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ANTIVIRALS
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As a consensus document these guidelines may well appear to be more or less radical than some physicians
or patients may wish. However, it does lend weight to minimum standards, many of which are not currently offered in the
UK. Patients not offered these minimum standards, along with their physicians (and BHIVA?) should pressure their local authority
to provide adequate treatment. Other, practical issues also have to be attended to before even these guidelines could be adhered to. Currently most centres offering viral load testing run the assay in batches leading to delays in obtaining results. Clinic structuring also means that test result reporting is frequently left until the follow-up appointment. These factors combined lead to delays of up to 2 months in reporting of results. It is becoming increasingly clear that a rising viral load on therapy must be attended to without delay. Some clinicians even advise stopping all therapy while alternative combinations are being considered, rather than risk the accumulation of mutations which may lead to wide cross-class resistance and inevitable subsequent therapeutic failure. Although they are still imperfect, we are beginning to obtain some of the tools to allow long-term management of HIV infection. However, ATP believes that a radical change of attitude is also necessary to allow these tools to work. We believe that a rising viral load on therapy should be considered as a medical emergency requiring prompt attention. We also believe that attempts should be made to individualise therapy to each patient where necessary through the use of blood drug level monitoring and HIV resistance assays. It is becoming increasingly clear that once initial therapy fails, any subsequent therapy is reduced in efficacy. All effort should be made to get it right first time, and to monitor constantly for failure.
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New data presented at the British HIV Association (BHIVA) conference in Warwick this
month add to the evidence that non-zidovudine containing combination regimens are valid choices for both initial and subsequent
therapy of HIV-infection.
Richard Pollard, MD, University of Texas, Galveston, presented the final results of
the BMS-460 study, in which levels of detectable virus in patients on d4T (stavudine) plus ddI (didanosine) were reduced by 93%
over an extended period of at least 52 weeks. the potency and durability of this combination compares favourably with current treatments, said Dr Pollard. The lack of viral resistance to d4T and ddI in combination may explain the sustained
decrease in viral load over time.
Commenting on the results of the double combination trial and further presentations
on d4T plus 3TC, Dr Ian Williams, University College Hospital, London, said These results are extremely encouraging. They clearly demonstrate the benefits of
d4T based combinations. HIV treating physicians should be considering the benefits of d4T based combinations whether patients are
antiretroviral therapy naive or they have already been treated with AZT.
Dr Graeme Moyle, Senior Research Fellow, Kobler Clinic, Chelsea and Westminster Hospital,
London, commented, The results of these trials, in conjunction with increasing emergence of AZT-resistant
disease and the low levels of resistance seen with d4T, mean that serious consideration must be given to the sequence of antiretroviral
therapies administered if patients are to receive sustained long-term benefits from therapy. The results suggest that
a d4T based combination should be considered as a first-line therapy in the treatment of HIV he concluded.
The d4T/ddI combination is currently entering a phase III trial to attempt to determine
the best dosage for the drugs. The pair of drugs will be tested by itself and as part of a three-drug combination with indinavir,
a protease inhibitor.
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See ATPs Doctor Fax Issue 16 for further data from Washington on d4T containing regimens.
Many patients are unable or unwilling to tolerate zidovudine (ZDV), or have HIV that may have become resistant to it. Furthermore,
it is estimated that 10-20% of all new HIV-infections may be with virus having pre-existent resistance to ZDV. These factors, along with reports of increased pathogenicity of ZDV resistant HIV has led to much consideration of its displacement from combination therapy, particularly in first-line treatment. The major factor that is shoring up ZDVs position is Glaxo Wellcomes other HIV treatment 3TC. Until recently, nearly all research on 3TC has involved the incestuous combination ZDV/3TC, a combination that has been touted as having a special magic. One of the main arguments for this magic was the in vitro indication that the mutation at codon 184 of the reverse transcriptase gene, a single point mutation which confers high level resistance to 3TC, counteracts the mutations giving rise to ZDV resistance. In short, HIV supposedly cannot be resistant to both drugs at once, and adding 3TC to the regimen of someone failing on ZDV might return that drug to effectiveness. This was proven false some time ago, although the appearance of resistance to the dual combination is delayed compared to monotherapy with ZDV. Still, ZDV/3TC appears to be the most used nucleoside analogue combination both as double nucleoside therapy and as the nucleoside component of triple combination protease inhibitor containing regimes. Others have argued that the 184 mutation conferred by 3TC acts to increase fidelity of the reverse transcriptase site, and will delay resistance to any concurrent reverse transcriptase inhibitors, not just ZDV. A further voice insists that the real value of 3TC lies in the fact that it is the most potent of all the currently available nucleoside analogues and that this potency should be exploited in viral suppression rather than in strategies allowing mutation to arise (ie. incompletely suppressive double nucleoside analogue combinations). A strategy to prevent 3TC resistance arising would therefore employ 3TC only in maximally suppressive regimens where minimal viral turnover would make mutation unlikely. Accumulating data on non-ZDV containing combinations, the ability of d4T to penetrate the CNS, and the adverse effects of harbouring ZDV -resistant HIV are encouraging clinicians to consider the alternatives. |
Glaxo Wellcome has announced that their drug 3TC (lamivudine, Epivir) has been shown
to be effective against hepatitis B infection.
In a clinical trial involving 358 Asian patients with chronic hepatitis B in Hong
Kong, Singapore and Taiwan, "results indicate that over a one-year period, improvements in liver histology were demonstrated in
a significantly higher percentage of lamivudine patients compared to a placebo." According to executive vice president Gervais Dionne
of Biochem Pharma, developer of 3TC, "Today's results...support lamivudine's potential as a powerful new antiviral therapy
for the treatment of chronic hepatitis B infection."
These results follow on from studies reported in ATPs DocFax Issue 11 showing positive effects of lamivudine on hepatitis B in patients
coinfected with HIV.
3TC has recently gained traditional regulatory clearance in the US for use in HIV-infection
on the strength of clinical end-point data from the CAESAR study. It had previously been licensed through the FDAs accelerated approval process.
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Whilst some doctors may choose to use 3TC in persons co-infected with HIV and Hep.
B, this may not represent the ideal approach to managing either disease. Referral to specialist Hep B clinics is encouraged. 3TC
has no activity against Hepatitis C. |
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OPPORTUNISTIC ILLNESS
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PATHOGENESIS
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Despite our immune response to HIV being to a large extent focused on the viral envelope,
and vaccine approaches often using gp41 or gp120, successful control of HIV through the initial immune response is gradually
lost over time, probably due to mutation at these sites. The challenge to basic science is to establish the conserved areas
of the envelope structure to enable targeting of drugs or immune responses to these regions. The above discovery is a promising
development. |
The much-celebrated advances made last year in understanding how HIV enters cells
have led to the discovery of what may be a new way to thwart the virus. In the journal Science, researchers describe a molecule,
modified from a naturally occurring immune messenger, that seems exceptionally capable of preventing HIV from entering uninfected
cells--at least in the test tube.
The work builds on a flood of findings published last year that linked HIV and chemokines,
the family of inflammation-promoting chemicals to which the new molecule, called AOP-RANTES, belongs. Researchers have
known for more than a decade that HIV enters white blood cells using a receptor found on their surface known as CD4, but it appeared
to need some other coreceptor, too. Last year, the missing player turned out to be the cell-surface molecules that normally
serve as receptors for chemokines. Since then, many researchers have begun exploring ways to prevent HIV infection by blocking
chemokine receptors.
While some AIDS researchers believe that injections of chemokines themselves may safely
block HIV infection, others worry that such treatments might cause severe inflammation. To get around this possible side effect,
a team of researchers from the Chester Beatty Laboratories in London, the Geneva division of drugmaker Glaxo Wellcome, and
the Laboratory for Molecular Pharmacology in Copenhagen have modified the chemokine RANTES so that it can bind to the receptor
without triggering an inflammatory response.
The new molecule appears to have much more potent anti-HIV powers than does RANTES--which
itself has the most potent anti-HIV affects of any natural chemokine--by tying up more receptors. "This particular compound
is a stronger inhibitor than anything [similar] shown so far," says Robin Weiss, who heads the lab at Chester Beatty in which
several of the paper's co-authors work. What's more, AOP-RANTES works both in immune cells known as T cells and in macrophages,
whereas RANTES only works in T cells.
Experts in the field are reacting with guarded optimism. "What they found may well
be a pretty good drug--if they can keep levels high enough in the body for 24 hours a day, 7 days a week," says chemokine researcher
Craig Gerard of Harvard University. That, of course, has proven to be an insurmountable "if" for many other promising compounds.
Source: ScienceNow
A pathogenic simian immunodeficiency virus (SIV) infects cells via the same coreceptor
as macrophage-tropic strains of HIV-1.
The finding suggests that HIV infectivity may depend on an extraordinarily well-conserved
region of HIV. If so, the virus would likely be very limited in its ability to develop resistance to future drugs or vaccines
exploiting this region.
"Human and simian CCR5 molecules are very closely related, with only four amino-acid
differences in the extracellular sequences of these proteins," reported Harvard researcher Luisa Marcon and colleagues. "Both
can serve as entry cofactors for HIV-1 and SIV." Marcon et al. published their findings in the Journal of Virology.
When either human or simian CCR5 was expressed by CD4+ cells, the cells were susceptible
to virus entry and syncytium formation mediated by SIVmac239. SIVmac239 causes AIDS-like illness in Old World monkeys.
If there is indeed a well-conserved structure in the binding portion of the HIV envelope,
it must be well hidden: genetic analysis show this to be one of the most variable parts of the virus. Indeed, this region
is known as the V3 loop, with the "V" standing for "variable."
"Conserved structures in the V3 loop that are not apparent from direct examination
of the primary amino acid sequence might interact with CCR5," Marcon et al. suggested. "It is also theoretically possible that
completely different HIV-1 and SIVmac envelope glycoprotein regions mediate the interaction with CCR5.
Ref: J Virol, 1997;71(3):2522-7).
Source: Aegis
A UK/US research team has shown that the ability of cell-culture-adapted feline immunodeficiency
virus (FIV) to infect and fuse with human cells is based on its use of the CXCR4 coreceptor.
"We believe that this is the first evidence of shared chemokine receptor use between
primate and non-primate lentiviruses," wrote University of Glasgow researchers Brian J. Willett and colleagues in a letter to
the journal Nature.
T-cell-tropic strains of HIV-1 require the CXCR4 coreceptor to enter cells. The link
between the two distantly related lentiviruses suggests that the ability to use chemokine receptors for cell entry is a basic,
and perhaps necessary, feature of HIV disease.
"It seems that the chemokine receptor may be a common link between FIV and the primate
lentiviruses and a key determinant of the pathogenesis of AIDS," Willett et al. concluded.
The corresponding author for this study is Brian J. Willett, Department of Veterinary
Pathology, University of Glasgow, Glasgow G61 1QH, United Kingdom. Email: bwillett@vet.gla.ac.uk.
Ref: Nature, 1997;385:587
Source: Aegis
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As with the research outlined above on RANTES, this work on co-receptors highlights
that basic research is a vital necessity in the search for mechanisms to control viral pathogenesis.
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Abstract: To address the possible role of replicative senescence in human immunodeficiency
virus (HIV) infection, telomere length, telomerase activity, and in vitro replicative capacity were assessed in peripheral
blood T cells from HIV+ and HIV- donors. Genetic and age-specific effects on these parameters were controlled by studying HIV-discordant
pairs of monozygotic twins. Telomere terminal restriction fragment (TRF) lengths from CD4+ T cells of HIV+ donors were
significantly greater than those from HIV- twins. In contrast, telomere lengths in CD8+ T cells from HIV+ donors were shorter
than in HIV- donors. The in vitro replicative capacity of CD4+ cells from HIV+ donors was equivalent to that of HIV- donors in
response to stimulation through T cell receptor CD3 and CD28. Little or no telomerase activity was detected in freshly isolated
CD4+ or CD8+ lymphocytes from HIV+ or HIV- donors, but was induced by in vitro stimulation of both HIV+ and HIV- donor cells. These
results suggest that HIV infection is associated with alterations in the population dynamics of both CD4+ and CD8+ T cells,
but fail to provide evidence for clonal exhaustion or replicative senescence as a mechanism underlying the decline in CD4+ T cells
of HIV-infected donors.
Ref: Journal of Experimental Medicine, April 7, 1997, 185(7):1381-1386
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Several lines of experimental evidence, including the mathematical models of Dr David
Ho, have suggested that there is increased destruction of CD4+ T cells in HIV infection, and that there is an increased production
rate of CD4+ T cells in HIV-infected individuals, possibly in response to this increased destruction. |
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DRUGS IN DEVELOPMENT
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It is reassuring for clinicians and patients embarking on therapy that new, potentially
active drugs are in development. More data on PMPA is now required to understand its potential. In vitro models of resistance
do not always predict in vivo realities.
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VIRAL ASSAYS
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A new assay permits physicians to rapidly determine whether a patient's HIV strain
is of a genetic type likely to be resistant to particular anti-HIV drugs. The genotypic assay, dubbed HIV-1 GenotypR Plus, is
manufactured by Specialty Laboratories Inc., Santa Monica, California.
It was less than three months ago that a leading AIDS researcher expressed the hope
that such a test would be available within a few years.
"I think the future of antiretroviral therapy will certainly be improved with a phenotypic
or genotypic assay," University of California, San Diego researcher Douglas D. Richman said in a state-of-the-art presentation
on HIV resistance to the 1997 Retrovirus conference.
"I'm more convinced that the genotypic assays will be more useful for reverse-transcriptase
inhibitors than protease inhibitors," Richman added. "But no well validated, reasonably constant assays are available
for clinical management today. Hopefully they will be available in next few years."
The assay uses polymerase chain reaction (PCR) technology and automated DNA sequencing
to determine the genotype of HIV-1 in patient blood samples. Viral genotypes are then evaluated for the presence of mutations
associated with resistance to anti-HIV drugs. Genotypic assays previously have been available only to researchers. Blood samples
must be sent to Specialty Laboratories for testing. Results can be expected in two to three weeks. The cost of the test is
$400. Targeting of drugs through the use of phenotypic or genotypic assays may give cost benefits.
Physicians may use such assays prior to beginning antiretroviral therapy, in order
to determine whether the patient's virus is already resistant to antiretroviral drugs. For example, it is estimated that ZDV-
resistant strains are responsible for 10 to 15 percent of new HIV infections in the U.S.
Researchers speaking at the 1997 Retrovirus conference also addressed the need to
tailor anti-HIV therapy to individual patients.
Ann Collier of the University of Washington, Seattle, suggested that given the great
interpatient differences in HIV disease, there may never be a single standard drug regimen. "We need to get better at individualising
our treatments," she said. "Each patient is an individual and we now have sensitive measures of disease activity to help
us. That said, we're all aware that the number of combinations which could be used will only increase as new drugs are added
to our armamentarium."
Collier said that if it turns out that HIV must be treated with lifelong suppressive
therapy, treatment will have to be altered as needed to deal with drug-resistant HIV strains that might emerge.
More information on the test can be obtained from Specialty Laboratories, 2211 Michigan
Avenue, Santa Monica, California 90404-3900. Telephone: (800) 421-7110. Website: http://www.specialtylabs.com.
Source: Aegis
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Genotypic assays must be interpreted within their limitations and in the context of
other markers. Limitations include: Compartmentalisation (eg. HIV in plasma resistant, in CNS sensitive), failure despite sensitive
virus (eg. through drug interactions or cellular resistance), overcoming resistance with higher concentrations of drug (eg.
by adding ritonavir to saquinavir), novel mutation patterns, reversal or dual resistance (eg. ZDV + 3TC), possible non-progression
in the face of mutation (eg. the mutated virus has reduced pathogenicity). A cheaper (could be around 75) PCR based probe - the line probe assay for HIV-1 RT mutations is due to be launched
mid-year. |
Quantification of viral load in patients infected with Non clade B HIV-1 viruses seems
to be much more accurate when using the bDNA assay. It should also be used in any situation where viral load results do not
seem to match the clinical picture.
Following the satellite meeting at the recent BHIVA conference it was thought useful
to alert clinicians to hospitals who are currently in a position to carry out the Chiron assay. These are: