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ANTIVIRALS
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Bristol-Myers today announced that stavudine, also known as d4T, received approval
by the European Union for use in combination therapy in the first-line treatment of HIV.
Stavudine is a thymidine analogue and member of the nucleoside analogue class of reverse
transcriptase inhibitors.
The licensing decision was based on recent data from clinical trials using stavudine
in adults and children which demonstrate that combinations that include d4T can reduce viral load, often to undetectable levels,
and increase the level of CD4 cells. Both are proven markers of disease improvement.
Stavudine has been available in the U.S. since June 1994 and in Europe since May 1996.
In the U.S., it is indicated for the treatment of HIV-infected patients who have received prolonged prior AZT (zidovudine)
therapy. The most notable clinical toxicity of stavudine is peripheral neuropathy, which usually resolves if treatment is withdrawn.
Resumption of treatment may be considered at a reduced dose.
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Comments? d4T already being used first line with many treatment specialists preferring
it to ZDV as the thymidine analogue component of combination therapy. Add Washington and after data on d4T/3TC and d4T/ddI |
Gerd Faetkenheuer, Albert Theisen, Juergen Rockstroh et al
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COMMENTS: Was the PI added or used in a newly initiated naive combination. Possible mechanisms of drug failure:
This study could not look at compliance as a factor in failure due to the nature of the retrospective data. Genotypic resistance to antiretroviral drugs is often assumed to be the key to failure of therapy. This resistance may be fostered by poor compliance, inadequate intracellular drug levels or suboptimal suppression of viral replication in presence of drug. However, in a study presented at the St. Petersburg resistance meeting by Mayers (abstract 80), more than 50% of patients failing combination drug regimens containing a protease inhibitor have no genotypic evidence of protease resistance. Intracellular drug levels were found to be a major determinate of treatment response in a study presented at Washington by Fletcher (abstract 13). Intracellular levels of triphosphate anabolites (the active metabolite) of nucleoside analogues were found to be a more precise determinant of anti-HIV effect rather than plasma concentrations of parent drug. Concentration controlled (titrated to intracellular levels) administration of zidovudine was associated with a better treatment response in CD4 count and viral load than standard dosing. These and other studies point to the clear need for closer investigation of treatment failure and the inclusion of drug level assays and individual titration of dose in poor responders BEFORE the onset of genotypic resistance. |
The risk of antiviral drug resistance is lessened in HIV-positive patients by using
combination therapy rather than sequential therapy, Dr. Joel E. Gallant of Johns Hopkins told the 15th annual symposium of the
Gay and Lesbian Medical Association.
"Confusing these two is one of the most common treatment mistakes," Dr. Gallant said.
Adding new drugs progressively may give temporary benefit, but the Maryland clinician warned that use of sequential therapy
can result in broad resistance to a number of agents.
"The single most important decision is the first drug regimen. Nothing else works
as well," he advised meeting attendees. Since compliance and side effects vary, the regimen must be individualised, according to
Dr. Gallant. He cited the example of a person who is not meticulous about a drug schedule. That patient should not be prescribed
indinavir, he said.
The definition of treatment failure varies, D. Gallant noted. The treatment goal for
a patient on a protease inhibitor should be maximal suppression of viral replication. Incomplete suppression might cause resistance,
Dr. Gallant warned. He also noted that if 3TC is not used in a highly suppressive combination, resistance can develop within
two weeks.
Source: Aegis
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COMMENTS?
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COMMENTS?
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AIDS investigators in Lyon, France, previously reported that the combination of didanosine
(ddI) and hydroxycarbamide (hydroxyurea) reduced and maintained HIV-1 viral load below detectable levels in a group of
patients in the very early stages of infection. They now report that there appears to be no viral rebound following cessation of
treatment.
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COMMENTS: Although limited to two patients this report is the first to show an absence
of viral rebound after the suspension of antiretroviral therapy. Could HIV have been eradicated from these two individuals?
Sustained inhibition of HIV after the withdrawal of hydroxyurea and ddI in vitro has been reported previously. Both patients in
this study were treated within one year of primary infection with HIV and both had unusually low plasma viral load prior to treatment
(676 and 1120 copies/mL) making them unusual amongst HIV-infected individuals. Even so, the undetectability of both infectious
virus and HIV-1 RNA in both PBMC and lymph node after one year off treatment is intriguing. In chronic infection, the combination of hydroxyurea with ddI or ddI + d4T has been less spectacular. The addition of hydroxyurea to these drugs appears to enhance antiviral effect but can dampen CD4 responses probably due to its myelosuppresive effects. In a study presented at Washington (abstract 550) in moderately immunosuppresed mainly treatment naive patients ddI/d4T/hydroxyurea reduced viraemia below 200 copies/mL in 55% of study subjects at 12 weeks. The mechanism of action of hydroxyurea is thought to be cellular. Hydroxyurea lowers the levels of the cellular competitor of ddI (dATP) thus favouring the incorporation of ddI. Although the combination of ddI and hydroxyurea is unable to prevent the emergence of mutants conferring resistance to ddI the resistant virus remains sensitive to ddI in the presence of hydroxyurea. |
European HIV/AIDS experts attending The First International Symposium on Compliance
with HIV Therapy heard that compliance has fast become one of the most critical issues for people living with HIV/AIDS - one that
can mean the difference between treatment success and failure.
Combination HIV therapy has improved quality of life allowing return to work or overseas
travel. In these circumstances the drugs can present new issues, such as adhering to complex regimens.
Many people on aggressive anti-HIV therapy face a daily pill count of 30 or more.
Keeping track of which to take, when and how to take them can lead to confusion. Even occasional missed doses, or doses that are
diminished by interactions with food or other drugs, may affect the amount of drug in the body allowing HIV to mutate, and drug-resistant
strains to develop. To optimise long-term success treatment must be potent, continuous and uninterrupted, say the
European AIDS Treatment Group (EATG), organisers of
the Rotterdam meeting.
EATG is a network of AIDS treatment activists representing 17 countries. "Our initial
goal at this conference is to assess the issues relating to patient difficulties in adhering to current AIDS therapies," said
executive director Arjen Broekhuizen. "More importantly, we hope to pool the experience and knowledge of experts from all over
the world to propose practical solutions to real-life situations and develop an international standard of care for HIV infection."
At the conference, EATG launched "Moments of Decision: HIV Treatments in Everyday
Life" the first educational video to explain why compliance is important and how to achieve it. The English-language video will
also be available in Spanish, Italian and French.
Broekhuizen told Reuters Medical News that the EATG will use information gathered
at the conference to draft guidelines for new clinical trials so that compliance issues are addressed in new drug protocols.
"Practical guides will also be developed to enhance compliance in current situations.
For example, some protease inhibitors now have the most difficult regimens, so in some cases physicians are recommending the
use of vitamins, to test whether a patient can observe a particular drug's dosing schedule for a couple of weeks. This means
they do not use the drug until they know they can adhere to its schedule," he said.
At the conference, sub-optimal HIV therapy was reported from some regions of Southern
Europe. Ms Lital Hollander, EATG Italy, presented results from a survey of 1300 Italian AIDS patients. One in five were still
receiving monotherapy with a reverse transcriptase inhibitor, 8% monotherapy with a protease inhibitor. More than half were not
aware of their current viral load status. (For sustained viral control, most AIDS specialists recommend combination therapy
regimes plus regular viral load testing as part of routine monitoring).
Source: EATG
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COMMENTS: The educational video on compliance Moments of Decision is available from: EATG, Borsigstrasse 39, D-40227, Dusseldorf, Germany. Tel
& Fax: +49 (0) 211/78 83 481. |
New research reported in the August issue of AIDS suggests that successful suppression
of HIV RNA load in blood is paralleled by a reduction of vital load in semen. Researchers, led by Pietro L. Vernazza of the
Institut for Clinical Microbiology in Switzerland, examined 44 HIV-positive men enrolled in various antiretroviral protocols.
They found that "more pronounced reductions of HIV RNA in semen were observed as the effectiveness of treatment on blood HIV RNA
levels increased." Based on their research, the scientists concluded that "effective antiretroviral treatment can be expected
to have a beneficial impact on the spread of the epidemic."
Source: AIDS Daily Summaries
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PATHOGENESIS
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Researchers have identified a second gene mutation that helps explain why some people
tend to remain healthy long after they've become infected with HIV.
The mutation occurs in the gene that directs construction of the CCR2 receptor on
the surface of human cells. The receptor is one of several molecular "docking bays" that the human immunodeficiency virus (HIV )
uses to enter a cell. Although the CCR2 mutation doesn't reduce a person's chance of acquiring HIV , once infection occurs it somehow
slows the progress of disease. How it does that is currently unknown.
A mutation in a similar receptor, called CCR5, was described a year ago. That one,
however, was found only in whites. The new mutation appears to be carried by 10 percent to 20 percent of people in all ethnic groups.
The researchers attempted to identify chemokine receptor genes, in addition to CCR5
and CXCR4, that play a role in HIV-1 progression. They note that CCR2-641, a mutation within the first transmembrane region of
the CCR2 chemokine and HIV-1 receptor gene, took place at an allele frequency of 10 percent to 15 percent among white and African
American individuals. Genetic association analysis indicated that while CCR2-641 had no effect on the incidence of HIV-1 infection,
persons with HIV who carried the allele developed AIDS two to four years later than persons homozygous for the common allele.
The survival of nearly 30 percent of long-time survivors can be attributed to a mutant CCR2 or CCR5 genotype, the researchers
estimated.
Ref: Science (15/08/97) Vol. 277, No. 5328, P. 959;
Source: AIDS Daily Summaries
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The decline in T cells seen as HIV infection progresses may be caused in part by a diminished capacity of peripheral blood to generate T cells, probably because of reduced numbers of functional precursors.
Dr Domimick DeLuca of the University of Arizona in Tucson and colleagues investigated
the effect of HIV-1 infection on the T cell generating capacity of precursors. "With the models of T cell development and HIV-1
infection utilising human thymic tissue to support T cell differentiation, it has been difficult to distinguish the effects
of HIV-1 infection on T cell precursors from the effect on thymic stroma," Dr. DeLuca explains in the September issue of the Journal
of Infectious Diseases. To overcome this problem, the researchers developed a xenogeneic in vitro organ culture system using
foetal thymus lobes of SCID mice, since HIV does not infect murine stromal cells.
Dr. DeLuca's team noted that, when placed in this culture system, peripheral blood
from HIV-1 infected subjects "...consistently produced fewer CD4 and CD8 cells compared with blood from controls." Further experiments
suggested that "...there were fewer functional precursors in the infected patients."
The investigators also found that the results were not associated with the subjects'
levels of peripheral CD4 cells and "...even samples from patients with normal CD4 cell counts were unable to generate T cells
in organ cultures."
The findings "... are consistent with a loss in the capacity of HIV-infected patients
to produce functional T cell progenitors in their peripheral blood." Based on these findings, they also believe that "...future
therapeutic regimens for HIV-1 infection must include therapies designed to be used before T cell progenitors are affected."
Ref: JID 1997;176:649-654.
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COMMENTS? This work supports that of Miedema and colleagues whose analysis of telomere
length shows a normal replicative history of CD4 lymphocytes in chronically HIV infected individuals (see DocFax Issue 13 &
21). In their model T-cell depletion is thought to be due to insufficient formation of new cells. This theory is opposed to the
model used by Ho where massive replication and clonal exhaustion is thought to be responsible for T-cell declines. |
In the August 23 issue of the Lancet, Dr. Claus Bohn Christiansen of the Statens Serum
Institut in Denmark and colleagues describe a case in which an individual infected with both HIV-1 and HIV-2 can transmit both
viruses or only one via sexual contact. Specifically, the group reports on two women--one of whom tested positive for both
HIV-1 and HIV-2, while the other tested positive for HIV-2--who had sexual contact with the same man, who was later found to be
infected with both viruses. The HIV-2-infected woman reported having had a single sexual episode with the man, while the woman
with both viruses reported several episodes. The researchers, who analysed serological data from all three individuals using direct
sequencing of the V3 region of both strains of HIV and performed PCR assays on both women, concluded that both female subjects
"were homozygous for the wild-type CCR-5 allele."
Source: AIDS Daily Summaries
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OPPORTUNISTIC ILLNESS
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Glucocorticoids increased the nerve-cell toxicity of an HIV protein in laboratory
studies, while oestrogen decreased the effect. If the results are the same in humans with AIDS, the findings may have far-reaching
clinical implications.
"One of the most serious complications of HIV infection is the frequent cases of Pneumocystis
carinii pneumonia [PCP], and the current treatment of choice for serious cases involves administration of megadoses
of synthetic glucocorticoids (GCs) such as those used in [our] study," wrote Stanford University researchers S. Brooke and colleagues.
Brooke et al. reported their findings in the Proceedings of the National Academy of
Sciences ("Endocrine Modulation of the Neurotoxicity of gp120: Implications for AIDS-Related Dementia Complex," PNAS, 1997;94:9457-62).
Some 20 percent of people with AIDS develop AIDS dementia complex (ADC), a wide range
of neurologic and neuropsychologic impairments apparently related to pathologic changes in the cortical and subcortical regions
of the brain. Both in vitro and in vivo studies show that HIV envelope glycoprotein gp120 damages neurons and glial cells.
HIV gp120 neurotoxicity involves a complicated cascade of events that apparently causes the release of a hypothetical, excitatory
amino acid that leads to overactivation of glutamate receptors and mobilisation of dangerous amounts of calcium.
Steroids also stimulate worsening calcium-dependent neurodegenerative events, while
oestrogens decrease glutamate- induced calcium mobilisation.
Putting these observations together, Brooke et al. explored the interactions of gp120,
GCs, and oestradiol (the most important naturally-occurring oestrogen) in cultures of primary hippocampal and cortical tissues
from foetal rats.
"We observe that gp120-induced calcium mobilisation and neurotoxicity are exacerbated
by glucocorticoids, the adrenal steroids secreted during stress," Brooke et al. found.
"Conversely, we also observe that oestradiol protects neurons from the deleterious
actions of gp120, reducing toxicity and calcium mobilisation."
If these findings hold true for humans, they would imply that HIV(+) men would have
a higher rate or degree of ADC than HIV(+) women. Moreover, they would suggest that oestrogen could be used to treat or prevent
ADC. Brooke et al. noted that ongoing clinical trials are testing the ability of oestrogen to protect against late-onset Alzheimer
disease.
On a more negative note, the findings would also mean that the use of large doses
of GCs to treat PCP could worsen or even cause ADC.
"Although the number of severe cases of P. carinii pneumonia is declining, best estimates
are that thousands of individuals are still treated annually in this megadose range (e.g., 160 mg of methylprednisolone
per day for seven days)," Brooke et al. observed. "The present findings suggest that ... exposure to elevated GC concentrations
might have adverse consequences; this possibility remains to be tested in a clinical setting."
Ref: PNAS, 1997;94:9457-62
Source: AIDS Weekly
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EPIDEMIOLOGY
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AIDS researchers in Italy say AIDS is having an "important" impact on premature mortality
in men and women, especially those between 25 and 44 years of age. AIDS is now the number one cause of death in this age
group.
Dr. Susanna Conti and colleagues at the Instituto Superiore di Sanita in Rome analysed
trends in early death from a variety of causes using data from the Italian Mortality Data Base for the years 1984 to 1993,
roughly the first 10 years of the AIDS epidemic.
They observed a "...marked increase..." in premature death due to AIDS during this
10-year period among both men and women. "Throughout the same period all the other causes of premature death have been declining,
with the exception of suicide and overdose among males, and overdose and lung cancer among females," the investigators report.
Currently, the northern and central parts of the country have the highest incidence
and mortality rates due to AIDS.
Ref: Int J Epidemiol 1997;26:873-878.
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CORRESPONDENCE
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Reply
: Although no reference to AIDS dementia complex (ADC) was made in the above mentioned article it is correct to point out that CNS penetration of an antiretroviral may not predict its utility in ADC. The statement on the CNS penetration of d4T was primarily based on data presented at Washington this year (abstract LB5). Mean absolute ZDV, d4T and 3TC concentrations achieved with standard dosing regimens in this study were 41 ng/mL, 56 ng/mL and 67 ng/mL respectively. Mean reduction in CSF HIV-RNA were similar for the combinations of ZDV/3TC and d4T/3TC. The pathogenesis of ADC remains unclear with a further study at Washington (abstract 141) demonstrating an absence of correlation between HIV RNA levels in CSF and dementia that suggests that AIDS dementia is not directly related to the extent of brain infection. CSF HIV-RNA levels reflect plasma HIV-RNA levels and antiretroviral treatment sees a change mirrored in both compartments. This effect may be independent of CNS penetration of antiretroviral agents suggesting either a blood-brain transfer of virus or a synchronisation of viral replication in lymphoid tissue and brain. A further study presented at St Petersburg (abstract 102) also failed to find any correlation between CSF HIV-1 viral load and presence of CNS disease including encephalopathy.. Interestingly the authors found a high correlation between CSF viral load and CSF white cell counts which indicated the possibility that CNS HIV is brain derived but synchronised with lymphoid tissue replication. Further suggested mechanisms of ADC involve the effect of gp-120, gp-41, nitric oxide TNF-alpha, and Tat on the CNS. Hints at the pathophysiology of ADC may be derived from studies such as those outlined above and biological plausibility would suggest that any treatment which lowers CSF HIV-RNA should protect against or treat HIV-related CNS disease. However, as Prof. Brew quite rightly states the efficacy of d4T in ADC is unknown and we look forward to the results of his groups multicentre study. |