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January 17, 2010)
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15 January 2010 by
Andy Coghlan
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HIV is striking back
against the antiretroviral drugs that keep it largely in check in rich
countries, thanks both to its exposure to the major drugs and to individuals who
don't realise they're infected and so spread resistant strains to new partners.
Drug-resistant strains of
HIV have already been documented in
What's more, as access to
antiretroviral therapy is expected to expand in poorer countries, they could
experience a rise in resistance too, predicts Sally Blower of the
Cocktail of resistance
Currently, people with HIV
tend to be given a cocktail of drugs, making it less likely that resistance will
emerge. That's because even if a strain evolves resistance to one of the drugs,
it will still succumb to the others.
However, the virus can
evolve resistance nonetheless. Currently, about 15 per cent of new
infections in
To see how this might
increase in future, Blower's team created a model of HIV transmission that
predicts how and when resistant strains will emerge. When they fed it data from
Self-sustaining epidemics
When the team used the
model to look into the future, it predicted a rapid upsurge in the spread of
resistant strains. The model suggested that 60 per cent of the resistant
strains currently circulating in San Francisco could cause "self-sustaining
epidemics", says Blower, in which each infected individual spreads the
resistant strain to more than one new recipient.
The most serious surge in
resistance it predicted was against non-nucleoside reverse transcriptase
inhibitors (NNRTIs) such as nevirapine, introduced in the mid-1990s. Like the
earliest anti-HIV drugs such as zidovudine (AZT), introduced 10 years earlier,
these block enzymes vital for viral multiplication.
"We predict a wave of
NNRTI-resistant strains will emerge over the next five years in
Rapid diagnosis
By 2013, the proportion of
new infections resistant to NNRTIs may have increased by 30 per cent in the
city compared with now, says Blower. The more individuals infected with
resistant strains, the faster they will spread.
Resistant strains can be
kept in check provided infected individuals are diagnosed rapidly, before they
pass on the virus, and treated with drugs to which the virus remains vulnerable,
says Blower.
But resistance may be more
difficult to contain in poorer countries. And according to Blower, a strategy
recently unveiled by the World Health Organization to "test and treat"
as many people as possible in such countries may hasten the emergence of
drug-resistant strains, by exposing more people to the drugs.
"The best approach
for resource-constrained countries would be to carefully roll out first-line
regimens, making sure second-line regimens are available whenever there's
resistance to the first-line regime," says Blower.
However, Carl Dieffenbach,
director of the division of AIDS at the US National Institute of Allergy and
Infectious Diseases in Bethesda, Maryland – which this week launched a similar
pilot "test and treat" program in Washington DC – says that
development of resistance is not an insoluble problem. "The emergence of
HIV drug resistance is not a dead end," he says. "We can identify
patients who are failing treatment and switch them to other, effective
regimens."
"The advantage of
having the model developed by Blower is that it can predict where problems may
occur, and this allows us not to move forward blindly, but to proceed while
taking the model's predictions into account," he adds.
Journal reference: Science, DOI: 10.1126/science.1180556
ScienceDaily (Jan. 12,
2010) — Chemists at UC San Diego and statisticians at Harvard University have
developed a novel way to trace mutations in HIV that lead to drug resistance.
Their findings, once expanded to the full range of drugs available to treat the
infection, would allow doctors to tailor drug cocktails to the particular
strains of the virus found in individual patients.
"We want to crack the
code of resistance," said Wei Wang, associate professor chemistry and
biochemistry at UC San Diego who led the collaboration along with Jun Liu of
Harvard. The team reports their work in the early online edition of the
Proceedings of the National Academy of Sciences.
HIV replicates quickly,
but the copies are imprecise. The constant mutation has made HIV infection
difficult to treat, much less cure, because drugs designed to interrupt the
cycle of infection fail when their targets change.
To better understand which
mutations matter for drug resistance, the researchers compared sequences of HIV
taken from patients treated with specific drugs to those from untreated
patients. Using a novel statistical method, they identified clusters of
mutations that seemed to be working together to help the virus escape treatment.
One drug, indinavir,
targets a protein called protease, which the virus needs to assemble the capsule
it uses to invade new cells. Substitutions in ten different places on protease
occurred in patients who were taking the drug, but what combination of mutations
would hinder the action of the drug wasn't clear before this analysis.
Chemists can determine how
a drug fits to a particular protein using computer modeling, but those
computations take considerable time. Evaluating all possible combinations of
those 10 substitutions is impractical. The statistical screen narrowed down the
possibilities.
"People never looked
at this, because they didn't know which mutation or which combination of
mutations to study," Wang said. "That's the advantage of using the
statistical method first to find the patterns. After the statisticians
discovered the connections between mutations, then we focused on those
combinations. We built structural models to understand the molecular basis of
drug resistance."
Using the computing
resources of the Center for Theoretical Biological Physics at UC San Diego where
Wang is a senior scientist, they worked out how the substitutions would change
the shape of protease and its affinity for the drug. One set of changes, for
example, would tend to dislodge the drug from the pocket where it normally fits.
The researchers also
determined that the mutations must happen in a particular order for replicants
to survive treatment with indinavir, a window into how drug resistance develops.
Looking back into the
database at samples taken from individual patients at several different times
during the course of their treatment, the team found that mutations accumulated
in the orders that they predicted would be possible during drug treatment.
Sequential mutations that their models predicted would leave the virus
vulnerable to drug treatment were not observed.
The team reports its
results for two additional drugs, zidovudine and nevirapine, which target a
different viral enzyme, in this paper and is extending its work to all nine
drugs currently approved by the FDA to treat HIV.
Additional authors include
Jing Zhang at
Risk factors for
cardiovascular disease are common amongst young, HIV-positive women in the
“More than one-third…reported a family history of heart disease or of type 2
diabetes, more than one-third smoked cigarettes, and fewer than one-third
exercised regularly”, comment the investigators.
When added to the inflammation caused by HIV and the side-effects of
antiretroviral therapy the researchers believe that “this population of young
women may be at particularly high risk of cardiovascular disease and other
adverse events.”
Over a third of new HIV infections in the
As the inflammation caused by HIV, and the side-effects of some anti-HIV drugs,
have been linked to an increased risk of cardiovascular diseases, the
investigators wished to determine the prevalence of other risk factors for such
illnesses in young, HIV-positive women.
A total of 173 individuals were recruited to the study between 2003 and 2005.
All were aged between 14 and 24 years.
The study population included 61 HIV-negative women who were included as
controls.
The HIV-positive women were categorised according to their antiretroviral
treatment status: therapy with a protease inhibitor; therapy with a
non-nucleoside reverse transcriptase inhibitor (NNRTI); therapy with neither of
these classes of drug; or no HIV treatment.
Fasting blood samples were taken to monitor lipids, triglycerides, glucose and
insulin. C-reactive protein levels, markers of inflammation that have been
linked to an increased risk of cardiovascular illnesses, were also monitored.
The women also had their height measured and were weighed. This enabled the
investigators to calculate body mass index (BMI). Other body measurements were
also taken. DEXA scans were performed to calculate total body fat percentage.
Detailed individual and family medical histories were provided by all the women.
Furthermore, they also completed food diaries and completed questionnaires that
included questions about exercise, smoking, and drug and alcohol use.
Median age was 20 years. Significantly more HIV-infected than HIV-negative women
were African Americans (77% vs 56%, p = 0.005).
Cigarette smoking was reported by 34% of women, with no difference according to
HIV status. However, HIV-positive individuals were significantly more likely to
report illicit drug use (59% vs 36%, p = 0.002). Furthermore, fewer HIV-positive
women reported regular exercise (32% vs 53%, p = 0.005).
Many of the women reported family histories of risk factors for cardiovascular
disease. A family history of type 2 diabetes was reported by 44% of women with
HIV, a history of lipid disorders by 27%, and a history of coronary heart
disease by 38%.
More than 40% of the women in each group had a BMI above 25 and were therefore
classified as overweight or obese.
Body shape differed little between the HIV-positive and HIV-negative women.
The investigators suggest that this was because use of d4T (stavudine, Zerit), a
drug particularly linked to body fat changes, was low amongst the HIV-infected
women.
Although AZT, (zidovudine, Retrovir) was widely used, the overall duration of
antiretroviral therapy was short (maximum, 3.9 years for those taking a protease
inhibitor). Therefore, the changes in body shape that can develop as a
consequence of therapy with this drug had not yet occurred.
Triglycerides were higher among the HIV-infected women compared to those who
were HIV-negative.
HIV treatment status affected cholesterol levels. Those taking a protease
inhibitor or an NNRTI had higher total cholesterol than both HIV-negative women
and the HIV-infected women who were not yet taking HIV treatment.
Furthermore, HDL or 'good' cholesterol, was lower amongst the
antiretroviral-naive women and those taking an NRTI only regimen than it was
amongst the HIV-negative women.
Insulin and glucose levels were comparable between the HIV-positive and
HIV-negative women.
However, the investigators found that levels of C-reactive protein were
significantly higher amongst women with HIV (p = 0.006).
Moreover, 40% of women taking antiretroviral therapy had a C-reactive protein
level above the upper limit of normal (3 mg/l).
“In summary, obesity, dyslipidemia, and inflammation were prominent findings
in this group of behaviourally HIV-infected adolescent women”, comment the
investigators.
The researchers suggest that several factors are likely to contribute to these
findings: “In addition to HIV infection and antiretroviral therapy, our data
illustrate the significant impact of overweight and obesity on dyslipidemia,
insulin resistance and elevated C-reactive protein levels in this population.”
When coupled with high levels of smoking, a low prevalence of exercise, and
family histories of diabetes, and heart disease, the investigators believe that
“these factors may accelerate the lifetime risk of cardiovascular disease and
other adverse events in a group that is facing lifelong exposure to
antiretroviral therapy.”
Reference
Mulligan K et al. Obesity and dyslipidemia in behaviourally HIV-infected young
women: Adolescents Trials Network Study 021. Clin Infect Dis 50: 106-14, 2010.
A low CD4 cell count is
associated with a poor prognosis for HIV-positive patients diagnosed with
pulmonary arterial hypertension, French investigators report in the January
edition of AIDS. The study also showed that the condition developed in patients
taking antiretroviral therapy, which did not, by itself, provide an effective
treatment for pulmonary arterial hypertension.
Pulmonary arterial hypertension results from the obstruction of the small
pulmonary arteries. This can lead to the failure of the right ventricle (one of
the four chambers of the heart) and ultimately lead to death.
HIV infection is an independent risk factor for the development of pulmonary
arterial hypertension. However, little is known about the condition in the era
of modern antiretroviral therapy.
Investigators from a French national treatment centre for pulmonary arterial
hypertension therefore performed a retrospective study to determine the
incidence, risk factors, optimum treatment, outcome and prognostic factors for
HIV-infected individuals diagnosed with the condition.
Between 2000 and 2008 a total of 944 patients were referred to the unit. Of
these 77 (8%) had HIV as they only risk factor for pulmonary arterial
hypertension.
Injecting drug use was the most common HIV-associated risk behaviour (36%) and
49% of the patients were co-infected with hepatitis B or hepatitis C virus.
At the time pulmonary arterial hypertension was diagnosed, 62% of patients were
taking antiretroviral therapy and 49% had a viral load below 50 copies/ml with
79% having a CD4 cell count above 200 cells/mm3.
“This observation confirms that pulmonary arterial hypertension can develop in
patients with well controlled HIV infection, and that HAART [highly active
antiretroviral therapy] is unable to prevent the development of pulmonary
arterial hypertension”, comment the investigators.
An established assessment of the functional status of patients with heart
disease is that of the New York Heart Association. In all, 9% of HIV-infected
patients with pulmonary arterial hypertension were in category IV, which is
indicative of very poor functioning.
Patients in this category were significantly older (p = 0.02), had a longer
duration of HIV infection (p = 0.02), were more likely to have a history of
heart failure (p < 0. 01), had a poorer six-minute walk distance assessment
(p < 0.0001), as well as poorer haemodynamic measurements (p = 0.01 to p <
0.01).
Antiretroviral therapy was immediately started by the 15 patients who were not
already taking it at the time of their diagnosis.
Specific treatment for pulmonary arterial hypertension was started by 50
patients, the most common being bosentam (45 individuals).
Treatment with antiretroviral therapy alone increased the six-minute walk
distance by a significant 18% (p = 0.04). However, it did not significantly
alter haemodynamic parameters.
At the end of follow-up, 26 patients had died and two had been lost to
follow-up. Fifteen of the 26 deaths were judged to be a consequence of
hypertension. The investigators calculated that the overall one-year survival
rate was 88%, the three-year rate 72%, and that 63% of individuals were alive
after five years.
These outcomes, the investigators note, are better than those seen in some other
studies of HIV-infected patients with pulmonary arterial hypertension.
However, the 63% five-year survival rate was significantly below the 85%
survival rate that would be expected in HIV-infected patients at diagnosis of a
first opportunistic infection.
Statistical analysis that controlled for potentially confounding factors showed
that a CD4 cell count below 200 cells/mm3 (odds ratio [OR], 6.26; 95% CI: 2.33
– 16.64, p = 0.0002) and a cardiac index below 2.81 l/m per m2 (OR, 5.02; 95%
CI: 1.70 – 14.29, p = 0.0028) were significant risk factors for poorer
survival.
“Pulmonary arterial hypertension remains a complication of HIV infection that
burdens the prognosis of HIV-infected patients”, write the investigators.
“Data from the current series indicate that HAART is very unlikely to improve
haemodynamic parameters in pulmonary arterial hypertension-HIV patients”, they
add.
They call for further studies to determine if “specific pulmonary arterial
hypertension therapy might be of benefit to HIV-infected patients with mildly
symptomatic pulmonary arterial hypertension”. They also recommend careful
follow-up of all patients with mild hypertension not receiving anti-hypertensive
treatment after starting antiretroviral treatment.
Reference
Degano B et al. HIV-associated pulmonary arterial hypertension: survival and
prognostic factors in the modern therapeutic era. AIDS 24: 67-75, 2010.
A new study has revealed
that stopping breastfeeding early might increase mortality risk among children
born to HIV infected mothers. By 4 months of age, children pass the critical
stage of development where breastfeeding is essential for their survival.
Longer breastfeeding is
necessary to protect children against potentially fatal and infectious diseases,
including HIV. To prevent post natal HIV transmission, however, mothers with HIV
should be on antiretroviral drugs.
Findings concluded that terminating breastfeeding before 4 months of the baby's
age, increases the mortality rate. Therefore, prolonged breast feeding plays a
significant role in protecting the child from HIV transmission.
The study results were
consistent for mothers not infected with HIV too.
"Our results help support the recent change in the World Health
Organization (WHO) guidelines for prevention of mother-to-child HIV
transmission," said study author, Louise Kuhn, Ph.D,
The new guidelines encourage post natal use of antiretrovirals through the
duration of breastfeeding to prevent vertical (mother to child) transmission.