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ANTIVIRALS
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New AIDS drugs have cut the death rate among patients in British Columbia dramatically,
according to data released on Tuesday.
In the last three months of 1996, the death rate among British Columbia AIDS sufferers
fell to 23 per 1,000 from 70 per 1,000 at the beginning of 1994, said Dr. Robert Hogg, manager of the province's AIDS drug
treatment program.
"It's dramatic. We attribute the drop to people going from monotherapy to double (drug)
combination or triple (drug) combination therapy," Hogg said.
The data are thought to be the first in the world based on an entire population rather
than just sample groups, he said. Researchers said they were perhaps the best indication so far of the success of new therapies.
Researchers elsewhere have also had startling success with combination therapies including
protease inhibitors, a new type of drug introduced in the past year, but the scope of their patient studies has not been
as big.
The British Columbia patients took different drugs in varying combinations. About
2,100 people with the virus causing AIDS participate in the province's AIDS drug program.
But Hogg stressed that the new treatments do not cure AIDS and it was not yet known
if the effectiveness of the new drugs would wear off.
"These drugs do not cure the disease, that's still an important message to get out,"
he said.
Source: Aegis
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Hospital admissions and diagnosis of new O.Is have fallen also fallen sharply at the major UK treatment centres. Chelsea & Westminster
Hospital are currently compiling an audit.. However, some patients continue to develop illness despite treatment. Many
treatment failures may be persons unreliable in taking their medication but other reasons for failure
include extensive prior treatment with antiretrovirals and presence of ongoing O.Is such as CMV, MAI or KS coupled with a low CD4 count. Obviously service provision
must be reassessed in the light of changing needs, but specialist in-patient care for O.Is is proving to be a continued need and must not be compromised. |
An extensive paper on the clinical use of protease inhibitors was published in the
January 8th edition of the Journal of the American Medical Association (JAMA). ATP are reproducing selected sections from this
review for the benefit of UK physicians.
Authors: Steven G. Deeks, MD; Mark Smith, MD, MBA; Mark Holodniy, MD; James O. Kahn,
MD
HIV-1 protease activity is critical for the terminal maturation of infectious virions.
Once HIV enters the cell, viral RNA undergoes reverse transcription to produce double-stranded DNA (a step inhibited by nucleoside
analogues such as zidovudine, didanosine, zalcitabine, stavudine, and lamivudine). This viral DNA is integrated into the
host genome and, eventually, transcribed and translated by cellular enzymes to produce large, nonfunctional polypeptide chains,
referred to as polyproteins. After these polyproteins are assembled and packaged at the cell surface, immature virions are produced
and released into the plasma. At this point, HIV-1 protease, acting as a "molecular scissors," cleaves the polyproteins into
smaller, functional proteins, thereby allowing the virion to mature. In the presence of HIV-1 protease inhibitors, the virion
is unable to mature and is rapidly cleared by poorly understood mechanisms.
HIV-1 protease is a complex enzyme composed of 2 identical halves, or dimers, with
an active site located at the base of the cleft created by the dimerization process. Large, HIV-1-derived polyproteins are inserted
into this cleft and undergo a chemical reaction resulting in cleavage. HIV-1 protease inhibitors competitively inhibit this
reaction, thus preventing the maturation of infectious virions. The successful development of protease inhibitors illustrates the
application of an exciting discipline in drug development, the linkage of structure to function. In 1988, the HIV-1 protease
enzyme was crystallized and its 3-dimensional structure determined. Computer modeling was then used to identify compounds that specifically
fit into the substrate binding pocket of the protease, thus potentially inhibiting its activity.
PHARMACOKINETICS AND DRUG INTERACTIONS
The pharmacokinetic and pharmacodynamic properties of HIV-1 protease inhibitors have
limited the development of this class of drugs and remain an important factor in their clinical use. In its current formulation,
saquinavir has limited oral bioavailability (average, 4%). In order to achieve adequate absorption, saquinavir must be taken
with meals, preferably meals with a high fat content. This dietary strategy for improved absorption does not overcome the large
first-pass effect in the liver, where saquinavir undergoes extensive metabolism by the hepatic cytochrome P450 3A system. Drugs
that induce cytochrome P450 activity, such as rifampin and rifabutin, reduce the bioavailability of saquinavir and should be avoided.
On the other hand, drugs that inhibit cytochrome P450 3A4, such as ketoconazole, may increase plasma concentrations of saquinavir.[6]
Of note, ritonavir is a potent inhibitor of the P450 3A4 system, and its concurrent use can result in dramatically
increased levels of saquinavir. Combination studies involving these 2 drugs are ongoing. Finally, similar to all HIV-1 protease
inhibitors, saquinavir may inhibit the metabolism of terfenadine (Seldane), astemizole (Hismanal), and cisapride (Propulsid), leading
to increased plasma concentrations of these drugs and potentially serious cardiac arrhythmias. Physicians should use alternatives
to these drugs for patients using any HIV-1 protease inhibitor.
Ritonavir is a powerful inhibitor and inducer of the cytochrome P450 metabolic pathway.
Ritonavir is expected to produce large increases in the plasma concentrations of astemizole, terfenadine, cisapride, and various
antiarrhythmics (amiodarone, encainide hydrochloride, flecainide acetate, quinidine), potentially leading to cardiac arrhythmias.
Use of ritonavir with any of these agents is contraindicated. Other contraindicated concurrent medications include the
sedative-hypnotics (such as alprazolam, diazepam, flurazepam hydrochloride, midazolam, and triazolam). Due to the potential for
oversedation with these agents, alternatives must be used for patients treated with ritonavir. A complete list of contraindicated
concurrent therapies is in the package insert.
Ritonavir is expected to produce large increases in the plasma concentrations of agents
metabolized by the cytochrome P450 CYP3A isoform. These drugs include analgesics (fentanyl citrate, hydrocodone, oxycodone,
methadone hydrochloride), antiarrhythmic agents (lidocaine, disopyramide), antibiotics (erythromycin), anticoagulants (warfarin
sodium), anticonvulsants (clonazepam, carbamazepine), antidepressants (trazodone hydrochloride, fluoxetine, and others), anti-emetics
(dronabinol, ondansetron hydrochloride), antifungal agents (ketoconazole, itraconazole), calcium channel blockers, many
chemotherapeutic agents, corticosteroids (prednisone, dexamethasone), ergotamine derivatives, hypolipidemics (lovastatin, pravastatin
sodium), and neuroleptics (haloperidol, perphenazine). Although not contraindicated, these medications and others should be
used with caution in patients receiving ritonavir. Dose modification or the monitoring of drug levels is recommended.
Medications that require metabolism via other cytochrome family pathways (2C9/19)
may have reduced bioavailability when used in combination with ritonavir. The most important agents in this class include nonsteroidal
anti-inflammatory agents, anticonvulsants (phenytoin), hypoglycemics (glipizide, glyburide), and antiulcer medications (omeprazole).
Since ritonavir is formulated in alcohol, patients treated with disulfiram or metronidazole may experience a severe
reaction to ritonavir. Ritonavir should be stored in a refrigerator and away from direct light.
Indinavir is also metabolized by the cytochrome P450 3A4 enzyme. However, approximately
20% of the drug is excreted unchanged in the urine. Indinavir inhibits the metabolism of rifabutin; therefore, the rifabutin
dose should be reduced 50% when the 2 drugs are used concurrently. Ketoconazole interferes with the metabolism of indinavir sulfate,
thereby increasing indinavir concentrations. If patients require ketoconazole, the indinavir dose should be reduced to 600
mg every 8 hours. Other agents that interact with cytochrome P450 3A4 (particularly rifampin, terfenadine, astemizole, cisapride,
triazolam, and midazolam) may be affected by administration with indinavir and should be avoided, since potentially serious
complications from each agent may result. Finally, didanosine (Videx, ddI) is acid labile and requires buffering for absorption.
The buffering agent can interfere with indinavir absorption, so the 2 drugs should be taken at least an hour apart.
The bioavailability of indinavir is reduced with most meals, so it should be taken
in the fasting state--at least 2 hours after or 1 hour before meals. If necessary to improve compliance, indinavir can be taken
with a light, low-fat, low-protein meal. To maintain constant therapeutic levels, indinavir should be taken every 8 hours (not
simply 3 times per day). Clinicians may need to specifically outline optimal meal and dosing schedules.
The drug interaction profile with nelfinavir is similar to that described with indinavir.
Nelfinavir should not be used with terfenadine, astemizole, or cisapride. Rifampin and possibly rifabutin will reduce nelfinavir
plasma concentrations; therefore, these agents should not be used concurrently. Although ketoconazole increases plasma
levels of nelfinavir, dose modifications are not necessary. Other drug interactions, including those with benzodiazepines, have
not been fully evaluated.
Recently, the US FDA approved nevirapine (Viramune) for use as an anti-HIV agent,
with a similar drug, delavirdine mesylate (Rescriptor), available through an expanded access program (US). These 2 drugs are members
of a novel class of antiretroviral therapies, the nonnucleoside reverse transcriptase inhibitors. Each drug has a complicated
pharmacokinetic profile, and information concerning drug interactions with the protease inhibitors is incomplete. Therefore,
despite their availability, nonnucleoside transcriptase inhibitors and protease inhibitors should be used in combination only with
caution until further interaction studies are reported.
SAFETY PROFILE
Saquinavir, ritonavir, indinavir, and nelfinavir have unique safety and tolerability
profiles. Saquinavir, in its current formulation, appears to be the best tolerated. The most common adverse effects are diarrhoea,
nausea, gastrointestinal discomfort, and rash, all typically mild and relatively uncommon. Saquinavir has not been consistently
associated with any laboratory test abnormalities. When added to zidovudine or zalcitabine, saquinavir does not alter or enhance
the known adverse effects of either of these drugs. A full safety profile from a large North American study, involving approximately
1000 patients followed for 74 weeks, is expected in early 1997.
Although ritonavir is the only protease inhibitor with convenient twice-a-day dosing,
it is the most problematic from a safety and tolerability perspective, particularly during the first few weeks of administration.
In clinical studies involving an oral suspension, ritonavir was associated with mild to moderate diarrhoea, nausea, vomiting,
anorexia, headaches, asthenia, fatigue, and taste disturbances. Circumoral paresthesia was also commonly reported. In the largest
study reported to date involving 1088 people (541 receiving ritonavir, 547 receiving placebo), 17% of patients with advanced
disease discontinued ritonavir due to adverse events (compared with 6% receiving placebo). Laboratory values associated with
adverse events include elevated plasma concentrations of liver transaminases, creatinine kinase, and triglycerides. There have not
been any significant hematologic or renal abnormalities associated with the use of ritonavir.
The degree of symptoms with ritonavir use appears to be directly related to plasma
concentration of the drug. Plasma concentrations are highest during the first several days of administration, declining as ritonavir
subsequently induces its own metabolism. Therefore, the manufacturer currently recommends that the drug be given in a dose-escalating
fashion. Ritonavir should be initiated at 300 mg twice daily and increased over 1 to 2 weeks, in 100-mg increments as
tolerated, to 600 mg twice daily. In addition, patients starting combination therapy may improve tolerance by initiating ritonavir
first, achieving full dose, and then subsequently adding nucleoside analogues as tolerated. Patients should be counseled that
many of the initial symptoms associated with ritonavir therapy will diminish with time. Administration of ritonavir during meals
also reduces its adverse effects.
Indinavir is relatively safe and well tolerated. The most important adverse effect
has been nephrolithiasis, occurring in approximately 5% of patients over the first year of treatment. Indinavir precipitates in
the renal collecting system, eventually leading to obstruction and the associated symptoms of renal colic (hematuria, flank pain,
nausea). To prevent this complication, patients should drink large quantities of fluid throughout the day (approximately 1.5
L [48 oz] per day). Indinavir-associated nephrolithiasis is typically treated with hydration and pain relief. Discontinuing or interrupting
therapy with indinavir is not necessary. Indinavir has also been associated with mild gastrointestinal symptoms, including
abdominal pain, nausea, vomiting, and gastroesophageal reflux. Mild to moderate elevations of indirect bilirubin are common,
but not associated with hepatitis or hepatic damage. Other laboratory test abnormalities with indinavir are rare.
Clinical experience with nelfinavir is limited. In small phase 2 studies, nelfinavir
was commonly associated with loose stools and mild to moderate diarrhoea. In general, this symptom required no therapy or was
easily controlled with over-the-counter antidiarrheal medications. Other symptoms have included mild fatigue and poor concentration,
both of which were uncommon. There have been no consistently reported laboratory value abnormalities. Safety data are currently
limited to less than 24 weeks of continuous administration.
Since all protease inhibitors have been approved under the FDA's accelerated approval
process, the long-term safety of these agents is unknown. As these drugs are widely prescribed, new reports of potential complications
may occur. For example, the FDA recently reported that there have been 15 case reports of spontaneous bleeding episodes
in HIV-positive patients with haemophilia who are being treated with protease inhibitors. Although it is unclear if the protease
inhibitors were directly responsible for these complications, caution is recommended. The use of these agents in pregnancy has
not been reported.
Ref: JAMA. 1997;277:145-153
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Saquinavir bioavailability is similar when taken with light or heavy meals. Regarding
CYP3A4, the majority is in fact, in the gut wall not the liver. Booster strategies for saquinavir plasma levels include administration
of ketoconazole ( 3-fold increase), grapefruit juice (1-1.5-fold increase, but may be unreliable due to variability in
grapefruit constituents), ritonavir (20-40-fold increase). The article also fails to mention the negative saquinavir- rifabutin/rifampicin
interaction where saquinavir levels are reduced. Regarding ritonavir, many UK physicians initiate antinausea agents
at initiation of treatment to limit side-effects. It must also be remembered that the 1.5L fluid intake recommended with indinavir
is additional
to usual requirements (2L/day) |
Agouron Pharmaceuticals, Inc. have announced that its HIV protease inhibitor nelfinavir
mesylate (ViraceptTM) will be made available to HIV-infected children in the United States aged 2 to 13
years through an expanded access program. Encouraged by preliminary evidence of safety and tolerability from an ongoing study
of nelfinavir in children, the company will make the drug available without charge to any HIV- infected child until the drug is
approved for marketing in the United States.
Agouron announced last month that it submitted a New Drug Application (NDA) for nelfinavir
covering both tablet and paediatric powder formulations in the United States. No paediatric formulation of an HIV protease
inhibitor has yet been approved by FDA. HIV protease inhibitors have been available for children only through small clinical
trials.
Preliminary results of the paediatric study are expected to be presented at The Fourth
Conference on Retroviruses and Opportunistic Infections later this month.
A press release from Agouron Pharmaceuticals to US treatment organisations has announced
a relaxation of the criteria for enrolling on their compassionate use expanded access programme..
People will qualify for expanded access if they are unable to take indinavir and/or
ritonavir due to intolerance or prior failure and who have had CD4+ t-cell counts of less than or equal to 100 during any past
medical examination.
Previous criteria required failure on ALL 3 approved protease inhibitors, and a CD4
count below 50 cells/mm3 at the time of enrolment.
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Despite this additional compassionate use in the US there is still NO access to nelfinavir
in Europe, adult or paediatric, During meetings with European treatment agencies Agouron insist on unworkable access
criteria lacking in any compassion, citing drug supply problems, while relaxing the criteria and increasing their supply to the
US. Agouron have also failed to apply to the EMEA for approval in Europe while actively pursuing approval through the FDA. Nelfinavir
could become a licensed treatment for HIV-disease as early as the second quarter of 1997 - why is Europe being denied? |
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OPPORTUNISTIC ILLNESS
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More than half of all HIV-infected women may develop cervical cancer, and nearly three
quarters of those may have evidence of the disease before they are ever diagnosed with HIV, according to a new study.
Unlike their male counterparts who suffer from high rates Kaposi's sarcoma, women
with AIDS are more disposed to gynaecological infections and herpetic outbreaks.
The new findings indicate that doctors may not be aware of the high rate of cervical
cancer in the HIV population, and may not be reporting thousands of potential AIDS cases.
In New York City, where the new study was conducted, rates of cervical cancer have
increased from fewer than 5 cases per 100,000 women to more than 7 per 100,000, reported Dr. Mitchell Maiman in the January issue
of Obstetrics & Gynecology.
Maiman, of SUNY-Health Science Center at Brooklyn, said it is too early to determine
whether the AIDS epidemic will influence the prevalence and mortality rates for cervical cancer nationwide, but the New York
data may reflect a trend in urban women at risk for both HIV and cervical cancer.
In 1993, the Centers for Disease Control and Prevention added cervical cancer to the
list of diseases that doctors use to diagnose AIDS. But its overall prevalence in this population is not well known.
In the study of 725 HIV-positive women, a large proportion of women had invasive cervical
cancer as their initial AIDS-defining illness, Maiman reported.
"In the first year (1993) of the expanded AIDS surveillance case definition, when
cervical cancer was included as an AIDS-defining illness, 1.3% of women with AIDS who were older than 12 years had invasive cervical
cancer; our rate of 4% is thus about three times the national average," she wrote.
Women with cervical cancer had less immune-system suppression, a later HIV diagnosis,
and a higher likelihood of dying from cancer-related complications than HIV-infected women who did not have cervical cancer.
Many women with HIV, especially the poor and elderly, are likely to have their cervical
cancer overlooked once a diagnosis of HIV has been made, Maiman added. Given the high death rate associated with invasive
cervical cancer, more of an effort should be made to test high-risk women and report cervical cancer cases in this population, she
said.
AIDS is now the fourth-leading cause of death among women aged 25 to 44. Nationwide,
14,177 women were diagnosed with AIDS last year in the US, up from 1,130 cases in 1985.
Ref: Obstetrics & Gynecology (1997;89:76-80)
Source: Aegis
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UK clinics generally recommend HIV-infected women to have 6 monthly smears and an annual colposcopy. |
AIDS dementia, which affects between 20 percent and 30 percent of all advanced AIDS
patients, may be linked to an overproduction of nitric oxide. Valina Dawson and colleagues at Johns Hopkins University found
that the brain tissue from patients who had AIDS dementia had eight times more nitric oxide synthase activity than HIV-1 negative
controls. High levels of HIV-1's coat protein gp41 were also found in the patients with dementia, and animal research has shown
that gp41 can induce nitric oxide synthase activity. Dawson said the findings could be applied to find a way to reduce AIDS
dementia by blocking nitric oxide production.
Ref: Lancet (12/21/96-12/28/96) Vol. 348, No. 9042, P. 1725
Source: AIDS Daily Summary
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PATHOGENESIS
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Certain patterns of immune responses to the human Immunodeficiency virus (HIV) during
the first weeks of infection are highly predictive of an individual's subsequent rate of disease progression, according to investigators
at the National Institute of Allergy and Infectious Diseases (NIAID) and their colleagues.
"Our data strongly suggest that the immunologic factors at work during this early
period of infection, as much or more than virologic factors, are the critical determinants of the ultimate outcome of HIV disease,"
says Anthony S. Fauci, M.D., NIAID director and chief of the NIAID Laboratory of Immunoregulation. "The growing understanding
of the initial interaction between HIV and the immune system, and of the immune responses to HIV during primary infection, both
favourable and unfavourable, is important to the development of effective HIV vaccines."
Drs. Fauci, Giuseppe Pantaleo, formerly of NIAID's Laboratory of Immunoregulation
and now with the Centre Hospitalier Vadois in Lausanne, Switzerland, and their co-workers report their findings in the January 1997
Proceedings of the National Academy of Sciences.
Once it enters the body, HIV infects a large number of CD4+ T cells and replicates
rapidly. During this acute, or primary phase of infection, the blood contains many viral particles that spread throughout the
body, seeding various organs, particularly the lymphoid organs such as the lymph nodes, spleen, tonsils and adenoids. Two to four
weeks after initial infection with the virus, up to 70 percent of HIV-infected persons suffer flu-like symptoms. The patient's
immune system fights back with killer T cells (CD8+ T cells)and B-cell-produced antibodies.
"One important way in which a person's immune system responds to primary HIV infection
is by mobilising different subsets of certain white blood cells -- CD8+ T cells -- that can destroy cells that
have been infected with HIV," says Dr. Fauci. "We found a clear correlation between
the patterns of CD8+ T cell expansion during primary infection and how well a patient did clinically during the subsequent year
or 18 months. Regardless of the amount of HIV in the blood during primary infection, patients who mobilised a broad repertoire
of CD8+ T cells had slower progression of disease than individuals who showed a pronounced expansion of only a single subset
of CD8+ T cells."
Scientists currently do not know the reasons for the qualitative differences in the
immune responses of different individuals during primary HIV infection, Dr. Fauci notes, but they probably include factors intrinsic
to the HIV-infected person, such as the genes that encode specific markers called human leukocyte antigens (HLAs) on immune
system cells.
The current report is the latest from an ongoing series of experiments begun several
years ago in the Laboratory of Immunoregulation. In their research, Dr. Fauci and his team have carefully analysed CD8+ T cells
taken from patients during primary HIV infection, classifying the cells according to the variable (V) regions of their receptors.
All T cells have receptors with alpha and beta chains, and on the beta chain is a region known as V-beta that varies among
T cells. Humans have 24 different V-beta families.
Previously, the NIAID team demonstrated that during primary infection, some HIV-infected
patients have a marked expansion of a limited variety of T cells, representing very few V-beta families. Other patients mobilise
a wider array of T cells, with many different V-beta families.
In the current study, the investigators studied 21 individuals with documented primary
HIV infection at clinics in the United States, Canada, Switzerland and Italy. Blood samples from these patients were analysed
in NIAID's Laboratory of Immunoregulation.
Four of these 21 patients had major expansions of a single V-beta subset during primary
infection. Approximately one year later, each of these four individuals had developed AIDS, as indicated by CD4+ T cell
counts below 200 cells per cubic millimeter (mm3) of blood. The mean CD4+ T cell count among these patients was 101 cells/mm3;
a healthy person without HIV infection usually has a CD4+ T cell count of 600-1500 cells/mm3.
Four other patients had moderate expansions of one or two V-beta subsets. At approximately
one year, this group of patients had a mean CD4+ T cell count of 456/mm3.
Thirteen patients had expansions of multiple V-beta families or no expansion at all.
The mean CD4+ T cell count in this group of patients was 651/mm3 after approximately one year.
Previous studies have shown that levels of HIV in a person's bloodstream six to 12
months following primary infection are highly predictive of that person's clinical course, with more virus generally correlating
with more rapid disease progression. The current findings add a new level of complexity to the understanding of the relationship
between "viral load" and a person's clinical outcome.
"In the current analysis, we studied an earlier stage of disease -- the primary infection
-- and found that the initial level of HIV in the blood does not predict clinical outcome. At this early stage of disease,
the qualitative nature of a person's immune response, rather than plasma viraemia, proved to be the best prognostic indicator,"
notes Dr. Pantaleo.
"Individuals with an effective primary immune response -- those with a broad expansion
of CD8+ T cell subsets -- appear to be the same people who will have low levels of virus six or 12 months later, levels which
in turn are predictive of relatively slow disease progression. In contrast, individuals with an ineffective primary immune
response (i.e., expansion of only a single subset of CD8+ T cells) may have less success in controlling the virus over time, and
therefore, have high levels of virus six to 12 months later," says Dr.Fauci.
Ref: Pantaleo G, et al. Proc Natl Acad Sci USA 1997;94:254-258.
Source: NIAID
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These data represent confirmation of the importance of host factors, possibly genetic,
in the rapidity of disease progression. The viral load after seroconversion represents the balance between the natural rate
of viral replication (thought to be similar for most wild-type viruses) and the antiviral effects of the immune response. The weaker
the immune response, the higher the viral load. With continued replication the immune system and its response further weakens
leading to progressive rise in viral load and increasing morbidity. |
An Italian team reports in the journal Blood that "...low levels of HIV load and replication
in peripheral blood are the strongest correlates of nonprogression..." in haemophiliacs with HIV infection.
Out of a group of 112 HIV-positive haemophiliacs, Dr. Elisa Vicenzi of San Raffaele
Scientific Institute, Milan, and colleagues identified 7 patients as long-term nonprogressors. These subjects, characterised by
good health, CD4 T cell levels of more than 500 cells per microliter and no history of antiretroviral treatment, were matched
and compared with HIV-positive haemophiliacs with progressive HIV disease.
Compared with progressors, Dr. Vicenzi found that long-term nonprogressors had "...[100]-fold,
20-fold, and 10-fold lower levels of full-length HIV RNA in plasma, peripheral blood mononuclear cells...and proviral
DNA in [peripheral blood mononuclear cells], respectively." She found no "...substantial differences...in the in vitro production
of chemokines including RANTES, MIP-1-alpha, MIP-1-beta and MCP-1, and interleukin 8..." in peripheral blood mononuclear cells
from any of the subjects.
Ref: Blood 1997;89:191-200.
Source: Aegis
HIV-positive individuals with slowly progressing infection may have qualitative differences
in their cytotoxic T lymphocyte (CTL) response compared with HIV-positive individuals with more rapidly progressing infection,
according researchers in the U.K. One such difference is an overrepresentation of the class I molecule HLA-B*57 as a
restriction element in the slow-progressors.
Dr. Philip J.R. Goulder at John Radcliffe Hospital in Oxford and colleagues evaluated
the CTL responses of 33 subjects defined as slow progressors and 29 subjects defined as progressors. They were able to identify
"...five new HLA-B*57-restricted CTL epitopes recognised by slow progressor donors, one of which [was] also HLA-B*5801 restricted."
These five new HLA-B*57-restricted CTL epitopes recognised by the slow progressors
"...may be an important component in future vaccine design." They also point out that "...a candidate HIV vaccine would ideally
incorporate epitopes that dominate CTL responses in slow progressor donors. Importantly, these epitopes would also need to be restricted
by HLA class I molecules commonly found in ethnic groups where the prevalence of HIV infection is high." Such is the
case with HLA-B*57 and HLA-B*58.
Ref: AIDS Research and Human Retroviruses 1997;12:1691-1698.
Source: Aegis
A European team reports "...a strong association between mother-to-child transmission
of HIV-1 and a high maternal viral RNA load in plasma at delivery."
Dr. O. Coll and colleagues of Ciudad Sanitaria Vall d'Hebron, in Barcelona, and others
at Utrecht University in The Netherlands, evaluated 67 HIV-1-positive women during pregnancy and delivery at two university
hospitals. The team monitored the subjects for HIV-1 RNA, p24, CD4 cell counts, and also measured tissue culture infectious doses.
HIV-1 infection was subsequently confirmed in 17 of the 69 children born to these women.
Dr. Coll's team found that "...[v]iral load was the main contributing factor for HIV-1
vertical transmission." No significant differences in the rate of vertical transmission appeared to be associated with route
of maternal HIV transmission, treatment or no treatment with zidovudine, mean gestational age, duration of ruptured membranes
or means of delivery, vaginal or caesarean.
The Spanish group says that this is the first large study to uncover "...a strong
association between transmission of HIV-1 from mother to child and a high maternal viral RNA load in serum at delivery." And although
the study was retrospective, Dr. Coll believes the results were not biased by a retrospective approach and that the data
are in agreement with results of previous studies.
Ref: J Acquir Immune Defic Syndr Hum Retrovirol 1997;14:26-30.
Source: Aegis
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Whilst higher viral load increases the risk of transmission, transmission may occur
at all viral load levels. Use of zidovudine in the ACTG 076 study was found to be effective in reducing transmission at all viral
load levels in the treatment na ve study subjects. |