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June 13, 2010)
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2010-06-10
Scientists have created a
three-dimensional picture of an important protein that is involved in how
HIV-the virus responsible for AIDS-is produced inside human cells.
The picture may help in
the development of drugs to prevent HIV from reproducing.
The research team, led by
David Price, UI professor of biochemistry, and Tahir Tahirov, professor of
structural biology at the Eppley Institute at the University of Iowa Carver
College of Medicine and University of Nebraska Medical Center (UNMC), combined
expertise in protein chemistry and X-ray crystallography -- a technique for
observing protein structures-to produce the first crystal structure of the HIV
protein called Tat.
The structure shows Tat
attached to the human protein (P-TEFb) that the virus hijacks during infection.
The structure shows how
Tat latches on to this particular human protein and how the interaction alters
the shape of the human protein.
"We have solved the
long sought-after structure of an important HIV protein. Now that we know the
details of the interaction between Tat and P-TEFb, it may be possible to design
inhibitors that target P-TEFb only when it is interacting with Tat," Price
said.
This distinction is
important because although inhibiting P-TEFb blocks replication of the HIV
virus, P-TEFb is a vital protein in human cells and inhibiting it kills cells.
If an inhibitor could be designed that distinguishes between the P-TEFb attached
to Tat and the form that is normal in human cells, that drug might target HIV
replication without harming normal cell function.
Such compounds could be
useful in combination with existing anti-HIV drugs to further reduce viral
levels in HIV-infected individuals.
In addition, drugs that
target P-TEFb may also be useful in treating drug-resistant HIV, which is a
growing problem. The HIV virus mutates very easily and can develop resistance to
current drug that target viral proteins. Targeting a human protein like P-TEFb
that the virus needs but cannot mutate may be a successful strategy to counter
drug-resistant HIV.
The study has been published in the June 10 issue of the journal Nature. (ANI)
Michael Carter, June 10, 2010
The prevalence of fatigue
amongst people with HIV ranged from between 33% and 88% in 42 studies examined
in a review article in the online edition of the AIDS.
Fatigue was strongly associated with psychological factors, such as anxiety and
depression. Evidence supporting the use of medication to treat fatigue was
limited. However, research showed that the use of cognitive behavioural therapy
(CBT) as a treatment had some success.
Thanks to antiretroviral therapy, many patients with HIV can look forward to
living a long and healthy life. But individuals with HIV still report a high
burden of symptoms, one of which is fatigue.
Fatigue has been defined as “a lessened capacity for work and reduced
efficiency of accomplishment, usually accompanied by a feeling of tiredness that
is not reduced by a good night’s sleep.”
The consequences of fatigue can include a diminished ability to work or maintain
social contact. Quality of life can also be reduced, a factor associated with
disease progression.
Therefore, Dutch investigators conducted a literature review to identify the
latest evidence regarding the causes and treatment of HIV-related fatigue in the
era of antiretroviral therapy.
A total of 42 studies conducted between 1996 and 2008 were identified. The
largest study included 1200 individuals, and the smallest just 19 patients. Most
had a cross-sectional design.
Sociodemographic factors and fatigue
Poverty and low income were associated with fatigue in four studies. There was
no consistent evidence linking either gender or ethnicity an increased risk of
reporting fatigue.
Perhaps surprisingly, fatigue appeared to be more prevalent in younger rather
than older patients, a finding which the investigators believe could be because
older patients have developed better strategies to cope with fatigue.
HIV-related factors
The was no consistent evidence demonstrating that experiencing other HIV-related
symptoms was associated with fatigue. However, when symptoms were associated
with fatigue, fever, gastrointestinal problems, and neuropathy predicted greater
fatigue severity.
Neither CD4 cell count nor viral load appeared to be associated with fatigue.
Patients who had been living with HIV for longer were less likely to report
fatigue than those who had been diagnosed more recently.
Elevated levels of interleukin-6 (IL-6) and other markers of inflammation were
not associated with fatigue.
Physiological factors
Generally, the presence of co-infections such as hepatitis B or hepatitis C, as
well as co-morbidities were associated with more severe fatigue.
Low levels of haemoglobin were not significantly associated with fatigue, but
there was some evidence that patients with lower testosterone were more likely
to report the condition.
There was no consistent evidence that fatigue was linked to body composition,
weight, or body mass index.
Although total reported sleep was not associated with fatigue, daytime napping
was.
Psychological factors
Stress, depression, anxiety and poor coping strategies were all consistently
related with greater severity of fatigue.
Treatment of fatigue – medication
A wide range of medicines were used to treat fatigue including testosterone,
antidepressants, and psycho-stimulants. But the evidence for their efficacy was
limited.
Treatment of fatigue – psychological interventions
Two studies showed that psychological interventions, such as cognitive
behavioural therapy, had benefits for HIV-related fatigue.
“Studies on the treatment of HIV-related fatigue are minor in nature and focus
on a selected group of patients”, comment the investigators.
They conclude, “treatment for HIV-related fatigue is important because of its
social, psychological and behavioural consequences and requires a
multidisciplinary approach. There is a need for an appropriate evidence-based
practice guide for the management of HIV-related fatigue.”
Reference
Jong E et al. Predictors and treatment strategies of HIV-related fatigue in the
combined antiretroviral therapy era. AIDS, 24: online edition, DOI:10
.1097/QAD.0b0113e3283339d004, 2010.
Aids organisations are
alarmed by plans from pharmaceutical company Bristol Myers Squibb to suspend the
manufacture of a vital HIV drug
Hard
to imagine a pharmaceutical company could so comprehensively shoot itself in the
foot, but apparently, the drug giant Bristol Myers Squibb is about to shut down
a factory in France that makes the only cheap Aids drug that can keep up to
7,000 babies alive in the developing world. Just imagine the headlines.
Do tell us it is not true,
Bristol Myers Squibb. But so far, your chief executive Lamberto Andreotti has
not even acknowledged a letter of protest from some of the board members of
UNITAID - which tries to facilitate access to Aids drugs in poor countries.
So in the absence of any
response, these board members, who represent NGOs and communities affected by
HIV/Aids on the board of the Geneva-based organisation, are going public today
with their letter to you. In case it has been lost in the post after all, this
is what they say:
Dear Mr Andreotti,
We, the UNITAID board members representing NGOs, and Communities affected by
HIV/AIDS, TB and malaria, are writing to you to express our deep concern that
Bristol-Myers Squibb is to close a factory in France that manufactures a second
line anti-retroviral medicine for children infected with HIV/AIDS who weigh less
than 10 kg: buffered didanosine (ddI) in the 25 mg formulation.
Closing this factory means that 4,000 to 7,000 babies currently enrolled in
treatment plans in developing countries through UNITAID could be left without
the medicines they need. Didanosine is the last therapeutic option for these
babies and without it they may die. We understand that closure of the plant will
take place in June of this year, with no plans for resumption of production
before April of 2011 at the earliest when a new plant is due to open. Therefore
there is likely to be a shortage of approximately 15,000 packs of ddI 25 mg,
across all UNITAID beneficiary countries between now and when production is
expected to resume in April 2011. Currently, there is no alternative generic
product that has been assessed by WHO and prequalified for use by UN agencies.
We urge you, as the Chief
Executive Officer of BMS, a company that prides itself on its high standards of
corporate responsibility, to respond urgently to our concerns, outlining the
steps you will take to avoid any treatment interruption. We would also like your
confirmation that a BMS plant will resume production of this vital medicine in
2011.
We look forward to hearing
from you.
In fact, we all look forward to hearing from you. Please tell us it isn't true.
Michael Carter, Wednesday,
June 09, 2010
Two studies have cast
doubt on the value of nutritional supplements for patients with HIV. The first
study, published in the July 1st edition of Clinical Infectious Diseases showed
that the provision of nutritional support has only modest benefits for
HIV-positive adults without severe wasting. A separate study conducted amongst
HIV-positive children in
A total of 636 antiretroviral-naïve patients were enrolled in the adult study
and on a three-to-one basis were given nutritional supplementation or standard
of care. “We observed an improvement in various nutritional parameters in the
supplement group, but this was not statistically significantly different from
the members of the control group”, comment the investigators.
Nevertheless, the investigators believe that their study has made a number of
important contributions, most especially that they showed that it was feasible
to deliver nutritional support to a food-insecure population via clinics.
Nutritional supplements and outcomes amongst HIV-positive adults in India
Food insecurity is widespread in the world regions hardest hit by HIV.
Malnutrition is common in people with HIV in these areas, and this has been
associated with faster disease progression.
Investigators hypothesised that supplementation with added calories and fat
would improve the nutritional status of patients with HIV, and possibly their
body composition and CD4 cell count.
They therefore conducted a prospective, six-month study in southern
At the first baseline visit, patients provided details of their diet to a
nutritionist who calculated their daily intake of calories, protein and fat. The
patients’ height and weight were assessed and their body mass index
calculated. Individuals’ mid-arm circumference was also measured.
Blood samples were obtained to assess the patients’ CD4 cell count and levels
of haemoglobin, serum albumin, triglycerides, and cholesterol.
All the patients were given multivitamins and prophylaxis against opportunistic
infections.
Nutritional supplementation providing 400 calories per day, 15 g of protein and
6 g of fat was given to three-quarters of patients. The other 25% of patients
constituted a control group.
After six months, the effect of supplementation on weight, BMI, body
composition, CD4 cell count and blood chemistry was measured.
There was a high rate of discontinuation (30%), and 10% of patients died. The
patients who did not complete the study had more advanced HIV disease having
significantly lower CD4 cell counts (p < 0.001), and lower serum albumin (p
< 0. 001) than individuals who completed the study.
The investigators comment, “patients who were severely ill, who were about to
initiate antiretroviral therapy, or who required hospitalisation were not
included in the study, and this may have been the group most likely to
benefit.”
Of the 361 patients who completed the study, 282 received supplementation. The
mean age was 31 years and mean weight was 50 kg. Approximately a third of
patients were severely malnourished.
Although patients in the control group had a lower daily calorific intake (1616
vs. 1911, p < 0.001), they nevertheless had a higher baseline CD4 cell count
than patients who received supplementation (488 vs. 365 cells/mm3).
The investigator’ first set of analysis showed that supplementation had a
number of benefits. Compared to the control group, the individuals who received
six months of nutritional supplements had significant gains in weight, BMI,
mid-arm circumference, and albumin levels (all p < 0.001).
However, after adjusting for baseline differences in CD4 cell count, age and sex
between the two study arms, none of these changes remained statistically
significant.
Next, the investigators categorised the patients who received supplementation
according to their CD4 cell count: below 200 cells/mm3; 201-499 cells/mm3; and
above 500 cells/mm3.
Regardless of CD4 cell count, six months of supplementation increased weight,
BMI and mid-arm circumference (p < 0.001).
Improvements were greatest in patients with the lowest CD4 cell counts.
“In summary”, write the investigators, “an energy-dense oral micronutrient
supplement did not have additional benefits on nutritional parameters or immune
function among antiretroviral therapy-naïve HIV-infected individuals in South
India, compared with high-quality standard of care. The effect of
supplementation on specific subsets of patients and on preserving immune
function needs further research.”
Micronutrients and disease progression in children
A separate study conducted in HIV-positive children in
A total of 847 children aged between 1 and 5 years were recruited to the study,
which is published in the Journal of the International AIDS Society.
The children were randomised to receive double the recommended daily allowance
of 14 vitamins and minerals, which were taken daily for twelve months, or the
standard daily dose of six vitamins, which were taken for six months.
After twelve months, 6% of the children who received increased amounts of
vitamins and minerals had died compared to 7% of those who received the standard
dose.
Mortality rates were also similar between the two groups when the investigators
restricted their analysis to those taking antiretroviral therapy (7% vs. 7%).
In addition, increased amounts of vitamins and minerals did have any benefits
for either weight or CD4 cell count.
Reference
Swaminathan S et al. Nutritional supplementation in HIV-infected individuals in
Ndeezi G et al. Effect of multiple micronutrient supplementation on survival for
HIV-infected children in