ANTIVIRALS
|
Glaxo Wellcome, makers of the experimental antiretroviral 1592U89 (also known as abacavir),
are warning doctors about the dangers of restarting treatment in patients who have reacted badly to the drug in the past.
According to data collected to date, about 3% of patients on 1592 experience a systemic hypersensitivity reaction to the drug
when it is first taken. These side effects tend to clear within days of stopping the drug. However, according to research recently
published in AIDS Treatment News, this reaction may become severe and potentially fatal in patients who begin the drug a second
time. Such patients risk high fever, severe nausea, vomiting, rash and dangerously low blood pressure.
1592 (Abacavir): Do Not Rechallenge After Hypersensitivity Reaction
In the experience to date with the experimental antiretroviral abacavir (1592U89),
about 3% of patients have developed a systemic hypersensitivity reaction. Initially this reaction is usually not severe and will
go away by itself within a couple of days on stopping the drug. But if it does occur, the patient must not try the drug again;
if they do, a serious and potentially life-threatening condition can develop within hours.
The initial reaction usually begins from a few days to four weeks after starting abacavir.
At first there is low-grade fever, nausea (with or without vomiting), and malaise (not feeling well, as with the flu);
these symptoms build up over a few days. There is usually a rash, although sometimes it is not noticed by the patient. As soon as
the fever and flu-like symptoms occur, the drug must be stopped, or the symptoms will become increasingly severe. After discontinuation
the symptoms will disappear rapidly, and there seems to be no further problem, as long as the patient never tries the
drug again. But when abacavir has been tried again, high fever, severe nausea and vomiting, and rash (not severe) have developed
within hours. In four of these cases there was life- threatening low blood pressure. These patients were hospitalised with intensive
care. No deaths have occurred.
Ref: AIDS TREATMENT NEWS Issue #285, December 19, 1997
Glaxo has now confirmed that FOUR patients have had dangerous drops in blood pressure
requiring hospitalisation, intravenous fluid support and dobutamine or dopamine (drugs given intravenously to increase blood
pressure). These severe reactions occur upon rechallenge (taking the drug again after the initial allergic reaction). The initial
allergic reaction is described, above. The allergic reaction when rechallenged is much worse with fevers approaching 40 oC, elevated liver function tests and decreased lymphocytes. THEREFORE, IT IS IMPORTANT
NOT TO TAKE ANOTHER DOSE OF THIS DRUG IF YOU EXPERIENCE THE INITIAL MILD ALLERGIC REACTION BEFORE CONSULTING YOUR DOCTOR. |
To determine the value of using changes in both viral load and CD4 cell counts to
assess the prognosis of people with HIV, a multicentre team from the University of Alabama in Birmingham--led by Dr. Michael Saag--evaluated
data for 1,330 HIV-positive people participating in seven antiretroviral therapy trials. The researchers--who reported
their findings in the January issue of the Journal of Infectious Diseases--discovered that the risk of clinical disease progression
falls in proportion to drops in HIV-1 RNA levels during the first six months of treatment, but it rises with a lack of HIV
RNA or CD4 response*. Based upon a comparison against subjects with a non-syncytium-inducing phenotype, the researchers found
that patients with the syncytium-inducing phenotype had a 100 percent higher risk of disease progression--a finding the researchers
say may suggest that viral phenotype is independent of patient prognosis. The team concluded that both HIV-1 RNA and CD4 lymphocyte
treatment responses and pretherapy levels should be used to measure patient prognosis after the initiation of antiretroviral
therapy.
Source: CDC NCHSTP Daily News Update
*Note: To be precise, risk does not rise with a lack of response - all reductions in VL reduce risk relative to no treatment - the greater the response the more the benefit, the more sustained the response the more the benefit (precluding drug toxicitys). |
Widely employed antiretroviral combination therapies appear to have no beneficial
effect on the course of HCV-induced chronic liver disease in HIV-infected asymptomatic patients. In contrast, treatment seems to
initially increase HCV replication and liver damage and can decompensate liver function. However, discontinuation of therapy seems
to be warranted in only a minority of patients with severe chronic hepatitis, because continuing treatment is associated with
a subsequent, slow, progressive reduction in HCV RNA and aminotransferase concentrations towards pre-treatment levels.
Ref: Vento S, Garofano T, Renzini C, Casali F, Ferraro T, Concia E. Enhancement of
hepatitis C virus replication and liver damage in HIV-coinfected patients on antiretroviral combination therapy. AIDS 12(1):116-117
(Jan 1998).
As more people use protease inhibitors, the range of side effects associated with
these drugs increases. In addition to changes in triglyceride, cholesterol and blood sugar levels, the use of protease inhibitors
has recently been associated with changes in body shape. Increased fat around the abdomen, commonly called 'Crix belly', and reduced
muscles on the arms and legs are often noted by people who take protease inhibitors. As well, some women experience breast
enlargement. Although these changes resemble a condition called Cushing's syndrome, where high levels of the hormone cortisol
are produced, people with Crix belly do not appear to have Cushing's syndrome. At this time, researchers are in fact not certain
about the exact cause(s) of the changes in body shape seen with the use of protease inhibitors. A severe case of breast enlargement,
which is detailed below, cleared when the patient stopped using indinavir (Crixivan).
Five months after beginning triple therapy with 3TC, d4T and indinavir, a 32-year-old
woman who had been infected with HIV for 10 years complained to her doctor about the increased size of her breasts. On examination,
the doctor found them to be swollen, red and painful. As the woman's breasts grew so did her abdomen, although her overall
body weight remained the same. Meanwhile, her thighs and buttocks became thinner. Her menstrual cycle was normal as were the
results of a mammogram and several hormone tests--prolactin and Beta-hCG [human chorionic gonadotropin]. Suspecting indinavir was
the cause of her problems, the women's doctors advised her to quit the drug while continuing to use 3TC and d4T. Two months later
her breasts had returned to their normal size and the skin was no longer red and painful. As well, the shape of her abdomen,
thighs and buttocks partly "returned to their initial shape."
Ref: Herry I, Bernard L, de Truchis P and Perrone C. Hypertrophy of the breasts in
a patient treated with indinavir. Clinical Infectious Diseases 1997;25:937-938.
Source: TreatmentUpdate83 - November 1997 CATIE
The addition of interferon-alpha-2a to the drug combination of zidovudine and zalcitabine
appears to be harmful over time, according to a study published in the December 1 issue of the Journal of Acquired Immune
Deficiency Syndromes and Human Retrovirology. Researchers for AIDS Clinical Trials Group Study 197 report that larger doses of
interferon produced substantially higher haematologic toxicity and peripheral neuropathy. The researchers did not notice a significant
difference in CD4 cell counts in any of the patients. They suggest, however, that intermediate doses of interferon or a
different dosing schedule might produce more lasting effects.
Source: CDC NCHSTP Daily News Update
An earlier trial (the Zidon trial, Fernandez-Cruz et al. AIDS 1995, 9:1025-1035) also
showed no benefit for IFN-alpha plus ZDV versus ZDV monotherapy in 402 patients after a median treatment period of 42 weeks.
It would therefore appear that IFN-alpha is not indicated in the treatment of HIV-infection itself. However, Interferon-alpha may
be used for the treatment of viral hepatitis or KS in patients with HIV receiving antiretroviral therapy. Responses to interferon
in persons with Hep B are poorer than in those without HIV-infection, but its use in low to moderate doses for the treatment
of KS and chronic hepatitis C appears to be safe and warranted in HIV patients with more than 200 CD4 cells/mm3. |
A group of U.K. and Irish researchers, led by David Back of the University of Liverpool,
recently found that the use of two protease inhibitors with two nucleoside analogues helps boost protease inhibitor bioavailability
to the therapeutic range among some patients. According to the study, published in the December issue of AIDS, the use
of nelfinavir raises the bioavailability of saquinavir by five times. In the study, that was conducted with six HIV-positive patients,
Black and his colleagues first provided a three-drug combination therapy, and then added nelfinavir three times daily for
two days. The team concluded that for some patients, the use of nelfinavir boosted the efficacy of the drug levels to the therapeutic
range. However, the variability among patients' baseline plasma saquinavir levels indicates that most effective dosing
should be individualised.
Source: CDC NCHSTP Daily News Update
This paper highlights the usefulness of drug level determinations of protease inhibitors
to optimise dosing in an attempt to prevent treatment failure due to subtherapeutic plasma levels. Because of variability
in p450 processing amongst individuals many physicians feel that drug level monitoring may be useful. |
A new protease inhibitor, currently in early clinical studies, is effective against
HIV strains resistant to ritonavir. The drug, code named PNU-140690, is a third-generation non-peptidic derivative of coumarin.
It is a sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrone.
In vitro studies show that PNU-140690 is equally effective against ritonavir-sensitive
and ritonavir-resistant strains of HIV-1. Moreover, the new drug has additive to moderately synergistic effects in combination
with ritonavir - even against ritonavir-resistant virus.
"These data suggest that PNU-140690 may be useful in combination regimens with a structurally
unrelated protease inhibitor such as ritonavir," wrote Upjohn researchers K.-T. Chong and P.J. Pagano in the journal
Antimicrobial Agents and Chemotherapy.
Ref: In Vitro Combination of PNU-140690, a Human Immunodeficiency Virus Type 1 Protease
Inhibitor, with Ritonavir against Ritonavir-Sensitive and -Resistant Clinical Isolates," Antimic Ag Chem, 1997;41(11):2367-73).
Source: AIDSWEEKLY Plus, Monday, December 15, 1997
Although promising, this data is only in vitro. If we look at in vitro constructs
we would assume that all RTV resistant viruses would remain fully sensitive to SQV, for instance. In vivo, however, with multiple
mutations and prolonged selection cross-resistance occurs to all available PIs. |
Dr. J.B. Marriott and colleagues from St. George's Medical School in London evaluated
10 HIV-positive men who received 100mg per day of thalidomide and nine HIV-positive men who received a placebo to determine
the effects of thalidomide on HIV infection. The researchers did not find any significant changes in CD4/CD8 count, tumour necrosis
factor (TNF)-alpha, TNFR1, or activation markers in the group treated with thalidomide, although the group did demonstrate
a low tolerance and a lack of systemic effects. The team also noted that fatigue--the primary cause of patient withdrawal--was
seen in both subject groups, suggesting a need for pharmacokinetic analysis to identify potential absorption problems. The researchers,
who reported their findings in the December issue of AIDS Research and Human Retroviruses, concluded that there is a need
for more research into the development of more potent and less toxic TNF-alpha inhibitors.
A separate study in the December issue of Antimicrobial Agents & Chemotherapy suggests
that single doses of thalidomide are well absorbed by patients infected with HIV. Researchers, led by Stephen C. Piscitelli
of the National Institutes of Health, found that doses of 100 mg and 300 mg were well absorbed and that the mean elimination half-life
was about six hours. Side effects associated with the drug were mild, with seven of nine subjects experiencing drowsiness,
said Piscitelli.
Source: CDC NCHSTP Daily News Update
Thalidomide appears useful for apthous ulceration and may help reduce secretory diarrhoeas eg. microsporidium. Its toxicitys include peripheral neuropathy therefore it should be used in HIV patients with caution.
|
PATHOGENESIS
|
The results of an analysis of HIV-1 variants in periphery, lymphoid and non-lymphoid
tissues indicate that the HIV-1 reservoir in AIDS patients may be limited, according to a multicentre team of investigators.
They believe the finding has "...important implications for the success of HIV-1 eradication." Their study is published in the January
issue of the Journal of Virology.
Dr. Hanneke Schuitemaker of The Netherlands Red Cross in Amsterdam and colleagues
evaluated HIV-1 quasispecies obtained from various organs and peripheral blood mononuclear cells of three HIV-positive patients
at autopsy. They were able to isolate syncytium-inducing and non-syncytium-inducing genotypes from various sites of the body including
brain, lung and testis, as well as lymphoid tissues.
Overall, excluding brain tissue, they found "...no evidence for the existence of true
tissue reservoirs that are installed early in infection and from which new variants are continuously generated." Instead, the
findings suggest that "...the presence of HIV-1 in most non-lymphoid tissue seems to be a late-stage event and secondary to lymphocyte
infiltration due to pathology." Dr. Schuitemaker's group concludes that "[t]he absence of a large tissue reservoir for
HIV-1 favours the possibility of completely eradicating HIV-1." However, they caution that a distinct virus reservoir in the brain
emphasises the importance of including drugs that have good bioavailability in brain tissue as a part of combination antiretroviral
regimens.
Ref: J Virol 1998;72:488-496.
Source: CDC NCHSTP Daily News Update
HIV apparently hijacks the immune system's signalling system and uses it to its own
ends. The culprit is the viral Vpr protein. Studies by University of Pennsylvania researchers Velpandi Ayyavoo, David B. Weiner,
and colleagues show that the protein acts like a glucocorticoid (GC) hormone to inhibit immune responses, to induce the programmed
cell death (apoptosis) of T cells, and to preserve antigen-stimulated T cells as long-lived "factories" for production of
new virus.
"These data suggest that Vpr may have a role in immune suppression and CD4 cell depletion
in HIV infected patients," Ayyavoo et al. wrote in the journal Nature Medicine. The HIV protein known as viral protein
R (Vpr) is the 96- amino acid, 15-kDa product of the HIV vpr gene. This gene and its sister HIV regulatory genes vif, vpu, and
nef are often referred to as auxiliary genes because they are not essential for HIV replication in established cell lines and because
their activities are poorly understood. But unlike the other auxiliary genes products, Vpr is carried by HIV virions. It
was once thought that Vpr was an accessory gene product with no important function. But recent studies have changed that perception.
Perhaps the most dramatic of these studies is the finding that a woman infected with
a vpr-defective HIV-1 mutant - and the child to whom she passed the infection - have remained disease free and asymptomatic for
13 years of follow-up (Wang et al., Virology, 1996;223:224-32).
Other studies have shown that extracellular Vpr makes cells more permissive to HIV
replication - even cells that normally permit only low-level production of the virus (Levy et al. J Virol, 1995;69(2):1243-52).
More recently, it was shown that Vpr permits HIV to infect promyelocytic cell lines via interactions with a GC receptor.
Because GCs have extensive immunosuppressive and apoptosis-influencing effects, Ayyavoo
and colleagues explored the ability of Vpr to mimic GC activity. They found that:
Vpr specifically blocks T-cell proliferation. This effect can be inhibited by the
antisteroid compound RU486.
Like GCs, Vpr suppresses production of the cytokines TNF- (alpha), IL-2, IL-4, IL-10,
and IL-12 but not IL-7. The most dramatic inhibition was with IL-2 and IL-12. "Vpr's inhibitory effect on cytokine production
could compromise the host immune response, particularly in cells that are not infected with HIV-1," Ayyavoo et al. suggested.
Like GCs, Vpr inhibits cellular NFkB (a transcription factor crucial for cytokine
regulation) by inducing transcription of the IkB (inhibitor of NFkB) gene.
Like GCs, Vpr induces apoptosis of T cells. Again this effect was inhibited by RU486.
But Vpr blocks apoptosis of antigen-stimulated T cells. "Infected cells that undergo antigen-specific activation could be
spared as targets for apoptosis, thus functioning as efficient, long-lived, and productive viral factories," Ayyavoo et al. wrote.
The researchers suggested that further studies will be needed to determine precisely
how the Vpr activities they identified elate to clinical HIV infection. They predicted that such studies will not only help
clarify HIV pathogenesis, but will also yield insights into general immune function.
Ref: HIV-1 Vpr Suppresses Immune Activation and Apoptosis through Regulation of Nuclear
Factor kB," Nature Med, 1997;3(10):1117- 23).
Source: AIDSWEEKLY Plus, Monday, December 15, 1997.
|
OBSTETRICS
|
Abstract:
Abstract:
Earlier studies from the US identified duration of labour, early membrane rupture
and maternal viral load as risk factors for vertical transmission. Across Europe a benefit for caesarian section has been reported
although in France alone no benefit has been observed. |
In North America, the rate of HIV transmission from mother to child during pregnancy
(vertical transmission) is estimated at 8%. In the developing world, this figure can soar as high as 30%. This difference is
largely explained by the widespread use in the developed world of zidovudine (ZDV) as a means to prevent HIV transmission during
pregnancy. Now, the results of a San Francisco-based program have revealed that combination therapy may reduce the risk of vertical
transmission even further still.
According to Dr. Karen Beckerman of the Bay Area Perinatal AIDS Center (BAPAC), none
of the HIV+ women participating in this program has given birth to an infected child during the past 2 1/2 years. Founded in
1989, the BAPAC program offers an array of services to pregnant women with HIV, including counselling and support, careful monitoring
and expert medical care, which, until last year, included ZDV monotherapy. In June 1996, however, program officials began
offering patients combination antiretroviral therapy based on updated recommendations for the care of HIV+ adults.
Of the 58 babies born over the last 2 1/2 years, none has tested positive for HIV,
nor has evidence of HIV infection been identified. Forty-three of the children have received at least 4 negative results during
the first 6 months of life. Nine others have tested negative twice by the end of 6 weeks and the final 6 received a negative test
result at birth. All the infants will be monitored until their second birthday. Dr. Beckerman attributes these results, at least
in large part, to the use of combination therapy.
If these results are promising for the children of HIV+ women, they may be less so
for the women themselves. For several of the BAPAC patients, the demands of new motherhood and a restrictive drug schedule have
not been easy to reconcile. As a result, some viral loads have begun to rise as compliance with treatment falters. The problem
of drug resistance, which may also be explained by poor compliance, has also become an issue for some women. The challenge for programs
such as BAPAC lies therefore in aiding HIV+ mothers to provide the best care possible for both their child and themselves.
Source: CATIE-News
Some UK physicians now feel that pregnant women should receive the same antiretroviral
therapy as non-pregnant adults - triple therapy. Indeed this is the recommendation in the latest US guidelines. A study is
now running at the Chelsea & Westminster Hospital, London with ZDV/3TC/saquinavir-SGC(Fortovase) to assess both safety and activity. |
In the January issue of The Journal of Infectious Diseases, US and Kenyan researchers
provide evidence to confirm that breast milk from HIV-infected mothers contributes to the vertical transmission of HIV-1. Specifically,
they found that "[t]he prevalence of cell-free HIV-1 was higher in mature milk (47%) than in colostrum (27%).
Breast milk has been suggested as an important source of vertical HIV transmission,
Dr. Paul Lewis of Oregon Health Sciences University in Portland and colleagues said. However, they believe that this is the first
study using a highly sensitive PCR assay for viral RNA to detect cell-free HIV-1 in breast milk.
Dr. Lewis' group analysed samples of breast milk from HIV-positive women in Nairobi.
"HIV-1 RNA was detected in 29 (39%) of 75 specimens tested." About half of the 29 specimens contained HIV-1 RNA levels near
the limit of detection, and 21% of the samples had more than 900 copies/mL. "The maximum concentration of HIV-1 RNA detected was
8,100 copies/mL."
Overall, ...the prevalence of HIV-1 RNA did not decrease as the milk supply matured."
Dr. Lewis' team concludes that transmission risk "...is likely to be related to the quantity of HIV-1 in cell-free breast milk
in addition to other factors, such as number of HIV-1-infected cells in breast milk, the presence of antiviral substances in
breast milk, and factors determining infant susceptibility."
Source: CDC NCHSTP Daily News
|
OPPORTUNISTIC ILLNESSES
|
Daunorubicin is a drug used to treat leukaemia. Recently it has been reformulated--the
drug has been packed into tiny balls of "fatty material" called liposomes. In its new liposomal form, daunorubicin is called
DaunoXome. Recently, the drug appeared to have activity in patients with less than 20 KS lesions. Although the drug clearly delays
the growth and spread of KS lesions by at least 90 days, it may reduce survival when compared to those patients with KS who
did not receive the drug. The Food and Drug Administration in the USA therefore recommends that DaunoXome not be used in people
who have "early" KS.
The study reported data on its use in "early" KS. By that term doctors meant people
with fewer than 20 lesions on their skin and none in their abdomen. Subjects were divided into 2 groups; the first group received
early treatment with DaunoXome and the second group initially received no treatment. This latter group was observed for 3 months
before being offered DaunoXome.
Researchers planned to enrol 40 subjects but stopped the study after 29 had entered.
Subjects who were given early treatment experienced a delay of at least 90 days before their lesions grew or spread. Those subjects
not given the drug usually had their lesions resume growth or spread after about 30 days.
Unfortunately, 50% of volunteers given early treatment lived for 359 days while for
those that "initially received no treatment" the figure was 586 days. As well, 50% of subjects given early treatment developed
life-threatening infections within 145 days. The equivalent figure for those who "initially received no treatment" was 371 days.
Because of the likelihood that DaunoXome could have had some "immunosuppressive" effects, it may be best to reserve the drug for
people with extensive KS lesions.
Ref: White RM. Liposomal daunorubicin is not recommended in patients with less than
advanced HIV-related Kaposi's sarcoma. AIDS 1997;11(11):1412-1413.
Source: TreatmentUpdate83 - November 1997. CATIE
Johan Neyts and Erik de Clercq of Belgium's Rega Institute report in the December
issue of Antimicrobial Agents and Chemotherapy that they have identified four agents with "marked anti-HHV-8 activity": cidofovir,
ganciclovir, foscarnet, and adefovir. The researchers also note that if HHV-8 can be blocked and is the aetiological factor in
Kaposi's syndrome--commonly seen in HIV-positive patients--and primary effusion lymphoma, the load of the virus may be kept too
low to cause HHV-8-related malignancies. Based on in vitro studies of the four agents, the researchers suggest that molecules
currently used as anti-HIV agents may be effective against HHV-8 and may offer useful information for prophylactic use among the
HIV-positive population that is at risk of HHV-8 infection.
Source: CDC NCHSTP Daily News
In the Dec. 13 edition of the Lancet, a report from Spanish researchers discusses
the appearance of a strain of multi-drug resistant (MDR) Mycobacterium bovis in advanced stages of HIV infection. The research team,
led by Antonio Guerrero of Madrid's Hospital Ramon y Cajal, studied nosocomial and primary tuberculosis among 19 HIV-positive
patients, with 33 HIV-positive patients serving as control subjects. The researchers found that among the 19 HIV-positive patients
infected with M. bovis, none survived the epidemic--despite receiving a median of eight drugs--because of M. bovis' resistance
to anti-TB drugs. The team concluded that an M. bovis MDR tuberculosis epidemic is highly difficult to treat and that it appears
to be spreading between hospitals in Europe.
Source: CDC NCHSTP Daily News Update
The glucocorticoid receptor (GR) belongs to a superfamily of ligand-regulated nuclear
steroid hormone receptors. The steps in the signal transduction pathway leading to the biological effects of glucocorticoids
(GCs) include sequentially binding of the steroid to the GR ligand binding domain (LBD), receptor transformation, nuclear translocation
and either positive or negative gene transactivation. Rifampicin (RIF) is a macrocyclic antibiotic used as an antituberculosis
agent. As the incidence of tuberculosis has been increasing, in part because of the AIDS epidemic, a growing number of patients
are being exposed to the adverse effects of this antibiotic. Indeed, this compound, as are the GCs, is often implicated
in noxious drug interactions, because of its strong ability to induce drug-metabolising enzymes. Moreover, in humans, RIF, as are
the GCs, has been described as a potential immunodepressor, associated notably with the reduction of mitogenic responsiveness
of human peripheral blood lymphocytes. Here, we report that RIF activates the human glucocorticoid receptor (hGR). Transient expression
of wild-type, deleted or mutated GRs; sucrose density gradient sedimentation; and the BIAcore technique strongly suggest
that RIF binds to the receptor with the physiological consequence that this antibiotic acts as an immunodepressor. Given the wide
use of RIF in the treatment of coinfection of tuberculosis and HIV, this report is highly relevant to current medical practice.
Ref: C. Calleja, J.M. Pascussi, J.C. Mani, P. Maurel & M.J. Vilarem The antibiotic
rifampicin is a nonsteroidal ligand and activator of the human glucocorticoid receptor Nature Medicine. Volume 4 Number 1 - January
1998 p.92