CURRENT OPINIONS - Treatment Sequencing
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IMMUNOMODULATORS
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IL-2 Therapy Doubles CD4+ T Cell Counts in HIV-infected People
In a one-year study of HIV-infected people, infusions of the immune system protein
interleukin-2 (IL-2) have resulted in dramatic and sustained increases in the primary immune system cells depleted during HIV infection,
according to investigators at the US National Institutes of Health (NIH).
In the study, patients randomly assigned to receive IL-2 plus standard antiretroviral
therapy had mean CD4+ T cell counts that increased from 428 cells per cubic millimeter of blood (mm3) at baseline to 916 cells/mm3
at month 12. Among patients randomly assigned to receive standard antiretroviral therapy alone, mean CD4+ T cell counts
decreased from 406 cells/mm3 to 349 cells/mm3.
Joseph A. Kovacs, M.D., H. Clifford Lane, M.D., and their colleagues report their
findings in the Oct. 31 issue of The New England Journal of Medicine.
"This work highlights the potential role of immune-based therapies in the treatment
of HIV-infected people," says Anthony S. Fauci, M.D., NIAID director.
Significantly, the amount of HIV in the blood of study patients receiving IL-2 therapy
remained stable over time. Previous studies had shown that IL-2 treatment can result in transient bursts of virus production
in some patients, but the current data clearly indicate that these bursts do not lead to sustained increases in viral load.
In addition, the side effects of IL-2 infusions in the current study were much less
severe than those seen in previous studies using higher doses of intravenous IL-2.
"Our study has clearly demonstrated that IL-2 therapy can have a substantial positive
impact on the major immunologic abnormality associated with HIV infection, the loss of CD4+ T cells, without leading to an overall
increase in the level of HIV in the bloodstream or to unmanageable toxicities," says Dr. Kovacs.
Despite flu-like symptoms and other side effects during IL-2 infusions, patients in
the study reported feeling as well overall as patients not receiving IL-2, according to a quality of life analysis presented at
the XIth International Conference on AIDS in Vancouver, B.C.
"We are encouraged that the increases in CD4+ T cells observed in this study did not
come at the expense of a patient's overall quality of life," says Dr. Kovacs. "Additional work by our group has shown that other
dosing regimens, especially subcutaneous administration of lower IL-2 doses, can further reduce toxicity."
All immunologic studies performed thus far suggest that the CD4+ cells that proliferate
during IL-2 therapy are functional, Dr. Lane notes. As further evidence of this, "the current study has provided the first
clinical data that IL-2 therapy may be able to prevent new AIDS- related conditions or death," he says. "Among individuals randomized
to standard antiretroviral therapy, five people developed AIDS-related symptoms or died, as compared to two in the group
randomized to IL-2 in addition to standard antiretroviral therapy. In each instance, these events occurred in patients with low
CD4+ T cell levels. Phase III studies are needed to accurately determine the clinical benefits of IL-2 therapy."
IL-2, originally called T cell-growth factor, is produced in the body by T cells and
has potent effects on the maturation and proliferation of a number of cell types, including T cells, B cells and natural killer
cells. Commercially, IL-2 is produced by recombinant DNA technology and is licensed in the United Sates for the treatment of
patients with metastatic renal cell cancer. The recombinant IL-2 used in the NIAID study was produced by Chiron Corporation of
Emeryville, Calif.
STUDY DETAILS
In the study, 60 patients with baseline CD4+ T cell counts above 200/mm3 of blood
were randomly assigned to receive IL-2 plus licensed antiretroviral therapy, or antiretroviral therapy alone. IL-2 was administered
at a starting dose of 18 million International Units (IU) a day for five days every two months. The dose was reduced as needed;
the mean dose used in the latter part of the study was approximately 8 million IU/day.
The most common side effects during IL-2 administration were fatigue or malaise, reported
by patients during 44 percent of the five-day treatment cycles, and headache, reported during 7 percent of treatment cycles.
The most common laboratory abnormality, seen during 8 percent of the treatment cycles, was an elevation in bilirubin levels,
indicating an effect on the liver. The elevations were not accompanied by clinical symptoms, and levels returned to normal after
the treatment period. The investigators note that toxicities decreased in frequency during later rounds of treatment as IL-2
dosages were reduced.
In an extension phase of the trial, the investigators found that increases in CD4+
T cells could be sustained for more than two years by continuing to administer IL-2 on an individualized schedule. In five patients,
CD4+ T cell counts remained over 1000/mm3 for at least 18 months after discontinuing IL-2.
"To date, no combination of antiretroviral agents has been shown capable of inducing
increases in CD4+ T cell counts of this magnitude or duration," the authors write.
Because IL-2 targets the immune system rather than HIV itself, viral mutations should
not reduce its effectiveness, the investigators note. In contrast, resistance to antiretroviral drugs occurs because of HIV's
high rate of mutation.
"The lack of resistance to IL-2 helps explain why some patients have continued to
respond to IL-2 therapy even 50 months after beginning therapy," says Dr. Kovacs.
While the current study of IL-2 enrolled only patients with CD4+ T cell counts above
200/mm3, additional Phase II work in NIAID's AIDS Clinical Trials Group is being planned in patients with more advanced disease.
Ronald T. Mitsuyasu, M.D., director of the UCLA Center for AIDS Research and Education and associate professor at the UCLA
School of Medicine, is focusing his efforts on patients with lower CD4+ T cell counts, and will assess IL-2 given with antiretroviral
regimens that include a protease inhibitor.
NEXT STEP: A PHASE III TRIAL OF IL-2
The NIH investigators currently are working with scientific colleagues in the United
States and abroad to develop a Phase III strategy to determine whether the increases in CD4+ T cells achieved with IL-2 therapy
will translate to fewer AIDS-related complications and improved survival for HIV-infected people.
Professor David Cooper, M.D., director of the National Centre in HIV Epidemiology
and Clinical Research in Sydney, Australia, has studied IL-2 and is working closely with the NIH investigators in the development
of a Phase III plan for evaluating IL-2 in HIV-infected patients with CD4+ T cell counts greater than 400 cells/mm3. He comments:
"Complementing antiretroviral therapy with IL-2 is an attractive approach to the treatment of HIV-infected people, offering
the opportunity to reduce the amount of virus in the body while boosting the immune system's capacity. We look forward to a trial
that will clarify the long-term clinical benefits associated with the IL-2-induced increases in CD4+ T cells."
Professor Maxime Seligmann, M.D., chairman of the Scientific Council of the ANRS in
France, comments, "When given in conjunction with antiretrovirals, IL-2 has the potential to directly boost the immune system
in a way that may be of clinical benefit. The only way to definitively establish this is in the context of a well-designed Phase
III trial."
In collaboration with Yves Levy, M.D., Professor Seligmann currently is conducting
a trial comparing intravenous and subcutaneous modes of IL-2 administration. This study will allow a detailed analysis of the
immunologic changes seen in people receiving IL-2 therapy and provide insights into how best to administer IL-2.
Source: National Institutes of Health National Institute of Allergy and Infectious
Diseases
Comment: Interleukin-2 or aldesleukin is licensed in the UK for the treatment of
metastatic renal cell carcinoma and is manufactured by Chiron under the tradename Proleukin. There have not been any studies into
the use of IL-2 in HIV-disease in the UK, Chiron are in discussion with at least one UK centre for inclusion in a phase II study.
Chiron appear unwilling to collaborate in this field and have not provided any amounts of the drug through compassionate use
schemes. This leaves the only access to IL-2 in the UK through off-label prescribing by individual physicians. Reimbursement is therefore extremely unlikely
and vital data on safety and efficacy will remain uncollected.
Phase III trials looking at clinical outcomes and expanded access/compassionate use
studies could yield much needed information on the place of IL-2 in the management of HIV-disease. Why are Chiron so reluctant
to carry out these studies, and why not in the UK? If the drug companies are unwilling to run these studies perhaps the MRC should
look to initiating clinical trials. The MRC currently has no plans for trials of IL-2 in the UK.
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Thalidomide and Ketoprofen Reduce the Incidence of Adverse Events of Interleukin-2
In a separate report from the 3rd International Congress on Drug Therapy in HIV Infection,
Birmingham UK, 3-7 November 1996, a Mexican team presented results on their randomised controlled clinical study of low-dose
IL-2.
Sub-cutaneous doses of 1 or 2 Million IU of IL-2 were used for three consecutive days
every two months in two groups of patients. Group 1 comprised 28 patients with advanced disease and a median CD4 count of 2515 cells/mm3 . Group 2 comprised 40 patients with early HIV disease. The initial four months of
treatment (6 doses of IL-2) were of IL-2 alone. From dose 7 onwards single oral doses of thalidomide 100mg and ketoprofen 200mg
were given simultaneously with the IL-2 over the three days every two months. All patients were being treated with combination
antiretroviral therapy and had viral load decreased to less than 10,000 copies/mL prior to IL-2 therapy. Patients have been followed
for 9 months and have received an average of 7.28 injections of IL-2 at the time of analysis.
Results Group 1 (increases from baseline)
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IL-2 dose | IL-2 alone | IL-2+keto+Thal |
| 1 million IU | CD4 - 25% | CD4 - 100% |
| CD8 - 70% | CD8 - 100% |
| 2 million IU | CD4 - 10% | CD4 - 80% |
| CD8 - 30% | CD8 - 120%
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Results Group 2 (increases from baseline)
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IL-2 dose | IL-2 alone | IL-2+keto+Thal |
| I million IU | CD4 - 80% | CD4 - 150% |
| CD8 - 120% | CD8 - 200% |
| 2 million IU | CD4 - 50% | CD4 - 100% |
| CD8 - 100% | CD8 - 150%
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2 cases had viral load increases which were controlled by adjusting antiviral therapy.
5 patients were non-responders. Minor adverse events were less frequent when ketotifen and thalidomide were administered concurrently
with the IL-2.
The team concluded that thalidomide and ketoprofen reduce the incidence of adverse
events and enhance the immunological response to low doses of subcutaneous interleukin-2.
Ref:
P.60. Thalidomide and ketoprofen reduce the incidence of adverse events of interleukin
2 and enhance the antiviral activity of CD8 in HIV/AIDS patients. M Feregrino-Goyos et al. 3rd Int. Congress on Drug Therapy
in HIV Infection. Birmingham, UK. Nov. 1996.
Control of symptoms and improved responses with thalidomide may relate to its effects
as an anti-TNF alpha agent, reducing the effects of this cytokine. Thalidomide is available on special supply at most UK HIV
centres, and may also may useful in managing apthous ulcers and chronic
diarrhoea.
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ANTIVIRALS
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Nevirapine Based Combinations at Birmingham
Researchers at the Third International Congress on Drug Therapy in HIV Infection presented
evidence that a new class of drugs, known as non-nucleoside reverse transcriptase inhibitors (NNRTIs), work synergistically
with nucleoside analogues offering new choices to AIDS patients. Mark Wainburg and colleagues at Montreal's McGill University
AIDS Center found that a combination of AZT, Bristol-Myers Squibb's ddI, and Boehringer Ingelheim's NNRTI nevirapine "led to
non-detectable levels of virus in plasma in over 75 percent of patients who were previously drug-naive." HIV RNA suppressioin and
CD4+ count elevations were sustained for 12 months. No evidence of nevirapine resistance could be found in a subset of compliant
patients who had suppressed viral load to less than 20 copies/mL with the triple combination
Another group of researchers, led by Joep Lange of Amsterdam's Academic Medical Center,
found similar results, concluding that "nevirapine provides new opportunities for combination treatment."
Viral load in both plasma and lymph node tissue was also compared in patients from
this triple combination study (NVP+ddI+AZT, INCAS study). Preliminary data suggests a substantial degree of suppression of viral
replication in both plasma and lymph nodes.
Ref:
OP7.1. Randomised, double-blind one year study of the immunologic and virologic effects
of nevirapine, didanosine and zidovudine combinatiuons among antiretroviral naive, AIDS-free patients with CD4 200-600. B
Conway et al.
OP7.2. Phenotypic and genotypic resistance emergent in naive HIV-1 patients treated
with combinations of reverse transcriptase inhibitors. MA Wainberg et al.
OP7.3. Correlation of viral load in plasma and lymph node tissue in patients undergoing
combination antiretroviral therapy. M Harris et al.
3rd Int. Congress on Drug Therapy in HIV Infection. Birmingham, UK. 3-7 Nov 1996.
Comment: Despite these studies showcasing at Birmingham there is no access to nevirapine in the UK or indeed anywhere in Europe
outside of placebo controlled trials. Nevirapine is a licensesd antiretroviral in the US, but an application for licensing
has not even been submitted to the EMEA in Europe.
Boeringer-Ingelheim the drugs manufacturer appear unwilling to discuss compassionate
use. They have been advised that more data is needed for an EMEA application.
Licensing of nevirapine was recently rejected in Australia. Current uncertainty and
confusion about the data requirements of the EMEA need clarification. Merck appears to have obtained licensing for indinavir with
no discrete clinical end-point trials on essentially surrogate marker data.
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Lamivudine Effectively Blocks Replication Of Hepatitis B Virus In HIV-Infected Men
Lamivudine treatment of male patients coinfected with the HIV and hepatitis B viruses
resulted in undetectable levels of hepatitis B viral replication in nearly 90% of patients with high hepatitis B virus (HBV)
replication at baseline. Results of 1 year of follow-up in an open-label study that is ongoing in France appear in the Annals
of Internal Medicine.
One-year results are available on 40 men with progressive HIV disease who were also
infected with hepatitis B. All of the patients were refractory to or unable to tolerate any antiviral treatment other than lamivudine.
Dr. Yves Benhamou of the Groupe Hospitalier Pitie-Salpetriere in Paris and colleagues administered lamivudine at a dosage
of 600 mg/day or 600 mg/day followed by 300 mg/day.
Thirty of the 40 patients in this series had high levels of HBV replication at baseline.
At the 1-year mark, Dr. Benhamou reports that, in those with high baseline replication, HBV DNA serum concentrations had
dropped below 5 pg/mL in 96.3%. HBV DNA could still be detected in the serum in 11.5% of the study subjects.
Meanwhile, U.K. investigators report in The Lancet that lamivudine "...may prove useful
in preventing recurrence of hepatitis B after liver transplantation, [although] the effect on survival....remains to be assessed."
Dr. G. Dushelko of the Royal Free Hospital School of Medicine, London, and colleagues base their conclusion on a study
of 17 patients with chronic hepatitis B requiring orthotropic liver transplantation.
Ref: Ann Intern Med 1996;125:705-712. Lancet 1996;348:1212-1215.
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FUNDING ISSUES
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Better Off in Brazil?: Brazil Funds Combination Therapy
Brazil, a country with the second-highest number of AIDS cases in the Americas next
to the United States, is to distribute anti-HIV drug combinations including protease inhibitors, for free.
Sao Paolo state started provision of the drugs on Monday 11th November. The joint
state and federal program will initially reach some 12,000 persons with AIDS in Sao Paolo state and could eventually reach some
30,000 people around the country.
The drugs can cost up to US$12,000 per patient per year but the Brazilian government
has made the commitment based on evidence that the new combination treatments relieve suffering, prolong life, and can lead to
savings in health care costs associated with caring for those with HIV-infection and AIDS.
Britain, with an estimated treatable HIV-infected population of less than 8,000, has
made no commitment to extra funding for these new treatments. In fact the British Government has reduced the budget by seven
per cent this year leading to senior consultants struggling to fund necessary treatments. Chris Smith, Labours Shadow Health Secretary pledged full NHS funding for these treatments under a Labour
Goverment at a fringe meeting of the party conference in Blackpool last month.
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Survival decreases under managed care
Over the past 5 years doctors in the US have found that increasing numbers of their
patients have their medical bills paid for by agencies called HMOs (health maintenance organizations). Today HMOs are large,
covering tens of thousands of patients, are increasingly influential, and can force doctors to reduce their fees and change prescribing
habits. This in turn cuts the costs to the HMOs and lowers the income of doctors. Some doctors complain about HMOs which
don't allow them to order certain expensive tests, carry out costly procedures or prescribe high-priced drugs, even if these options
are in the best interests of their patients. This system of health care run by HMOs is called managed care. One team of doctors
has been monitoring 1,000 men with HIV/AIDS to find out the effect managed care has on their health.
Results
The doctors found that 50% of men who had AIDS at the time they entered the study
or who developed AIDS while in the study lived for 17 months under managed care. The equivalent figure for men who were in the traditional
fee for service system (which exists in Canada) was 30 months. This difference--an increase in survival time of 60% --
was [statistically] significant, that is; not likely caused by chance alone.
Ref: Palenick J, Graham NMH, Wu A, et al . Poorer survival among AIDS patients enrolled
in managed care organisations versus traditional indemnity insurance. Abstract N024.
Source: TreatmentUpdate 72, Vol. 8, No. 8 - October 1996; A publication of the Community
AIDS Treatment Information Exchange (CATIE).
The NHS and some pharmaceutical companies are currently examining the potential of
a UK HMO system. National protocols represent a step in this direction. The idea of managed care within the NHS periodically raises
its ugly head as an attractive option for cost control and rationing. Managed care and associated disease management programmes are, however, widely regarded as a threat to both patient and physician
choice in clinical decision making. Even more sinister is the involvement of major pharmaceutical companies in developing so-called
disease management packages. This is not the first report that reveals the worrying finding of increased morbidity and mortality
as a result of the managed care of patients with HIV infection.
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CURRENT OPINIONS
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Treatment Sequencing
by Dr Graeme Moyle
The goal of therapy for persons with HIV is to improve both length and quality of
life. At present, this appears best achieved by combination therapy with antiretroviral agents to reduce the viral turnover to as
low as possible: below the detection of a sensitive viral load assay. Whilst reducing viral load below assay detection slows HIV-mediated
immune destruction, the extent of immune restoration or regeneration is not clear. Immunotherapies such as interleukin-2
represent the first steps in developing ways to reconstitute an HIV-damaged immune system.
Failure of antiretroviral therapy in most individuals is inevitable. Failure of therapy
is mostly related to the appearance of drug-resistant variants. The generation of resistant variants generally requires continued
viral replication although viral polymorphism may mean small amounts of virus resistant to an agent are present prior to
therapy initiation. Additionally, some individuals may seroconvert with drug-resistant virus or possibly, may acquire resistant
virus after seroconversion. Persistence of viral replication in individuals who achieve plasma viral load below detectable may occur due to adherence failure, drug interactions or gastro-intestinal upsets
which cause effective drug levels to fall, and may continue at low levels in the lymphoid tissues or sanctuary body compartments such as the CNS, where drugs may not achieve full inhibitory concentrations.
Given that failure of an initial regimen is likely, the choice of initial combination
must be a strategic one; a potent combination of antiretrovirals to achieve the desired virological effect but with a low potential
to limit future therapy options through cross-resistance.
Amongst the nucleoside analogues ddC and ddI represent ideal initial co-therapies
with AZT as resistance to these agents is rare when used in combination. 3TC, whilst providing similar antiviral effects, invariably
selects a mutation at RT codon 184 which reduces sensitivity to ddC and ddI by 4-10 fold, suggesting it may limit the future
value of these agents. d4T, an increasingly popular agent due to its good tolerability and convenient b.d. dosing, has been reported
to select for cross-resistance to AZT and ddI in one study raising concerns about future therapy options.
Unfortunately, ddC and ddI do not delay AZT-resistance. Reports for the US ACTG 116/117
study have suggested AZT-resistance is not only associated with loss of antiviral effect with this drug, but also may lead
to accelerated disease progression and death. It therefore seems prudent to include an agent which delays AZT-resistance in any
AZT containing regimen: this effect has so far only been reported for the protease inhibitors saquinavir and indinavir.
With protease inhibitors (PIs) resistance patterns also vary. Indinavir has been reported to select for a cross-class resistant virus with 100% of indinavir-resistant viruses being cross-resistant to
ritonavir, 60-80% cross-resistant to saquinavir and nelfinavir. This limits the attractiveness of indinavir as the first-choice
protease inhibitor; in terms of antiviral activity and tolerability it represents an excellent antiretroviral. Ritonavir-resistance
leads to reduced sensitivity to indinavir and in some instances to nelfinavir. Its effects on saquinavir and VX-478 (1263W94)
sensitivity are more limited. Saquinavir and nelfinavir infrequently select cross-resistant virus to other PIs, therefore, represent attractive first-line PIs. Whilst saquinavirs activity may be limited by poor bioavailability, (an improved formulation is in
development), its efficacy as a combination agent is proven to clinical endpoints and cross-study comparisons of PI combination
studies suggest differences between responses of saquinavir-based triple combinations compared with ritonavir or indinavir based
combinations. as initial therapy are in the range of 0.5 log10. Saquinavir is the best tolerated PI, with the lowest number of adverse drug interactions
and low potential for cross-resistance, therefore represents an attractive initial PI choice. Use of viral load testing
at , say 8-12 weeks, will enable determination of whether sufficient benefit has been observed with this initial combination or whether adjustment of
components of the regimen are required.
At this early time point, substitution of one protease inhibitor for another is likely
to be possible. However, after failure of an initially successful regimen, substitution of all components of the regimen appears
the most prudent and effective approach.
Prudent choice of initial agents can enable full use of the expanded therapy menu.
However, pursuing immediate gratification with a perceived most active combination may represent short-term gain but long-term difficulties.
This article was written by Dr Graeme Moyle as part of our CURRENT OPINIONS series.
AIDS Treatment Project welcomes the submission of similar articles.
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