, Jaap Goudsmit, Sven A. Danner, Ashley T.
Haase Science 9 May 1997; 276 (5314):960 (in Reports)
This is the first publication on the eradication theory which has been much touted
around AIDS conferences over the past year and a half. Questions remain as to the accuracy of the estimated T 1/2 of longlived
(mostly monocyte-macrophage) cells - if much longer than the 4 weeks estimated then eradication becomes unlikely within a persons
lifetime. Similarly the model uses a bi-phasic decay. If there is a third phase (such as from CNS cells) then the estimates may
again be extended beyond a life-span. Ho et al. estimate eradication in 2.3 - 3.1 years: many recipients of triple therapy in
phase II studies are now approaching this time range. Confidence in these calculations amongst many clinicians and theoreticians
are low. Additionally, would one spike in viral load - say from an intercurrent infection or vaccination set the clock back
to zero and mean another 3 years?
Regarding the paper by Cavert et al. as 99% of daily viral production is from lymphoid
tissue it is not surprising that changes in plasma viral load reflect changes in tissues such as the tonsils. The important
issue here is the persistence of proviral DNA, and its replicative potential.
Giuseppe Pantaleo states in a recent Nature Medicine article (see next issue of ATPs Doctor Fax) that low HIV-replicating cells such as macrophages and dendritic cells
are refractory to antiretroviral therapy thus casting doubts as to the
specificity of the drugs for HIV enzymes. Macrophages are terminally differentiated
cells which produce virus without clonal expansion.
Pantaleo reported that, on cessation of therapy and within one to four weeks, plasma
viraemia returns to baseline. This occurs even after extended periods of undetectable casting doubt on the idea that total body burden of virus is decaying over time
on treatment.
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CLINICAL TRIALS AND DRUG APPROVAL
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The use of suboptimal treatments in clinical trials is both wrong and dangerous, a
leading AIDS researcher argues. In an extraordinary article in the journal Science, Joep M.A. Lange of the University of Amsterdam
blasted the short-sightedness of clinical trial planners, the self-defeating requirements of regulatory agencies, and the greed
of drug companies.
"Suboptimal therapies are still being used," Lange wrote. "This is a severe problem
that deserves far more attention and regulation than it actually gets."
Lange's argument is based on the conviction - not shared by all AIDS clinicians -
that the only acceptable treatment for HIV infection (in patients physically and mentally ready for such treatment) is the use of
combination regimens that maximally suppress viral burden. In today's world, this generally means the use of a protease inhibitor
in combination with two reverse-transcriptase inhibitors (RTIs).
With maximal virus suppression, Lange expects to prevent or at least greatly delay
the emergence of drug-resistant HIV strains. When one or more drugs in a potent combination must be changed due to intolerance,
patient preference, or other reasons, a new drug can be substituted safely.
But with suboptimal virus suppression, as is seen with sequential monotherapy, the
virus achieves resistance to each of the drugs in turn. Because of cross resistance - and a limit to the number of available antiretroviral
medications - such a strategy severely limits a patient's future treatment options.
Lange listed several reasons he believes account for the continuing use of suboptimal
therapy.
"This may be because of economic considerations, the need to treat patients who have
already undergone multiple therapies, patient intolerance of the drugs, poor compliance, or physician ineptitude, to name a few
common reasons," he wrote.
But he can think of no excuse for permitting the use of suboptimal therapies in clinical
trials.
"In clinical trials, the least we can do for patients who are willing to help advance
knowledge is to try to treat them according to the highest current standard," Lange wrote. "Yet even today, suboptimal regimens
are still being evaluated for many reasons."
He explored four of these reasons.
The first is the accidental use of suboptimal therapies in trials of drugs whose in
vitro efficacy fail to translate to clinical efficacy. The famous failure of soluble recombinant CD4 stands as the most famous
example.
"The risk of such accidents may be minimised by doing the appropriate groundwork,"
Lange suggested.
Secondly, regulatory requirements often call for monotherapy data, and for new agents
to demonstrate clinical superiority over outdated standards of care.
Lange pointed to the Abbott 247 trial in which more than a thousand participants with
long histories of antiretroviral drug use and low CD4 counts were randomised to receive either the protease inhibitor ritonavir
or a placebo in addition to their ongoing RTI regimen. After six months, the ritonavir group had a 43 percent reduction in
mortality.
"For practical reasons and from a regulatory perspective, this is the most efficient
trial design, but it is also the best way to select for resistance to the invaluable protease inhibitor," Lange wrote.
"I believe that it would have been in the best interest of the patients if, instead
of ritonavir being added to the drugs they were already taking, the patients had been switched to non-cross-resistant nucleoside
analogue RT inhibitors simultaneously with the beginning of ritonavir treatment."
Lange would permit only a brief period of monotherapy testing, as the ability of a
drug to reduce viral replication is usually obvious within a few days of treatment.
He also called for universal adoption of rapid conditional approval of drugs, a policy
adopted by the U.S. but not by the European Community. The financial gain from such approval could be balanced by a requirement
for drug company-financed postmarketing testing.
The third reason cited by Lange for the use of suboptimal therapy in clinical trials
results from trial planners "ignoring the biology of the disease."
As an example, he pointed to the Quattro trial sponsored by the U.K. Medical Research
Council. This trial began in 1995 and is scheduled for completion in 1997. The trial has three arms comparing simultaneous
quadruple therapy to sequential monotherapy with the same drugs and to simultaneous therapy with two of the four drugs; all treatment
arms include lamivudine (3TC).
At the start of the trial, it had already been demonstrated that HIV rapidly develops
resistance to 3TC and to the non-nucleoside RT inhibitors (NNRTIs) included in the trial when viral replication is not minimised.
Moreover, previous trials had cast doubt on the efficacy of sequential therapy.
"In light of all the available data on viral dynamics, the prognostic value of viral
load, resistance development, and the superiority of various triple-therapy regimens over less suppressive regimens, I am amazed
at the design and continuation of such a trial," Lange wrote.
Finally, Lange blasted drug companies for restricting combination testing of promising
drugs. Companies may require investigators to use other drugs of their own manufacture, or they may prohibit combination testing
with specific drugs made by competitors.
"Investigators around the world are experiencing this type of restriction," Lange
claimed. "Necessary trials are delayed or cannot be done because of it. There is also a tendency to rapidly and widely publicise
positive data and to delay or refrain from publication of studies with a negative outcome.
"All of this is wrong and disgraceful and is not in the long-term interests of the
pharmaceutical companies themselves. ... Burning up therapeutic options prematurely is not only very cynical, but in the end, self
defeating."
Lange called for anti-trust-like legislation to prohibit clinical trials from the
exclusive use of "incestuous" drug combinations. He also called for regulatory agencies and medical journals to require publication
of all relevant data.
What can clinical trials do if they can use only maximally suppressive therapies?
Lange supplied a list of avenues for investigation:
- How durable and robust are the antiviral effects of various regimens that maximally
suppress HIV?
- Can the regimens affect virus sanctuaries such as the central nervous system and long-lived
cells?
- What are the regimens' toxicitys in the short and long terms?
- How do regimens compare in terms of patient compliance, quality of life, and cost efficiency?
- What level of immune reconstitution can be seen with each regimen, and can immune-based therapies improve these regimens?
- Do various regimens that maximally suppress HIV differ in terms of clinical endpoints and survival?
- Can prophylaxis against opportunistic infections eventually be withdrawn, and if so, when?
"In my view, now that adequate monitoring tools are available, 'strategic trials' to
answer questions such as when to start, when to change, and when to stop are obsolete," Lange wrote. "Except for long-term nonprogressors,
who are exceedingly rare, from a medical perspective there is no good reason not to start antiretroviral therapy as
soon as the HIV infected patient is mentally ready for it."
In an accompanying article, Science writer Jon Cohen reported on conversations with
a number of AIDS workers regarding Lange's arguments.
"The biology is really screaming at us to get everyone to undetectable levels [of
HIV], but there is more to medicine than biology," Michael Saag of the University of Alabama, Birmingham, told Cohen.
Saag has recommended initiation of a clinical trial to test "strategic timing of antiretroviral
therapy (START)." The START strategy would give patients a list of treatment options, and would switch regimens when
viral load increased beyond a set point.
Such a trial would necessarily be long and complex; the AIDS Clinical Trials Groups
(ACTG) recently rejected Saag's plan. According to Cohen, the ACTG instead will attempt to achieve similar results by meta-analysis
of all relevant data from its clinical trials.
Robin Weiss of Chester Beatty Laboratories, London, U.K., defended the Quattro trial
design that Lange so bitterly condemned. He admitted to Cohen that combination therapy yields a greater initial decline in viral
load, but he said that the long-term efficacy of this approach was questionable.
"It is pure speculation whether a year later or two years later these patients [who
receive aggressive combination therapy] are going to have a lower [HIV] load than those patients given drugs sequentially," Cohen
quoted Weiss as saying. "It's just a rationale, and it's turning into a dogma. Quattro might give answers."
Robert Yarchoan of the National Cancer Institute also spoke to Cohen; he has long
been involved in the design of AIDS clinical trials.
"If you really take a hard line and say everyone should be on triple therapy and drive
the virus down to zero and everything else is amoral, then you get into a situation of how do you test new drugs," Cohen quoted
Yarchoan. "I don't have the answer."
But Yarchoan agreed with Lange that the U.S. Food and Drug Administration, and other
regulatory authorities, must re-examine rules that lead drug companies to test their new agents against the worst existing therapy.
Source: Aegis
Ref: Current Problems and the Future of Antiretroviral Drug Trials. Science, 1997;276:548-50.
AIDS Trials Ethics Questioned," Science, 1997;276:520-3.
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