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ANTIVIRALS
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On 4th October 1996, the European Commission announced the approval of two HIV protease
inhibitor drugs, indinavir (Crixivan, Merck and Co.) and saquinavir (Invirase, Hoffman-La Roche).
INSERT INDICATIONS
INSERT AVAILABILITY DATES
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Comments: With ritonavir brings to three the number of PIs now licensed in the UK. Guidance for physicians in choice of agent? |
Papers detailing the results of two large-scale HIV treatment studies, supported by
the National Institute of Allergy and Infectious Diseases (NIAID), and an accompanying editorial, were published in the Oct. 10,
1996 issue of The New England Journal of Medicine.
Preliminary results of the two studies, known as ACTG 175 and CPCRA 007, were first
announced by NIAID in 1995, and have played an important role in helping define the standard of care for HIV-infected people and
shaping subsequent clinical studies of antiretroviral medications.
"ACTG 175 was noteworthy because it was the first trial to provide conclusive evidence
that antiretroviral therapy could reduce the risk of death in people with intermediate-stage HIV disease and no symptoms, and
CPCRA 007 provided important information on combination therapy for HIV-infected people with more advanced disease," says Anthony
S. Fauci, M.D., NIAID director. "Both ACTG 175 and CPCRA 007, in addition to other recent studies, underscore the importance
of careful planning in the use of antiretroviral drugs since prior antiretroviral experience can profoundly influence the effectiveness
of some treatments."
"Subsequent to these two studies, results from other trials, especially those that
have assessed protease inhibitors in combination with other drugs, have provided impressive results, giving hope for a level of
control of HIV disease that has thus far eluded patients and physicians," he adds.
ACTG 175 was conducted at 43 sites of the AIDS Clinical Trials Group and nine sites
of the National Haemophilia Foundation. The study investigators analysed data from 2,467 patients with initial CD4+ T cell counts
between 200 and 500 per cubic millimetre (mm3) of blood. Fifty-seven percent of these patients had previously received anti-HIV
therapy; most had no HIV-related symptoms at study entry.
Patients in ACTG 175 received one of four anti-HIV treatment regimens: zidovudine
(AZT) alone; AZT plus didanosine (ddI); AZT plus zalcitabine (ddC); or ddI alone. They were followed for a median of 143 weeks.
In their analyses of the study results, ACTG 175 investigators found that ddI alone,
the AZT+ddI combination, and the AZT+ddC combination were each superior to AZT alone in preventing one or more of the serious
consequences of HIV infection: significantly declining CD4+ T cell counts, a new AIDS-defining condition (e.g., Pneumocystis carinii
pneumonia) or death.
When the investigators looked only at the clinical endpoints of a new AIDS-defining
condition or death, treatment with either AZT+ddI or ddI alone was more effective than AZT alone. In the analysis of clinical
endpoints, the benefit of AZT+ddC over AZT alone appeared to be limited to volunteers without prior antiretroviral treatment.
In the study, there were no major differences in the toxicitys associated with the four treatments.
CPCRA 007 was conducted at sites that are part of the Terry Beirn Community Programs
for Clinical Research on AIDS; it is also known as the "NuCombo" study.
This trial assessed the safety and efficacy of combination therapy -- AZT+ddI or AZT+ddC
-- as compared to AZT alone in 1,102 HIV-infected people who had fewer than 200 CD4+ T cells/mm3 of blood at study entry
or who previously had suffered an AIDS- defining condition. Seventy-seven percent of the patients who enrolled in CPCRA 007 had
received prior antiretroviral therapy.
Over a median follow-up time of 35 months, combination therapy (AZT+ddI or AZT+ddC)
provided only marginal benefits, which were not statistically significant, in slowing progression of clinical disease and reducing
the rate of death as compared to AZT alone. In addition, toxicitys were more frequent in the two combination groups than among patients taking AZT
alone.
However, in subgroup analyses of patients with little or no prior AZT use, combination
therapy was more effective than AZT alone in terms of slowing disease progression to AIDS or death. Use of combination therapy
provided no additional benefit to patients who
had previously used AZT for more than 12 months.
Ref: New England Journal of Medicine 1996;15:1081- 1090, 1091-1098, 1099-1106, 1142-1144.
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Comments: Where do these results stand in relation to Delta?, CPCRA 007 - recommendations for prescribing in advanced disease? |
Background. We studied measures of human immunodeficiency virus (HIV) replication,
the viral phenotype, and immune function (CD4 cell counts) and the relation of changes in these indicators to clinical outcomes
in a subgroup of patients in a controlled trial of early antiretroviral treatment for HIV, the AIDS Clinical Trials Group Study
175.
Methods. The 391 subjects, each of whom entered the study with a single screening
CD4 cell count of 200 to 500 per cubic millimetre, were randomly assigned to receive zidovudine alone, didanosine alone, zidovudine
plus didanosine, or zidovudine plus zalcitabine. Plasma concentrations of HIV RNA were assessed in 366 subjects, and viral isolates
from 332 subjects were assayed for the presence of the syncytium-inducing phenotype.
Results. After eight weeks, the mean (+/-SE) decrease from base line in the concentration
of HIV RNA, expressed as the change in the base 10 log of the number of copies per millilitre, was 0.26+/-0.06 for patients
treated with zidovudine alone, 0.65+/-0.07 for didanosine alone, 0.93+/-0.10 for zidovudine plus didanosine, and 0.89+/-0.06
for zidovudine plus zalcitabine (P<0.001 for each of the pairwise comparisons with zidovudine alone). Multivariate proportional-hazards
models showed that higher base-line concentrations of plasma HIV RNA, less suppression of plasma HIV RNA by treatment,
and the presence of the syncytium-inducing phenotype were significantly associated with an increased risk of progression to the
acquired immunodeficiency syndrome and death. After adjustment for these measures of viral replication and for the viral phenotype,
CD4 cell counts were not significant predictors of clinical outcome.
Conclusions. Both the risk of the progression of HIV disease and the efficacy of antiretroviral
therapy are strongly associated with the plasma level of HIV RNA and with the viral phenotype. The changes in the
plasma concentration of HIV RNA predict the changes in CD4 cell counts and survival after treatment with reverse-transcriptase inhibitors.
Ref: N Engl J Med 1996;335:1091-8.
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Comments: Delta virology substudy? Observations limited to patients treated with ZDV,
ddI and ddC. Much larger decreases in viral load are seen with combinations including a protease inhibitor. Will these combinations
also show decreases in rates of disease progression proportional to the viral suppression achieved? |
September 23,1996
Dear Doctor:
As a reminder, nevirapine (VIRAMUNE(R)) has been approved by the U.S. FDA for use
in combination with nucleoside analogues for the treatment of HIV-1 infected adults who have experienced clinical and/or immunologic
deterioration. The use of nevirapine in combination with protease inhibitors is not currently recommended by Roxane Laboratories,
Inc. in the package insert and is still considered investigational. We would like to update you on the current status of
ongoing pharmacokinetic interaction trials with nevirapine and the protease inhibitors saquinavir, indinavir and ritonavir because
of the interest by many in determining any interaction potential.
Nevirapine is a mild-to-moderate inducer of the hepatic enzyme CYP3A and the potential
exists to reduce plasma levels of other drugs metabolized by this pathway, including the protease inhibitors. It is also possible
that nevirapine plasma levels may be affected by concomitant use with other drugs that utilize the same pathway.
Preliminary date from the nevirapine/saquinavir interaction trial are provided below;
data from the nevirapine/indinavir and nevirapine/ritonavir interaction trials will be available by the end of this year.
Saquinavir and Nevirapine
An open label, sequential administration study is being jointly supported by Hoffmann-LaRoche
Ltd. and Boehringer Ingelheim Pharmaceuticals, lnc. The trial requires enrolment of 24 evaluable HIV-infected patients
who will receive saquinavir (SQV; currently approved formulation) for seven days followed by nevirapine (NVP) in the recommended
dose escalation method for 28 days, followed by the combination of SQV+NVP for seven days. A summary of the regimens is shown
below.
Summary of Periods and Regimens
Period | Regimen |
1 | SQV 600mg tid for 7 days |
2 | NVP 200mg qd for 14 days then 200mg bid for 14 days |
3 | SQV 600mg tid + NVP bid for 7 days |
Disposition | Number Patients |
| Enrolled | 31 |
| Completed | 21 |
| Evaluable | 20 |
| Currently ongoing | 4 |
| Withdrawn prior to completion | 6 |
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Comments: Nevirapine in the UK, still no expanded access? -27% AUC of SQV is this really insignificant? Given the clear dose-response relation should PIs be seen as other anti-infective agents where a 50% reduction before significance is the rule? Delarvidine interaction data clearly more favourable for a combination including SQV? |
Recent research has shown that HIV-1 depends on chemokine receptors to act as cell
surface co-receptors to enter and infect cells. Scientists from the Pasteur Institute, the University of British Columbia, and
the University of Bern report that a modified version of the chemokine RANTES can block HIV-1 without prompting the adverse effects
the original compound causes. The findings suggest that "receptor signalling and cell activation is probably not required
for the anti-HIV effect of chemokines," and that therapeutic agents could be developed as a result, the authors conclude.
Ref: Nature (10/03/96) Vol. 383, No. 6599, P. 400
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Comments????? |
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PATHOGENESIS
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Recent research has shown that the chemokine receptor CKR5 serves s a critical co-receptor
for certain strains of HIV-1. Further studies have suggested that a defect in co-receptors may protect some individuals
from HIV-1 infection. Stephen J. O'Brien, of he National Cancer Institute, and colleagues, mapped the location of the CKR5 structural
gene and determined the frequency of the defect in the population. From a total of 1,955 patients at high risk for HIV,
who were involved in large AIDS studies, 17 people, who had all been exposed to HIV-1 but tested negative for viral antibodies,
were found to have two copies of the defective gene. In individuals who had survived with HIV for more than 10 years, the presence
of one copy of the defective gene was much more common. An analysis of the frequency of the defect and survival time showed
that disease progression is slower in people with one copy of the defective gene than in individuals without the defect.
Dr. O'Brien believes these findings have clear clinical implications. "Now that we
are beginning to see the benefits of attacking HIV with, not one, but a combination of different drugs, today's finding points
out a different, but naturally proven, angle from which to attack the virus and make its life really rough," he writes.
In an accompanying editorial, Jon Cohen points out some "notable differences" between
the current findings and previous reports. "O'Brien found no indications that heterozygotes were protected against HIV infection:
There were roughly the same number of heterozygotes was found in both infected (15%) and uninfected (14%) populations." However,
Dr. O'Brien's group does provide some evidence, "...that having one mutant [CKR5] gene copy might slow the progression of
AIDS," Cohen wrote.
"Many AIDS researchers are now interested in investigating whether these findings
can be translated into treatments or vaccines that delay or prevent disease," he continues. But other researchers urge caution,
pointing out that "...chemokines and their receptors are part of a vast, delicately controlled immunologic network."
Ref: Science (09/27/96) Vol. 273, No. 5283, P. 1856; Dean, Michael; Carrington, Mary;
Winkler, Cheryl; et al.
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Comments????? |
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Comments????? UK clinical trials?? |
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OPPORTUNISTIC ILLNESS
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Human herpesvirus type 8 (HHV-8) has been detected in individuals with all forms of
Kaposi's sarcoma (KS), as well as HIV-seropositive individuals with and without KS, and individuals with other diseases, suggesting
that the virus may be widely distributed in the population. Previous seroepidemiological studies of the virus have been hindered
by unreliable tests. Evelyne T. Lennette, of Virolab in Berkeley, Calif., and colleagues at the University of California,
San Francisco, used a immunofluorescence assay to measure HHV-8 seroprevalence in the general population and in KS patients and
individuals at risk for HIV infection. They report that all patients with African endemic KS and 96 percent of American patients
with AIDS-associated KS tested positive for HHV-8 antibodies. Additionally, 90 percent of American homosexual men with HIV tested
positive, compared to 23 percent of HIV-seropositive drug users and 21 percent of HIV seropositive women. In the general
U.S. population, about 25 percent of adults and 2 percent to 8 percent of children had antibodies to HHV-8. The authors say the
data support the theory that HHV-8 is associated with sexual transmission, but that the rate of infection in children suggests
another route of transmission exists as well.
Ref: Lancet (09/28/96) Vol. 348, No. 9031, P. 858; Lennette, Evelyne T.; Blackbourn,
David J.; Levy, Jay A.
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Comments????? |
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GYNAECOLOGY
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Progesterone, a hormone commonly used in oral contraceptives, has been found to increase
vaginal transmission of an AIDS-like virus in monkeys and boost concentrations of the virus in their blood. Preston A. Marx
of the Aaron Diamond AIDS Research Center and colleagues report their findings in the 01/10/96 issue of the journal Nature
Medicine. The study suggests that the more than 2.5 million U.S. women using progesterone contraceptives may be at increased risk
for HIV infection through vaginal intercourse. The findings are not conclusive enough for the authors to recommend that women
change their contraceptive, however. More research is needed to determine if the increased risk in monkeys is also present for
women.
Ref: Washington Times (01/10/96) P. A9; Price, Joyce
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Comments????? |
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PAEDIATRICS
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A specific pattern distinguishes children with AIDS who develop central brain encephalopathy
from HIV-negative children who develop cerebral atrophy from other causes, according to Dr. Victor Scarmato of Cornell
University Medical College.
Dr. Scarmato and colleagues at North Shore University Hospital in Manhasset, NY compared
the results of MRI examinations to determine the patterns associated with AIDS-related encephalopathy. The subjects included
9 children with progressive AIDS encephalopathy, 25 children with AIDS but without encephalopathy, 23 HIV-negative children
with cerebral atrophy from other causes and 42 normal controls. He used ventricle-brain ratio, bicaudate ratio and bifrontal ratio
as measures of brain atrophy.
Dr. Scarmato found that "...compared with controls, encephalopathy patients showed
significantly increased bicaudate and ventricle-brain ratios, but no significant increase in bifrontal ratio, whereas children
with brain atrophy from causes other than AIDS showed increases in all three ratios."
These findings support the "...predominance of 'central' atrophy in AIDS encephalopathy,"
and are similar to those patterns reported for adult patients with AIDS encephalopathy. The results also "...suggest a specific
pattern of cerebral atrophy associated with AIDS when compared with other disease processes, a subject not addressed in
previous studies." The clinical usefulness of this pattern of central brain atrophy as a diagnostic marker, or in therapeutic trials,
requires further investigation, he added.
Ref: AIDS 1996;10:1227-1231.
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Comments????? |
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CURRENT OPINIONS
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Reproduced from Project Inform Perspective #19 (September 1996) as part of AIDS Treatment
Projects endeavour to stimulate debate on standards of care and treatment strategies. Project Inform are one of the leading
treatment advocate agencies in the U.S.
PART ONE OF THIS ARTICLE - strategies for primary and chronic infection was reproduced in ATPs Doctor Fax Issue 8 |