--------------------------------------------------------------------------------

COMMUNITY BRIEFING: Multi-drug Resistant, Fast Progressing HIV in NYC
Project Inform Press Statement on the New York City Department of
Health Report of a "Super" Strain of HIV
Commentary: How Important is the New York Resistance Case?
U.S. NIH Chief Seeks Conflict-of-Interest Summit
Higher HIV Load Worsens Neuropsychological Functioning in Children
Transient Blips in HIV Viremia Not Clinically Significant
HIV Infection Increases Risk of Other STDs in Women
HIV Co-receptor Use in the Blood and Central Nervous System Differs in
20% of Patients
Low Weight in Women a Risk Factor for Severe Nevirapine Liver
Toxicities
Methamphetamine Use Can Worsen Brain Damage Caused by HIV Infection
HIV 'Could Destroy Cancer Cells'
Shape of Unbound HIV Gp120 Elucidated
GBV-C Infection Does Not Protect Against CD4+ Cell Loss or HIV
Progression
Risk of MI Increases with Longer HAART Exposure
Imatinib Can Produce Rapid Regression of AIDS-related KS Lesions
HIV Tat Protein Implicated in Amyloid Beta Accumulation in the Brain
Differences in HIV Viral Load Between Men and Women Can't be Explained
by CD8 Response, Finds Study
Fish Oils Can Reverse High Blood Lipids Caused by Antiretrovirals
Long-term CD4 Increase on HAART Averages 250-350 Cells, Plateaus After
3-4 Years
Addition of Capravirine to a Three-drug Regimen Not Beneficial in
Patients with NNRTI Resistance
Therapeutic Drug Monitoring Useful for Improving Treatment Outcomes in
Many Patients Taking HAART
MRSA in HIV-positive Patients Often Community Acquired, Associated
with HIV Disease Severity
Two New Drug Classes Given to People with HIV for the First Time
Therapeutic Vaccine Plus Interleukin-2 Shows Best Viral Control in
Treatment Breaks
ADVOCACY ALERT: Call Your U.S. Senators Before March 7—Or We May Lose


Also: "This Week @ The CFA"

Note: As many of you are already aware, The Rita! Weekly Newsletter
was not delivered last week. The editor apologizes for any
inconvenience this may have caused. This edition of the newsletter
contains news from Monday, February 14, 2005 though Friday, February
25, 2005. Thank you.

--------------------------------------------------------------------------------

1. COMMUNITY BRIEFING: Multi-drug Resistant, Fast Progressing HIV in
NYC
Community HIV/AIDS Champ Mobilization Project (2/25/05)

In the past several weeks, there has been much media attention on a
case of a man with HIV who progressed to an AIDS diagnosis in a
relatively short time, and whose virus is resistant to many kinds of
AIDS drugs. This has raised alarm for many people in a time in which
there is much fear of drug resistance as well as concerns about the
challenges of HIV prevention. This fact sheet has been created by HIV
prevention and treatment activists to supplement available materials
on this case. It will be updated as more information becomes
available, and was completed on February 24, 2004. We hope it will
present background information on this case and provoke additional
inquiry to understand more about its implications. In addition, it
presents historical data that might be useful in putting this case
into context. It does not repeat basic information on HIV prevention,
crystal meth, or the importance of medication adherence, as these are
available elsewhere. In addition, it does not address significant
concerns about the way this story was released and its subsequent
coverage in the media, which are initiated in other document and still
require additional discussion. We have collected some of these
additional materials on a webpage, including a community sign-on
letter, organizational statements, and a service provider advisory
from the New York State Department of Health [please see below].

For more information, contact:
Richard Jefferys, TAG / Richard.jefferys@verizon.net o 212-253-7922
Julie Davids, CHAMP / jdavids@champnetwork.org o 212-966-0466 x 1206

[To access the fact sheet and other information please visit:
http://www.champnetwork.org/index.php?name=newcase ]

2. Project Inform Press Statement on the New York City Department of
Health Report of a "Super" Strain of HIV
Project Inform (2/11/2005)

The New York City Department of Health and Mental Hygiene, in
collaboration with the Aaron Diamond AIDS Research Center, released a
press statement today reporting on a finding of man newly infected
with a multi-drug resistant strain of HIV. The report described the
man as being resistant to three classes of anti-HIV drugs and as
having a particularly virulent strain of HIV. Although the
transmission of drug-resistant HIV is a serious concern, Project
Inform believes that the current reports may be unnecessarily alarming
to the public. There is currently too little information available,
and doctors have followed the patient for too short a time, to draw
any conclusions about the significance of this situation. However,
several aspects of the story being reported warrant further
explanation.

First, there is nothing new about people becoming infected with
resistant strains of HIV, including multi-drug resistant strains. Such
cases have been reported at scientific conferences for the last
several years. In a study reported in the Journal AIDS : Volume 18(10)
2 July 2004, author Douglas Richman reports that "… Resistance to all
three drug classes was detected in an estimated 13.1% (of 17,300
patients) …" If triple class drug resistance is as common in the U.S.
as Dr. Richman reports, it is likely that we will continue to see some
portion of newly infected patients present with this level of
resistance.

The advisory and press statement from New York City suggests that the
patient is virtually untreatable, but this statement seems
contradicted by other claims in the same report. The article says that
the patient is responsive to the drug Fuzeon and may be responsive to
Sustiva. If responsive to Sustiva, he is not "resistant to 3 classes
of HIV medication" as claimed in the headline.

Another aspect of the reported case which is troubling is that the
patient has a low CD4+ count. This was being interpreted as a sign of
very rapid disease progression. However, it is common for people newly
infected with HIV to have a period of low CD4+ counts and high viral
load often lasting as long as 6 months after initial infection. Since
the researchers involved suspect that the patient was infected in
December 2004, it is not possible to determine at this time whether
the patient's low CD4+ count suggests a particularly aggressive form
of HIV or whether it is simply a reflection of the short time since
infection. Only longer follow-up will answer this question.

Another concern stated by the researchers is that the patient has what
is known as a "dual tropic" form of HIV. This means that the virus can
use either of two different secondary receptors on cells. This
characteristic is usually associated with virus seen in people with
advanced disease. At the very least, this means the patient acquired
the virus from someone with an advanced form of the disease. There is
as yet no evidence though that this means he will retain this form of
the virus over time.

We believe that it is premature to conclude that this event represents
evidence of a "superbug" or a particularly virulent strain of HIV, or
that the patient is "untreatable" or will suffer a particularly rapid
disease progression. These conclusions can neither be ruled in nor
ruled out at this time. What's needed is an extensive period of
follow-up and careful continued monitoring of the patient. In many
previously reported cases of people presenting with multi-drug
resistance, the characteristics of their virus changed over time and
they were able to develop normal sensitivity to the available drugs.

HIV infection presents a complex mix of factors that determine the
outcome in individual patients. These include the characteristics of
the initial virus a person acquires, but also how a person's immune
system responds to the virus, and in turn, how the virus evolves in
reaction to the immune system and any drugs used to treat it. No
single snapshot of data can accurately predict the course of disease
for an individual.

Project Inform shares the concern of scientists and public health
workers over the spread of resistant virus, but we also recognize how
difficult it is to predict the significance of any individual case and
what it may or may not mean for the at-risk populations. Every effort
must be made to stop the spread of HIV, regardless of whether it is in
drug resistant or drug sensitive form. We also believe that new
information should be studied carefully and interpreted with caution
and that care should be taken not to cause undue alarm when the facts
are uncertain, as they are in this case.

Our understanding of the current situation is based on extended
conversations with a number of AIDS experts and researchers, who like
us, can only base their assessments on the limited information
currently available. We strongly support the efforts of the New York
City Department of Health and Mental Hygiene to continue following
this case and to determine how frequently similar types of HIV
transmission might be occurring.

Established in 1985 as a national non-profit community-based
organization, Project Inform is the nation's leading independent
HIV/AIDS treatment information and advocacy resource. Relied upon for
information about optimal treatment strategies, access to care and
treatment, and advances in research, Project Inform is committed to an
integrated approach to treatment education, advocacy and inspiration
for people living with HIV/AIDS, their family, friends, caregivers,
healthcare and service providers.

Treatment Hotline: 800-822-7422 (toll-free) or 415-558-9051 (in the
San Francisco Bay Area and internationally)
Hotline hours: Monday, Wednesday–Friday, 9am–4pm and Tuesday, 9am–7pm
(Pacific Time)
Office Telephone: 415-558-8669
Fax: 415-558-0684
Web site: http://www.projectinform.org
Contact person: Martin Delaney, mdelaney@projectinform.org

3. Commentary: How Important is the New York Resistance Case?
AIDSmap.org (2/14/05) Carter M

New York City's health department has announced that a gay man in his
40s has been newly infected with a strain of HIV resistant to drugs
from the three main classes of antiretrovirals, and has experienced
rapid disease progression. In summary, the man was diagnosed with HIV
in December 2004, having previously received a negative test result in
May 2003. However, the man subsequently had unprotected anal sex with
multiple male partners, often after taking the recreational drug
methamphetamine. After his diagnosis, the man experienced rapid HIV
disease progression and has received an AIDS-diagnosis. On both sides
of the Atlantic, the media have been quick to pick up on the story,
warning of a new, 'impossible' to treat strain of HIV, and the
consequences of promiscuous sex and drug use.

But is the alarm generated by this case really justified? In actual
fact, very few details are available. Information about the man's case
is provided not in an article in a medical journal where the facts
have been verified by other doctors and researchers, but in a press
release which contains scant information. In this press release, New
York City health officials announced the man was infected with "3-DCR
HIV", a strain of HIV resistant to three of the four classes of
antiretroviral drugs, which is "difficult or impossible to treat." The
press release adds "cases of 3-DCR HIV in newly diagnosed, previously
untreated patients are extremely rare."

Rapid disease progression also appears to have occurred in this man's
case. New York City health officials state that the individual
progressed to AIDS "within two or three months, and at most 20 months,
after HIV infection" rather than the usual ten or more years. Details
are, once again, thin on the ground. New York City did not provide
details of the condition leading to the man receiving an AIDS
diagnosis. Once again, it appears journalists did not bother to ask,
although in their report the New York Times did state that the man had
experienced weight loss, and had a high viral load. Neither of these
symptoms necessarily indicates rapid HIV disease progression, indeed,
both can be indicative of the early stages of HIV infection.
Furthermore, it is well known that the precise rate of HIV disease
progression varies considerably from individual to individual.
Although it may take ten years or more in some patients, others
develop an AIDS-defining condition much more quickly, even when
"3-DCR" HIV is not present. Cases of rapid disease progression after
the acquisition of multi-drug resistant virus have been reported
rarely, and evidence presented at recent conferences suggests that the
transmissibility of MDR HIV is much lower than that of wild-type
virus.

Not all media reports accepted the New York City press release at face
value. In the UK, The Observer quoted Roger Pomerantz of Thomas
Jefferson University in Philadelphia who said "every medical centre in
a major metropolitan area will have a case like this. You've got to
really prove something before you go on CNN and scream about a
super-strain." They also contacted Dr Barry Evans of the UK Health
Protection Agency who urged caution, and said he was waiting for the
case to be published in a medical journal before reaching any
conclusions.

HIV prevention messages have been reiterated due to this case. The
City's Health Commissioner Thomas Frieden calling it a "wake-up call
to men who have sex with men", drawing attention to increased rates of
syphilis and the emergence of lymphogranuloma venereum (LGV) amongst
gay men in the city, and called on gay men to take action to prevent
the "devastation" that drug resistant HIV could cause. Concern has
also been expressed about the apparent use of methamphetamine by the
man. The drug has been associated with increased sexual risk-taking by
gay men in the US, and it has been suggested that the man in the New
York case may have experienced faster disease progression because of
his drug use behaviours. Sections of the media have used the case as
an excuse to revive a tone of moral panic reminiscent of the early
days of the HIV epidemic. The New York Times reported that the man's
case had implications for "promiscuous gay men" and sent a reporter to
the Big Cup gay coffee shop in the city's Chelsea district to find
that younger gay men who had not had the "searing" experience of
seeing friends die of HIV were reporting "complacency" due to the
success of antiretroviral therapy. A report in their February 14th
edition, found that gay men using the internet to seek sex in the city
were paying little attention to the warning of the "new" strain,
despite the fact that the man is thought to have met some of his
partners on-line.

There is no mention in any of the media reports of research which has
found that the recent syphilis outbreaks affecting gay men across the
US and Europe have an epidemiology separate from HIV. Nor is there any
reference to research actually looking at the sexual behaviour of gay
men since the advent of effective anti-HIV therapy which has found
little evidence of the complacency suggested by some reporters.
Perhaps the reason for the reaction to this case and its reporting
lies not in its medical significance, but in its importance to current
US debates on comprehensive or abstinence-only HIV prevention.

4. U.S. NIH Chief Seeks Conflict-of-Interest Summit
Reuters Health Information Services (2/14/05)

The head of the U.S. National Institutes of Health said he wants
government and academic leaders to meet to address conflicts of
interest in medical research, the Los Angeles Times reported on
Saturday."We need to have a summit discussion to say, 'Look, what is
the interest of the public?' The interest of the public is to make
sure the science that's done is not tainted," the Times quoted NIH
Director Dr. Elias Zerhouni as saying."We can't lose the public trust.
Not just at NIH, but into research in general. There is work to be
done. Stay tuned," he told the Times in an interview. The newspaper
said Dr. Zerhouni did not indicate whether he would organize such a
meeting.

On Feb. 1, the agency announced a ban on outside employment by its
scientists aimed at ending some high-profile consulting arrangements
that have tarnished the agency's image. The rule forbids any NIH
employee to work for pharmaceutical or biotechnology companies or
other organizations substantially affected by NIH policy such as
universities or non-profit groups that get NIH funding. Certain
employees also are barred from owning stock or investing in companies
affected by NIH, a flagship agency that funds much of the medical
research done in the United States. Dr. Zerhouni announced plans for
the new rules in June at a congressional hearing about reports that a
few NIH staffers had made hundreds of thousands of dollars in
consulting arrangements.The NIH is considered the world's premiere
research institution, with an annual budget of $28 million and 18,000
employees.

5. Higher HIV Load Worsens Neuropsychological Functioning in Children
Reuters Health Information Services (2/15/05) Boggs W

Higher viral load is associated with poorer neuropsychological
functioning that responds little to antiretroviral therapy in children
infected with HIV, according to a report in the February issue of
Pediatrics (115:2, p. 380, 2005). Given these findings, "perhaps
physicians treating HIV-infected children need to intervene with
medications as early as possible...to keep the viral load very low
from the start," Dr. Rita J. Jeremy from University of California, San
Francisco [stated]. Dr. Jeremy and colleagues investigated
neuropsychological functioning in 489 children who received one of
seven antiretroviral treatment regimens, six of which contained a
protease inhibitor, for 48 weeks.

A higher baseline viral load was significantly correlated with poorer
cognitive and fine-motor functioning, the authors report, but there
was no correlation between behavioral functioning and baseline viral
load. Except for minimal improvements in vocabulary scores, the report
indicates, treatment with a PI-containing regimen did not
significantly improve any of the neuropsychological measures.
Cognitive, short-term memory, vocabulary, and fine-motor score means
remained one third to one full standard deviation below the
age-related norms. Even children who achieved and maintained a viral
load at or below 400 copies/mL from week 24 to week 48 showed no clear
improvement in neuropsychological mean scores, the investigators
report.

"HIV is only one factor affecting children's brain development...Many
uninfected children of HIV-infected women fare poorly in this
respect," Dr. Jeremy said. "So besides an early pharmacological
intervention, physicians and healthcare providers need to coordinate
the medical care with social support for the children's families and
caregivers...to intervene early in some of the environmental factors,
such as nutrition, education, and parent mental health." "As
destructive as HIV infection is for children's brain development,
other factors in their life add up to affect them perhaps even more
and need to be dealt with as part of the children's treatment," Dr.
Jeremy added. "Among these factors are prenatal exposure to tobacco,
alcohol, other drugs, and malnutrition, and postnatal poor nutrition,
poor parental education, poor schooling, and poor housing."

6. Transient Blips in HIV Viremia Not Clinically Significant
Reuters Health Information Services (2/16/05)

Intermittent episodes of detectable viremia in patients with
well-controlled HIV infection represent random biological and
statistical variation, and may not be associated with new drug
resistance mutations, investigators report. "These results should
provide relief to hundreds of thousands of HIV-positive patients in
the United States currently taking drug therapy...and reassure them
that their medications have not failed," principal investigator Dr.
Robert F. Siliciano, a physician at Johns Hopkins University School of
Medicine in Baltimore, said in a University statement. Dr. Siliciano
and his associates prospectively followed 10 patients receiving HAART
who had achieved suppression of viremia to below 50 copies/mL. Blood
samples were drawn every 2 to 3 days for 3 to 4 months to check for
viral load, drug levels and drug resistant mutations.

A total of 18 blips occurred in 9 patients, lasting a median of 2.5
days, they report the February 16 issue of the Journal of the American
Medical Association (293:7, p. 817, 2005). Median magnitude of the
blips was 79 copies/mL (maximum 201 copies/mL), which is "consistent
with random variation around a mean level of 10 to 20 copies/mL," the
authors note. Seventy-eight percent occurred when drug levels were
above suggested trough concentrations. Blips were not associated with
demographic, clinical or therapeutic parameters, such as CD4 count,
number of drugs in the current regimen, intercurrent illnesses or
vaccinations. According to the investigators, the only factor for
which there was a marginal association (p = 0.08) was patient-reported
adherence.

The authors observed no new drug resistance mutations, either during
or immediately after blips, suggesting that blips do not lead to
resistance and "raising concerns about the usefulness of therapeutic
drug monitoring in the management of patients experiencing blips."
While concluding that viral blips may not be cause for clinical
concern, Dr. Siliciano's group also notes that "blips with a magnitude
of greater than 200 copies/mL or blips that are detected in at least
two independent or consecutive measurements may be more of a cause for
concern."

7. HIV Infection Increases Risk of Other STDs in Women
Reuters Health Information Services (2/17/05) Boggs W

Women infected with HIV-1 are at increased risk of infection with
other sexually transmitted diseases (STDs), according to a report in
the February 1 issue of The Journal of Infectious Diseases (191:3, p.
333, 2005). "Women with HIV-1 remain at risk for other STDs, some of
which may be asymptomatic," Dr. R. Scott McClelland from University of
Washington, Seattle [stated]. "It is important to ask about sexual
risk, to counsel women about the risk of STDs, and to provide patients
specific information about reducing the risk of these infections." Dr.
McClelland and colleagues used data from a 10-year prospective study
of 1215 female sex workers in Kenya to determine the effect of HIV-1
infection on the incidence of STDs and other genital tract infections.

HIV-positive women had 2.8-fold more genital ulcer disease, 1.6-fold
more gonorrhea, and 1.5-fold more vulvovaginal candidiasis than did
HIV-negative women, the authors report. There was also a trend toward
higher trichomoniasis rates among HIV-positive women. HIV status did
not, however, appear to influence the rates of syphilis, chlamydia,
cervical mucopus, cervicitis, bacterial vaginosis, and abnormal
vaginal discharge, the results indicate. Decreasing CD4 cell counts
were associated with increasing risk of genital ulcer disease and
vulvovaginal candidiasis in HIV-positive women, the researchers note,
but decreases in CD4 cell counts were not associated with an increased
risk of gonorrhea or trichomoniasis. Women who reported 100% condom
use experienced significantly lower incidence rates for gonorrhea,
chlamydia, cervical mucopus, genital ulcer disease, and bacterial
vaginosis, the report indicates. Reported condom use was not
associated with the incidence of other sexually transmitted diseases
in this cohort.

"Physicians should consider screening for STDs in HIV-1 seropositive
women who report risk factors for these infections," Dr. McClelland
concluded. "There is a need for operational research to explore the
best way to address the problem of STDs among women with HIV-1
infection," Dr. McClelland added. "Possible strategies include risk
reduction programs, improved diagnostic capabilities in resource
limited settings, periodic screening of asymptomatic patients [and]
periodic presumptive treatment." "Each of these strategies has
potential advantages and disadvantages," Dr. McClelland said.
"Operations research would help to clarify what is most effective and
cost-effective."

8. HIV Co-receptor Use in the Blood and Central Nervous System Differs
in 20% of Patients
AIDSmap.org (2/14/05) Gadd

HIV from the blood and cerebrospinal fluid of most patients with
detectable viral loads uses the same co-receptors to enter cells,
according to a study published in the electronic edition of The
Journal of Infectious Diseases (191: 6, p. 890, 2005) on 9 February.
However, the study found that a minority of patients have different
types of HIV in the two compartments. This may influence the risk of
developing AIDS-related dementia and the effectiveness of entry
inhibitor drugs that target HIV's co-receptors. In addition to the CD4
receptor, HIV also requires the presence of other co-receptors on the
cell surface to infect its target cells. Most HIV strains use the CCR5
receptor to infect macrophage cells. It is thought that macrophages
infected with HIV are a primary source of HIV crossing into the
central nervous system. Other HIV strains, called X4 viruses,
preferentially use the CXCR4 receptor to infect lymphocytes as well as
macrophages and microglial cells in the central nervous system.

"In general, R5 viruses predominate during early infection," explain
the study's authors. "X4 viruses are most often detected later in the
course of infection and may be associated with more-rapid CD4 T-cell
loss." To assess the relationship between co-receptor use by HIV in
the blood plasma and in the cerebrospinal fluid that surrounds the
brain and spinal cord, investigators from San Francisco analysed
co-receptor use in paired samples from a cohort of 46 HIV-positive
subjects with viral loads above 1000 copies/ml. The patients had a
median CD4 cell count of 245 cells/mm3 (range 5 to 612 cells/mm3), and
9 (20%) were receiving antiretroviral therapy. "Most cerebrospinal
fluid populations utilised CCR5 as the principal co-receptor, and the
majority of subjects had concordant tropism in the two compartments,"
they conclude. "However, approximately one fifth of subjects displayed
the R5+X4 phenotype in one or both fluids, and one tenth of subjects
had discordant plasma and cerebrospinal fluid tropism."

Each patient underwent lumbar puncture to extract a sample of
cerebrospinal fluid at the same time as a blood sample was taken. The
Pheno-Sense HIV entry assay was used to determine the co-receptor
favoured by the HIV particles extracted from each sample, and this was
compared to the patients' CD4 cell count, viral load and mental
function. In 38 plasma samples and 39 cerebrospinal fluid samples, R5
virus predominated. In contrast, none of the samples contained pure X4
virus, although six plasma and seven cerebrospinal fluid samples
contained a combination of R5 and X4 virus. R5 virus was more common
in patients with higher CD4 cell counts, as has been observed in
previous studies. However, the four patients with AIDS-related
dementia all had R5 virus in the cerebrospinal fluid. This is
consistent with the known role of infected macrophages in transporting
HIV into the central nervous system and R5 viruses damaging brain
cells.

Forty-one (89%) of the pairs of samples were concordant (36 for R5 and
five for R5+X4). However, two patients had R5+X4 in the cerebrospinal
fluid and R5 in the blood plasma, and three had the opposite pattern.
The investigators selected three patients with R5+X4 virus in blood,
cerebrospinal fluid or both for detailed genetic analysis of the
relationship between HIV species in the two compartments. In all three
cases, they found evidence of multiple exchanges of HIV species
between the blood and the cerebrospinal fluid. However, they also
concluded that some independent evolution HIV occurs within each
compartment, which may explain the low prevalence of discordance seen
in their full analysis. This, they argue, raises the possibility that
measurements of co-receptor use by HIV in the blood may not reflect
the make-up of the HIV throughout the body, increasing the risk of
failure of new entry inhibitor drugs that only target one co-receptor.
"Our detailed analysis…provides evidence of extensive, subtle
discordance between and variation within compartments," they write.
"Our results have implications not only for better understanding of
viral compartmentalisation but also for optimising future therapy with
chemokine-receptor entry inhibitors. "Screening of viral tropism in
plasma alone may be inadequate for determination of optimal therapy
with entry inhibitors… Assessment of co-receptor utilisation in
cerebrospinal fluid and other tissue compartments will contribute to
understanding the uses and short-comings of this mode of therapy
during clinical trials."

9. Low Weight in Women a Risk Factor for Severe Nevirapine Liver
Toxicities
AIDSmap.org (2/17/05) Carter M

The use of the nevirapine (Viramune) by women with a low body mass
index (BMI) should be discouraged, according to a study published in
the March 15 edition of The Journal of Infectious Diseases (191:6, p.
825, 2005) which found that women with a BMI below 18.5 who received
the drug were significantly more likely to develop severe liver
side-effects. Liver toxicities are a well established side-effect of
nevirapine, and the use of the drug is not recommended in men with a
pre-treatment CD4 cell count above 400 cells/mm3 and in women with a
pre-treatment CD4 cell count above 250 cells/mm3. Investigators wish
to determine the risk factors and symptoms associated with the
emergence of grade three or grade four elevations in ALT or AST levels
during the first twelve weeks of antiretroviral therapy. The study
population consisted of treatment naïve South African men and
non-pregnant women with a viral load above 5,000 copies/ml and a CD4
cell count above 200 cells/mm3. All patients were screened for
hepatitis B virus prior to entry to the study, and those who developed
liver toxicities were retrospectively tested for hepatitis C virus.

Individuals were randomised to receive either FTC or 3TC with d4T and
either nevirapine or efavirenz. A total of 468 individuals were
recruited to the study between August 1999 and February 2000, and they
were equally randomisation was equal between the nevirapine and
efavirenz arms. In total 66 (14%) patients developed severe
hepatotoxicity, with the frequency of severe liver toxicity being 17%
in the nevirapine arm and 0% in the efavirenz arm (p < 0.001). Amongst
men receiving nevirapine, the frequency of severe hepatotoxicity was
13% (20 individuals) and amongst women receiving the drug the
frequency was 20% (46 patients). The occurance of severe liver
toxicity was equal between nevirapine patients randomised to receive
FTC and 3TC. Clinical symptoms occurred in 83% of patients prior to
the diagnosis of hepatotoxicity. Symptoms included nausea, vomiting,
fever, malaise, rash, diarrhoea, jaundice and abdominal pain. Rash was
significantly associated with the occurrence of severe liver toxicity
(p = 0.01).

In multiple regression analysis, the investigators identified female
sex, BMI below 18.5, serum albumin levels below 35g/l, mean
corpuscular volume above 85fl, viral load below 20,000 copies/ml,
lactate dehydrogenase below 164IU/l and AST below 75IU/l as being
independent and significant risk factors for the emergence of severe
liver side-effects in the first twelve weeks of nevirapine treatment.
Women with a BMI below 18.5 had a 50% probability of experiencing
severe hepatotoxicity, however the probability for women with a BMI
above 18.5 was 17%. For men with a BMI below 18.5 the probability of
developing severe liver toxicities was 15% and 7% for men with a BMI
above 18.5. Two women died as a result of the severe liver toxicities
they developed during the study. Both had normal ALT and AST levels at
baseline and neither had hepatitis coinfection. ALT/AST levels
returned to grade two level or lower within a median of 37 days in
patients who continued taking nevirapine and in 19 days in patients
who stopped treatment.

"Our data demonstrate a high risk (17%) of early hepatotoxicity
associated with the use of nevirapine. The specific study population,
which consisted mainly of African women with relatively high baseline
CD4 cell counts (mean 398 cells/mm3), may have increased the
likelihood of hepatotoxicity. These observations are important,
because nevirapine is commonly used as a component in first-line
therapy, in resource limited settings, especially in women", write the
investigators. The investigators note that a low BMI was an
independent risk factor for the development of severe liver toxicities
amongst women taking nevirapine. They believe that a low BMI could
leave to over-exposure to nevirapine, which triggers toxicity. Doctors
should avoid treating women with a BMI below 18.5 with nevirapine,
conclude the investigators and should conduct weekly monitoring of
ALT/AST levels to spot the early signs of liver toxicity during the
initial weeks of treatment with the drug when it is used. Rash,
nausea, or fever during the first twelve weeks of nevirapine treatment
should trigger closer monitoring.

10. Methamphetamine Use Can Worsen Brain Damage Caused by HIV
Infection
AIDSmap.org (2/18/05) Gadd C

Long-term heavy use of methamphetamine can exacerbate the damage to
brain cells caused by HIV, according to a study presented in the
February edition of The American Journal of Psychiatry (162:2, p. 361,
2005). Although both methamphetamine use and HIV infection contributed
to brain damage, the study showed that their effects were additive,
and not due to a more complex interaction between HIV and drug use.
Methamphetamine ('crystal meth' or 'ice') is a psychostimulant drug
that is commonly used by HIV-positive and –negative people. It can be
injected, smoked or 'snorted'. The use of methamphetamine has been
identified as an important factor in the spread of HIV, not only
through unsafe injection practices, but also through its association
with increased rates of unprotected sex in both men and women. Studies
have shown that long-term methamphetamine users exhibit similar
changes in behaviour to patients with HIV-associated dementia. These
include slowed reaction times and poor decision-making, memory,
attention and concentration skills.

As previous investigations have suggested that similar toxic effects
in the brain cause these psychological effects, this study set out to
determine how methamphetamine use affected the development of brain
abnormalities caused by HIV. Investigators from Hawaii, California and
Germany carried out brain scans on 68 HIV-positive and 75 HIV-negative
volunteers. Twenty-four of the HIV-positive, and 36 of the
HIV-negative subjects had a history of methamphetamine dependence or
abuse. This was defined as methamphetamine use for at least a year as
the primary drug of abuse, with an average dose of at least 0.25g per
day on two or more days per week. The investigators scanned three
regions of each volunteer's brain using a technique called proton
magnetic resonance spectroscopy. This allowed them to measure the
levels of the metabolite N-acetylaspartate, a marker of neurones, the
electrically active cells that transmit signals through the brain.
They also measured levels of choline and myo-inositol, which are found
in the brain's structural 'glial' cells.

Volunteers with a history of methamphetamine use showed lower
concentrations of N-acetylaspartate in the 'basal ganglia' (-4%, p =
0.03), an area of the brain involved in the co-ordination of movement.
In agreement with previous studies, this indicated that there had been
damage to neurones in this brain region. In contrast, methamphetamine
users had higher levels of choline in the 'frontal white matter' (5%,
p = 0.03) and the 'frontal cortex' (10%, p = 0.008). Myo-inositol
levels were also 9% higher in the frontal cortex (p = 0.009),
suggesting that inflammation had occurred in these areas of the brain,
which are involved in thinking, planning and decision-making. HIV
infection caused similar patterns of change. The HIV-positive
volunteers had lower levels of N-acetylaspartate in the frontal cortex
(-5%, p = 0.001) and in the basal ganglia (-5%, p = 0.004) than the
participants who were uninfected. They also had higher levels of
myo-inositol in the frontal white matter (7%, p = 0.01). In all three
brain regions, there was an additive effect of methamphetamine and HIV
on the levels of N-acetylaspartate (basal ganglia: -9%, p < 0.001;
frontal white matter: -6%, p = 0.02; frontal cortex: -6%, p = 0.03).
There were no differences in HIV disease stage between the drug and
non-drug groups.

"The HIV-positive subjects with a history of chronic methamphetamine
use had the lowest concentration of N-acetylaspartate in all three
brain regions studied, compared to the other three subject groups,"
state the investigators. "This finding suggests significant neuronal
loss or dysfunction in these brain regions." Similarly, HIV and
methamphetamine use had an additive effect on creatine levels in the
basal ganglia (-7%, p = 0.007) and on myo-inositol in the frontal
white matter (12%, p = 0.02). The investigators speculate that the
additive effect of HIV and methamphetamine may be related to the
drug's effect on the neurotransmitter dopamine. Methamphetamine causes
the release of massive amounts of dopamine from the ends of neurones,
notably in the basal ganglia. This release of dopamine often causes
the ends of the neurones to shrivel and eventually die back. The
researchers hypothesise that this release of dopamine can also
stimulate HIV replication and worsen the damage caused by the drug.

"As predicted, the region most affected was the basal ganglia, which
has the highest density of dopaminergic nerve terminals," they
explain. "One possible pathway to the combined neurotoxicity might be
a methamphetamine-induced increase in extracellular dopamine, which in
turn would activate HIV replication." These results from brain scans
of living volunteers mirror previous findings from animal experiments
and post mortem studies of human brain. "Future studies using other
non-invasive neuroimaging techniques...may provide further insights
into the in vivo pathophysiological changes associated with the
combined effects of HIV and methamphetamine," the investigators
conclude.

11. HIV 'Could Destroy Cancer Cells'
BBC News (2/13/05)

US scientists hope to be able to use a harmless form of the AIDS virus
to seek and destroy cancer cells. A University of California team
found an "impotent" version of HIV, with the disease-causing parts of
it removed, tracked down cancer cells in mice. The next step would be
to insert a gene into the virus that would kill the cancer upon
contact. The team told Nature Medicine more safety studies were needed
before such a method could be tested in humans.

Gene therapy
The mice they studied had a form of skin cancer, called melanoma, that
had spread to the lungs. In the laboratory, the scientists took HIV
and removed the parts of the virus that causes disease. They then
stripped off the virus' outer coat and redressed it with the outer
suit of another virus. By doing this, the researchers had changed the
target of the virus. HIV normally infects immune cells called T cells.
The new outer coat instead directed HIV to hunt down molecules present
on cancer cells, called P-glycoproteins. The scientists also added a
substance to the virus that would make it visibly glow when looked at
with a special camera so they could track where it travelled once
injected into the mice. Researcher Dr Irvin Chen, from UCLA's Aids
Institute, said: "The virus travelled through the bloodstream and
homed straight to the cancer cells in the lungs, where the melanoma
had migrated. "Gene therapy has been hampered by the lack of a good
carrier. Our approach proves that it is possible to develop an
effective carrier and reprogram it to target specific cells in the
body."

Beating cancer's spread
His team is planning to see whether the virus could carry a
therapeutic gene to the precise location of the cancer. As well as
controlling cancer, they hope this technique might be useful for
treating genetic diseases. Dr Georges Vassaux, from Cancer Research
UK's clinical centre at Barts and The London, said: "This is the first
time that a vector - or delivery system - for gene therapy has
targeted a tumour in such a specific manner. "This means the technique
could be used to use gene therapy in cases where cancer has spread
around the body. "So far gene therapy has been successfully used only
on tumours that are confined to their original location." He said
there had been concerns that such methods might cause leukaemia in
normal cells. "As the team has managed to target the therapy to cancer
cells, it looks as though a hazard associated with the use of
integrative viruses may have been overcome," he said.

12. Shape of Unbound HIV Gp120 Elucidated
Reuters Health Information Services (2/23/05)

Researchers at the Children's Hospital Boston and Harvard Medical
School in the United States have determined the three-dimensional
conformation of HIV's envelope protein gp120, before it binds to CD4
receptors on target cells. The structure of the protein after it binds
to the receptor has already been deciphered. "Knowing how gp120
changes shape is a new route to inhibiting HIV—by using compounds that
inhibit the shape change," Dr. Stephen Harrison, head of the research
team, said. Peter Kwong, of the National Institutes of Health in
Maryland, described the research using X-ray crystallography as a
"technical tour de force," because scientists have sought the
structure of unliganded gp120 for almost 20 years. "In terms of
vaccine design, the structure ... reveals the envelope at its
potentially most vulnerable," he said in a commentary in Nature (433:
7028, p. 834, 2005). "The findings also will help us understand why
it's so hard to make an HIV vaccine, and will help us start
strategizing about new approaches to vaccine development," Dr.
Harrison explained in a statement. "We can now compare the bound and
unbound forms and try to understand whether there are any immunologic
properties that differ and that might provide a route to new vaccine
or drug strategies," said Dr. Harrison.

13. GBV-C Infection Does Not Protect Against CD4+ Cell Loss or HIV
Progression
Reuters Health Information Services (2/24/05)

Despite earlier studies suggesting that GB virus C (GBV-C) infection
may protect against HIV-1 disease progression, a new study shows no
such protection. However, loss of GBV-C, as opposed to its continuous
absence, appears to be associated with accelerated progression of
HIV-1 disease, investigators report in The Journal of Infectious
Diseases for March 1 (191: 5, p. 678, 2005). There are conflicting
reports on what effect GBV-C co-infection has on HIV-1 disease
progression. Some research groups have observed a strong association
between GBV-C viremia and improved survival in HIV-infected patients
(See Reuters Health report Feb. 13), while others have not (See
Reuters Health report May 3, 2004). Dr. Akke K. Van der Bij from the
Municipal Health Service of Amsterdam and colleagues studied this
issue in 326 men with an established date of HIV-1 seroconversion who
were followed for a median of 8 years in The Amsterdam Cohort Studies.
For each participant, researchers tested a first plasma sample
obtained at entry shortly after seroconversion and a last serum sample
obtained before 1996 for GBV-C RNA and envelope protein-2 antibodies
(anti-E2).

Tests on the first samples revealed GBV-C RNA in 137 men (42%) and E2
antibodies, signifying resolved GBV-C viremia, in 134 men (41%). Tests
on the last sample revealed GBV-C RNA in 69 men (21%) and E2
antibodies in 126 (39%). According to the investigators, "men who lost
GBV-C RNA between collection of the first sample and collection of the
last sample had a nearly 3-fold higher risk of HIV-1 disease
progression than did men who never had GBV-C RNA." However, the
negative effect of GBV-C RNA loss on disease progression disappeared
when the researchers adjusted for changes in CD4+ cell count, they
report. Therefore, it seems that "GBV-C RNA loss is due to CD4+ cell
loss, not vice versa," they hypothesize. Because GBV-C can replicate
in CD4+ cells, a drop in CD4+ cells during the course of HIV-1
infection reduces the number of target cells for GBV-C. "This might
explain why GBV-C RNA loss is associated with an increased risk of
death in HIV-1-infected individuals," the investigators write. GBV-C
infection has been "seriously considered as a potentially protective
agent in the fight against HIV-1 disease progression," the authors
point out. Based on the current study, they urge caution until further
studies are performed in large, well-defined cohorts of HIV-1-infected
patients.

14. Risk of MI Increases with Longer HAART Exposure
Medscape Medical News (2/24/05) Ready T

While the risk of myocardial infarction (MI) remains "modest" for
patients receiving highly active antiretroviral therapy (HAART), it
increases with longer exposure, researchers reported here yesterday at
the 12th Conference on Retroviruses and Opportunistic Infections
(Abstract: 42, 2/23/2005). At baseline, the incidence of MI was 1.39
per 1,000 patient-years for HAART-naive patients. The incidence
increased to 2.53 per 1,000 patient-years for those receiving HAART
for less than one year, and to 6.07 per 1,000 patient-years for those
exposed to HAART for more than six years, according to the latest
results from the Data Collection on Adverse Events of Anti-HIV Drugs
(D:A:D) study, a ongoing observational study of 23,000 HIV-infected
patients from 11 cohorts in Europe. The D:A:D study is led by Jens D.
Lundgren, MD, DMSc, director of the Copenhagen HIV Programme. The
effect of combination therapy exposure on the risk of MI was equally
observed regardless of sex and age. Elevated cholesterol levels
appeared to explain a portion of the association between HAART and the
risk of MI, but not the entire effect, according to Dr. Lundgren.

The findings suggest that physicians need to closely monitor HAART
patients with risk factors for cardiovascular disease, said Wafaa
El-Sadr, MD, MPH, the Columbia University researcher who presented the
data. The increase in risk remained unchanged when the researchers
included repeat MIs, when they looked only at definite MIs, and when
they looked at patients who were treatment-naive when they entered the
study, according to the abstract. Although the MI rate was higher for
men than for women (relative risk [RR], 2.04; 95% confidence interval
[CI], 1.30 - 3.21), the RR was similar for men (RR, 1.14; 95% CI, 1.06
- 1.24) and women (RR, 1.38; 95% CI, 107 - 1.76). The researchers also
found few differences in the RR for younger and older patients (P =
.51 for the interaction). Older patients were women older than 55
years and men older than 45 years. Adjusting for cholesterol levels
lowered per year of HAART risk from 1.17 per year of HAART to 1.10.
But lipodystrophy was not associated with a higher risk of MI (RR,
0.99; 95% CI, 0.75 - 1.30).

Physicians should routinely evaluate a patient's risk of heart disease
before starting HAART, whenever the HAART regimen is changed, and once
a year while receiving therapy, according to a separate presentation
by Esteban Martinez, MD, from the Infectious Diseases Unit at the
Hospital Clinic in Barcelona, Spain. The evaluation should include
taking a medical history and tests for cholesterol and blood pressure
levels. Physicians should recommend traditional lifestyle changes to
lower high lipid levels, including diets low in saturated fat,
exercise, and smoking cessation; smoking is often high in HIV-infected
cohorts, he said. Dr. Martinez recommended a two-step approach for
HIV/AIDS patients with elevated or borderline lipid levels. For
treatment-naive patients, physicians should initially try HAART with a
lower lipid impact, and if that fails, move to lipid-lowering therapy.

For treatment-experienced patients, physicians should start with
lipid-lowering therapy and if that fails, try changing the HAART
regimen. He suggested that patients receiving protease inhibitors
should be switched to nonnucleotide reverse transcriptase inhibitors
or to antiretroviral therapy like atazanavir (Reyataz). Patients
receiving stavudine (d4T or Zerit) should be switched to tenofovir dF
(Viread or TDF), according to Dr. Martinez. As the link between HAART
and MI becomes clearer, researchers need to move toward understanding
how the drugs drive the increase in cardiovascular risk, principal
investigator Dr. Lundgren [stated]. "Exactly how that operates is the
key research question," he said. "We are making headway in this
respect."

15. Imatinib Can Produce Rapid Regression of AIDS-related KS Lesions
Reuters Health Information Services (2/25/05) Harding A

Blocking two receptors believed to be involved in the progression of
Kaposi's sarcoma (KS) causes clinical and histologic regression of KS
lesions in some cases, a new study shows. Both the platelet-derived
growth factor (PDGF) receptor and the c-kit receptor have been
implicated in the formation of KS lesions, Dr. Bruce J. Dezube of Beth
Israel Deaconess Medical Center in Boston and colleagues note in their
report in the February 10 issue of the Journal of Clinical Oncology
(23: 5, p. 982, 2005). They conducted the current study to determine
whether Gleevec (imatinib), currently used to treat chronic
myelogenous leukemia and gastrointestinal stromal tumors, might be
useful in AIDS-related KS, because the drug is known to be active
against both c-kit and PDGF.

Ten patients with AIDS-related KS that had not responded to highly
active antiretroviral therapy (HAART) were given 300 mg of Gleevec
twice daily for four weeks. Tumor measurements showed a partial
response in half of the patients, while tumor biopsies of six patients
found histological regression in four. Of particular interest,
immunohistochemistry showed that, in three of the biopsies, treatment
resulted in reduced activation of the PDGFR and extracellular receptor
kinase (ERK) pathways. ERK is a downstream effector of PDGFR. "This is
really translational science," Dr. Dezube [stated]. The molecular
findings of the current study are more important than the clinical
ones, he added, particularly as there is already an effective,
well-tolerated medication for KS—Doxil (liposomal doxorubicin)—taken
by thousands of patients. "We almost did it like a proof of principle
trial—we wanted to see if it affected the genes," he explained.
Gleevec, which was given at a higher-than-normal-dose in the current
study, was poorly tolerated by patients, with all developing diarrhea.
It is not clear, the researchers note, whether this was because the
drug interacted with HAART. The researchers are now conducting a study
in 80 KS patients using a 400 mg daily dose of Gleevec to further
evaluate efficacy and toxicity of the drug.

16. HIV Tat Protein Implicated in Amyloid Beta Accumulation in the
Brain
Reuters Health Information Services (2/25/05) Rauscher M

The HIV-1 Tat protein inhibits neprilysin, the main amyloid beta
degrading enzyme in the brain, leading to elevated amyloid beta levels
in the brain, two AIDS researchers report in the January 28 issue of
AIDS (19:2, p. 127, 2005). "This is an important report because it
strongly suggests that individuals with HIV-1 infection may have an
unusually high burden of amyloid beta in their brain at an age where
healthy individuals have little to none," Dr. Lynn Pulliam from the
University of California-San Francisco [stated]. Amyloid beta
accumulation is thought to be neurotoxic and a precursor for
Alzheimer's disease, although it alone may not be sufficient to cause
the disease. Neuroinflammation, also present in individuals with HIV-1
infection, plus genetic polymorphisms, like APOE4, are also considered
to be contributors.

In an in vitro neural cell aggregate model, Dr. Pulliam, in
collaboration with Dr. Hans C. Rempel, observed that HIV-1 Tat
inhibited neprilysin activity by 80%. Adding recombinant Tat directly
to brain cultures resulted in a 125% increase in soluble amyloid beta
levels. Moreover, diffuse amyloid plaque was significantly increased
in postmortem brain tissue from patients with HIV-1 infection compared
to age-matched HIV-seronegative controls. "Surprisingly," Dr. Pulliam
said, "people who had been infected the longest had the most amyloid
beta so there was not a correlation with age but rather length of
infection. This, unfortunately, suggests that individuals infected
with HIV-1 early may have an unusually high amyloid beta load at an
early age, in their 40's or earlier," she said.

"Clinically, we need to identify which individuals are harboring an
increased amyloid beta load," Dr. Pulliam continued. "Treatments will
probably be similar to treatment of Alzheimer's, with antiretrovirals
to keep viral load down. It would make sense that those with a high
viral load may be at risk," she concluded. Co-authors of an editorial
in the journal make the point that current antiretroviral therapies
have no impact on Tat production once the cell is infected and
proviral DNA produced. "This may be particularly important in the
brain where the virus may be sequestered in glial cells and
macrophages and may evolve over a period of time," Drs. Avindra Nath
from Johns Hopkins in Baltimore and Louis B. Hersh from the University
of Kentucky in Lexington note. "Hence understanding the interactions
of Tat with the aging brain may be critically important."

17. Differences in HIV Viral Load Between Men and Women Can't be
Explained by CD8 Response, Finds Study
AIDSmap.org (2/22/05) Carter M

Lower HIV viral load in women in the early years of HIV infection
cannot be explained by the sex-based differences in the strength of
HIV-specific CD8 cell response, according to a small US study
published in the March 15 edition of The Journal of Infectious
Diseases (191: 6, p. 881, 2005). The investigators did however find
that the strength of CD8 cell response in women was associated with a
lower CD4 cell count than that seen in men five to seven years after
initial infection with HIV. Several studies have demonstrated a close
relationship between HIV viral load and the strength of HIV-specific
CD8 cell response. In the period after initial infection with HIV, CD8
response is associated with control of HIV replication and a lower
viral load. Loss of CD8 cell response is associated with increased
levels of HIV and faster disease progression. Investigators
hypothesised that the lower HIV viral load seen in women in the early
years of HIV infection was associated with a stronger CD8 HIV-specific
response than that seen in men. They also reasoned that the strength
of this response weakened in women during the course of HIV infection,
just as sex-based differences in viral load diminished.

To test these hypotheses investigators studied frozen blood samples
obtained between 1988 and 1989 from injecting drug users enrolled in a
longitudinal study. A documented date of HIV seroconversion was
available for all the blood samples. Frozen blood samples were
available for two time periods: period A, zero to two years after the
estimated date of HIV seroconversion and period B, five to seven years
after initial infection with HIV. The date of HIV seroconversion was
estimated as the midpoint between the individuals' last negative HIV
test and the date of their HIV diagnosis. A total of 18 men and 15
women were included in the investigators analysis. During period A the
investigators were surprised to see that more men (39%) had a CD8
HIV-specific response than women (13%). By period B, 67% of both men
and women had a CD8 HIV-specific response. Although viral load was
higher in men than women at both period A (approximately 30,000
copies/ml versus 15, 000 copies/ml, p = 0.94) and period B (58,000
copies/ml versus 43, 000 copies/ml, p = 0.84), at neither period was
the difference significant.

In addition, the investigators were surprised to see that at time B a
strong HIV-specific CD8 cell response was associated with a
significantly lower CD4 cell count in women (p = 0.05). "The most
significant finding of this study was that a correlation between
immune status and CD8 effector response was found in women but not
men, particularly at time B", write the investigators, adding "in
women, but not men, a stronger CD8 effector response was associated
with a lower number of CD4 lymphocytes." The investigators' initial
hypotheses, that lower HIV viral load in women would be associated
with stronger HIV-specific CD8 cell response was not confirmed, in
fact, although the difference was not statistically significant, men
were found to have a stronger HIV-specific CD8 cell response at period
A.

18. Fish Oils Can Reverse High Blood Lipids Caused by Antiretrovirals
AIDSmap.org (2/24/05) Gadd C & Alcorn K

Increased levels of blood lipids caused by the administration of
antiretroviral drugs can be decreased by fish oil capsules, according
to the results of a randomised controlled trial presented on Wednesday
at the Twelfth Annual Retrovirus Conference in Boston (Abstract: 39,
2/23/2005). Maxepa is a formulation of fish oils rich in omega-3 fatty
acids that has been shown to reduce low density lipoprotein (LDL)
cholesterol and triglyceride levels in adults without HIV infection.
This study was carried out to assess whether it could also reduce
triglyceride levels and the risk of heart disease in HIV-positive
patients taking antiretroviral therapy.

Researchers in France randomised 122 HIV-positive individuals on
highly active antiretroviral therapy to receive either two 1g capsules
of Maxepa three times a day or placebo for eight weeks, followed by
eight weeks of open-label Maxepa treatment for all patients. All
participants had baseline triglyceride levels above 2g/l after four
weeks of diet intended to reduce triglyceride levels, and the mean
baseline triglyceride level was 4.5g/l. After eight weeks of
treatment, the 58 patients randomised to receive Maxepa had
experienced a median 26% reduction in triglyceride levels, compared to
a 1% increase in the placebo group (p = 0.003). Triglyceride levels
normalised in 22% of Maxepa recipients, but in only 7% of the placebo
group (p = 0.012). The reduction in triglyceride levels was sustained
during the open label treatment period among those originally
randomised to Maxepa, whilst median levels fell by 21% during this
phase among those who originally received placebo. There were no
changes in total or high density lipoprotein (HDL) cholesterol over
the course of the study in either group.

Ten patients with baseline triglycerides above 10g/l were given open
label Maxepa treatment. These patients also experienced a 44%
reduction in triglycerides after eight weeks' treatment, demonstrating
that Maxepa is even effective in patients with severe elevations in
blood lipids. Pierre de Truchis, presenting, said that the treatment
was well tolerated, with no significant differences between the Maxepa
and placebo groups in reported adverse events. The researchers suggest
that Maxepa treatment, despite the high pill burden and dosing
frequency, may represent an attractive option for first-line treatment
of elevated triglycerides because of a lack of drug interactions and
good efficacy.

19. Long-term CD4 Increase on HAART Averages 250-350 Cells, Plateaus
After 3-4 Years
AIDSmap.org (2/25/05) Cairns G

A series of four poster presentations at the 12th Retrovirus
Conference looked at the immune recovery of patients staying on HAART
for periods of between three and seven years and found that the
average CD4 count increase achievable on HAART appears to be in the
region of 350. They found median CD4 increases varying from 230 over
3.6 years in a Spanish study to 337 over 4.75 years in a French one.
The study with the longest follow-up period of all, which followed
patients from the Swiss HIV cohort for seven years, found a CD4 count
increase over that period of 349 in patients who had never interrupted
therapy but only 153 in patients whose therapy had ever been
interrupted, despite the fact that the median length of therapy
interruption was only 32 days. Three of the four studies also found
that 11-14% of patients starting HAART at low CD4 counts never
achieved a CD4 count over 200, while a fourth study with the shortest
follow-up time (just under three years) found one in six patients did
not a achieve a CD4 increase within that time of more than 100 cells.

In a discussion session, the poster presenters debated their
conflicting conclusions as to whether CD4 cells continue to increase
on HAART or reach a 'plateau' after 3-4 years; the consensus was that
counts scarcely increase after this time except in patients who start
with the very lowest CD4 counts. An interesting chart on the Swiss HIV
Cohort study poster illustrated that CD4 counts over time tend to
converge. The largest CD4 increases over the seven years were in the
people who started HAART at the lowest CD4 counts (under 100);
conversely people starting HAART at the highest CD4 counts (over 700)
actually had a slight fall in CD4 counts. Some investigators suggested
this was evidence of a homeostasis mechanism in the immune system that
adjusts T-cell counts to a pre-determined limit. The four studies
featuring long-term immune recovery were:

The French APROCO study. This enrolled 1281 patients on to a
protease-inhibitor-based regimen between 1997 and 1999. The poster
looked at a subset of 438 patients who remained completely
virologically suppressed, with no viral load reading over 500, over an
average follow-up period of just under five years. It found a median
CD4 rise of 337 cells in these patients and evidence of a 'plateau
effect'; after three years, the average CD4 count rise was 0.5 cells a
month, statistically equivalent to zero. It found that 15% of patients
starting HAART at a CD4 count under 100 never achieved a count over
200, even though remaining virally suppressed (Le Moing) (Abstract:
609)
The American ACTG 384 study. This study enrolled 980 people to compare
the effect of six different NRTI/PI combinations. It had the shortest
follow-up period (just under three years). The median CD4 count
increase over this time was 252, with no evidence of a 'plateau'
before three years, and 16 per cent of subjects had increases of less
than 100 despite continued viral suppression. Women and younger people
had slightly higher CD4 count increases. It found that patients with
higher baseline viral loads had higher CD4 increases – the opposite to
what the APRCO study found (Abstract: 610).
The Spanish PISCIS study. This looked at 1542 patients treated mainly
with PI-based regimens, 787 of whom remained virally suppressed over
the median follow-up time of 3.6 years. This study looked at the
patient group as a whole, not only at the fully-suppressed patients,
and found a median CD4 count rise of 230 over this time, with eleven
per cent of patients never achieving a CD4 count over 200. They found
evidence of a 'plateau' after four years, except among patients who
had started with a CD4 count under 100 (Abstract: 611).
The Swiss HIV Cohort Study. This found a median CD4 rise of 302 cells
among 6497 patients followed-up for seven years. Forty-one per cent
had CD4 increases of over 500 and 13 per cent of less than 200.
Forty-two per cent remained virally suppressed for the seven years. As
detailed above, the most striking finding was that having had a
treatment break made a big difference to immune recovery (Abstract:
612).

20. Addition of Capravirine to a Three-drug Regimen Not Beneficial in
Patients with NNRTI Resistance
AIDSmap.org (2/25/05) Mascolini M

Capravirine, a new nonnucleoside reverse transcriptase inhibitor
(NNRTI), failed to control HIV better than placebo in a 48-week study
of people with resistance to NNRTIs, according to a report at the
Twelfth Conference on Retroviruses and Opportunistic Infections held
in Boston, Massachusetts (Pesano, R; Abstract: 550). However, a
subgroup analysis suggested that a regimen including capravirine,
nelfinavir, and two nucleoside reverse transcriptase inhibitors
(NRTIs) had some activity against virus resistant to both zidovudine
and lamivudine. In vitro studies indicate that capravirine is able to
inhibit some HIV strains resistant to current NNRTIs. Laboratory work
also suggests that resistance to capravirine evolves more slowly than
to other NNRTIs, Rick Pesano, MD, PhD reported.

The current trial randomised people taking a failing NNRTI regimen to
receive 700mg or 1400mg of capravirine twice daily or placebo. All
participants also received twice-daily nelfinavir and two NRTIs picked
on the basis of treatment history and genotype. None of the 179 study
participants had been previously treated with a protease inhibitor.
Trial enrollees had moderately advanced disease, with an average viral
load around 4.4 log copies/mL and median CD4 counts of 206 cells/mm3
in the placebo group, 248 cells/mm3 in the 700-mg capravirine group,
and 249 cells/mm3 in the 1400-mg capravirine group. Resistance to
NRTIs and NNRTIs was similar across the study arms. Pesano reported
48-week failure rates—defined as failure to reduce the viral load by
0.5 log by Week 4, or rebounding after a 0.5 log reduction—of 24% with
placebo, 15% with 700 mg of capravirine, and 13% with 1400 mg,
differences that were not statistically significant. The reductions in
viral load from baseline to Week 48 also did not differ significantly:
2.1 logs, 2.3 logs, and 2.4 logs, respectively.

A 48-week noncompleter-equals-failure analysis determined that 58% of
patients taking 1400 mg of capravirine twice daily had a viral load
below 400 copies/ml, compared with 43% taking 700mg twice daily, and
46% taking placebo. These differences also fell short of statistical
significance. In a preplanned analysis of nonrandomised subgroups who
began treatment with virus resistant to zidovudine and lamivudine, 54%
in the 1400mg group had a viral load under 400 copies/ml at Week 48,
compared with 36% taking 700mg, and 31% taking placebo. This trend was
not statistically significant, however. The better noncompleter
response with 1400mg of capravirine partly reflects the high dropout
rates in the other 2 arms—44% with placebo, 42% with 700mg
capravirine, and 30% with 1400mg capravirine. Whereas 15% of patients
stopped the 700mg dose because of side effects, 7% stopped the 1400-mg
dose for that reason.

Diarrhoea affected 65% in the 1400mg group and 53% in the 700mg group.
However, diarrhoea also was reported by 49% given placebo, and the
incidence of diarrhea in all treatment arms may have been due to
nelfinavir therapy. Rates of nausea were 35% with 1400mg, 27% with
700mg, and 20% with placebo. Dr. Pesano noted that the high failure
rates in all three study arms came as a surprise, since people started
nelfinavir with no protease inhibitor experience and also began
carefully chosen NRTIs. The study outcomes will be further scrutinized
as the development of capravirine continues.

This content licensed to aidsmap by iMedOptions, publishers of
http://clinicaloptions.com. Copyright iMedOptions, LLC, 2005.

For more coverage of CROI from Clinical Care Options for HIV,
including news reports, detailed Capsule Summaries and PowerPoint
slides of the key studies, and analysis from our panels of leading
experts, visit http://clinicaloptions.com/croi 

21. Therapeutic Drug Monitoring Useful for Improving Treatment
Outcomes in Many Patients Taking HAART
AIDSmap.org (2/26/05) Gadd C & Bernard E

Two studies presented in poster discussion sessions on Thursday at the
Twelfth Annual Retrovirus Conference in Boston confirmed the
importance of therapeutic drug level monitoring in monitoring the
effectiveness of antiretroviral therapy (Abstract: 639, Abstract: 640,
2/24/05). The studies found that measuring levels of protease
inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors
(NNRTIs) in patients can be used to ensure that drug levels are high
enough to suppress HIV and to guide decisions on dose adjustments when
high levels of drug lead to toxicity. It is also more useful in
patients with higher body weight and taking certain antiretroviral
drugs. Researchers from France performed therapeutic drug monitoring
on 115 PI-naive individuals who had recently begun highly active
antiretroviral therapy (HAART). Forty-two patients were taking
indinavir (Crixivan) boosted with ritonavir (Norvir), 38 were on a
ritonavir-boosted lopinavir (Kaletra)-based regimen, and the remaining
35 were taking nelfinavir (Viracept) as 625mg tablets.

All PIs were dosed twice daily, and drug levels were measured at weeks
2, 8 or 16, 24, and 48 after initiating HAART. During the first 24
weeks, PI doses were adjusted if trough concentrations were outside of
the manufacturers' recommended range. After 48 weeks, failure, which
was defined by either two consecutive viral load tests above 200
copies/ml after week 16, or a PI-related adverse event, was observed
in three, five, and twelve participants taking indinavir, lopinavir
and nelfinavir, respectively. In an intent-to-treat analysis, 70% of
the patients taking indinavir, and 69% of the lopinavir group were
successfully treated by week 48. In contrast, only 44% of the patients
in the nelfinavir arm were successfully treated. The researchers note
that a majority of the participants taking nelfinavir had suboptimal
levels early on in the study, with 62% being outside the therapeutic
range at week 8. Consequently, ritonavir was added to ten of the
participants' regimens. This, say the researchers, was well tolerated
and efficiently increased the concentrations in six of the ten. The
researchers concluded that early systematic therapeutic drug
monitoring is an efficient method for improving virological outcomes
and toxicity in individuals on boosted indinavir or Kaletra but
recommended that boosted nelfinavir be evaluated further for
individuals with low drug levels.

In the second presentation, researchers from California set out to
determine whether therapeutic drug monitoring could be targeted at
specific patients, finding that 38% of study participants needed drug
level adjustments. In this substudy of CCTG 578, a randomised
controlled, factorial study that compared therapeutic drug monitoring
and standard of care, an expert committee reviewed blinded drug level,
viral load, CD4 cell count, and toxicity data from 177 of the 199
participants and recommended regimen changes if they were deemed
necessary. Drugs levels were measured just before, and at two and four
hours after a directly observed dose two weeks after the participants
had begun a new PI- or NNRTI-based HAART. The most commonly-used PI
was Kaletra, while efavirenz (Sustiva) was the commonest NNRTI. At
baseline, 29% of the participants were antiretroviral naive, 33% were
treatment experienced on a current regimen, and 38% were treatment
experienced but on a treatment interruption. The expert committee
recommended that 67 (38%) of the patients change the dose of at least
one drug. However, only three (2%) of these recommendations were to
decrease exposure.

In multivariate analysis, risk factors that independently predicted
the need for a change in drug dose were body weight (odds ratio [OR]
1.16, p = 0.003) and use of efavirenz (OR 4.6, p = 0.001) or lopinavir
(OR 4.6, p = 0.008). However, age, gender, baseline viral load and CD4
cell counts, prior use of antiretroviral therapy and adherence were
not associated with a recommendation to change drug dosage in
univariate or multivariate analyses. In the poster discussion session,
the researchers were praised for combining assessment of the patients'
drug levels with information on toxicity and virological and
immunological effectiveness in deciding whether a dose adjustment was
necessary. However, the researchers concluded that future research
should aim to refine the identification of candidates for therapeutic
drug monitoring, since their study revealed that it was not necessary
in the majority of their study population.

22. MRSA in HIV-positive Patients Often Community Acquired, Associated
with HIV Disease Severity
AIDSmap.org (2/26/05) Gadd C & Alcorn K

Infection with MRSA, or methicillin-resistant Staphylococcus aureus,
is being observed with greater frequency among HIV-positive patients,
according to an epidemiological study presented on Friday at the
Twelfth Annual Retrovirus Conference in Boston (Abstract: 142;
2/25/05). The study also suggests that the majority of MRSA infections
in HIV-positive people are being acquired in the community, rather
than in hospital, and that the risk of being diagnosed is increased by
more advanced HIV disease. Clinical illness due to infection with MRSA
is becoming an increasingly frequent post-surgical complication
throughout the developed world due to antibiotic resistance. However,
recent studies have begun to suggest that the bacterial infection is
often acquired in the community and can be unrelated to recent medical
treatment. To assess its prevalence in people with HIV, researchers
from the University of California set out to evaluate MRSA episodes in
a retrospective cohort of patients attending an HIV clinic in San
Diego. In total, the investigators analysed the medical records of
3455 patients with 7003 person-years of follow-up.

One hundred and twenty six episodes of MRSA were identified between
January 2000 and December 31 2003, of which 94 were judged to be
clinically significant. Eighty-three percent of the cases involved
skin or soft tissue infection, 10% blood infection, 6% respiratory
infection and 1% other infection sites. Working on the assumption that
an episode of MRSA infection within six months of a hospital stay
indicated MRSA acquisition in the health care setting (nosocomial),
researchers were surprised to discover that 60% of cases appeared to
be community acquired. When antibiotic susceptibility was assessed,
only co-trimoxazole (Septrin / Bactrim) resistance in the MRSA isolate
was significantly associated with nosocomial acquisition. Another
surprising finding was a 6.2-fold increase in MRSA incidence between
the first six month period and the last six month period evaluated.
People who had acquired HIV through heterosexual intercourse were 90%
less likely to be diagnosed with MRSA than other risk groups (p =
0.012), and people with viral load above 100,000 copies/ml were almost
twice as likely to be diagnosed with MRSA when compared with people
who had viral load below 10,000 copies/ml (p < 0.001).

Having a low CD4 cell count also increased the risk of diagnosis with
MRSA: patients with CD4 cell counts below 50 cells/mm3 were 2.5 times
more likely to be diagnosed than those with higher cell counts (p =
0.003). Conversely, being on antiretroviral therapy reduced the risk
of MRSA by 40% (p = 0.02). Being African American was not associated
with any modified risk of being diagnosed with MRSA. However, no data
were presented on the risk of current intravenous drug use on MRSA
diagnosis. Christopher Mathews, presenting, acknowledged that the
study's findings are limited by their analysis of cases from a single
clinic. He also conceded that a proportion of the reported increase in
MRSA prevalence could be explained by increased vigilance on behalf of
doctors following publication of previous reports. However, the study
suggests that community-acquired MRSA may be worrying problem among
HIV-positive populations, and that there is a direct effect of HIV
disease severity on the risk of being diagnosed with the infection.

23. Two New Drug Classes Given to People with HIV for the First Time
AIDSmap.org (2/26/05) Cairns G

The 12th Retrovirus Conference heard the results of the first dosing
trials to give people with HIV two completely new classes of drugs –
maturation inhibitors and integrase inhibitors (Little, S,
Abstract:161; Martin, D, Abstract: 159). Although both have been given
to a few HIV negative volunteers in safety studies before, these were
the first trials to give them to people with HIV and observe their
effect on HIV in vivo.

PA-457: maturation inhibitor
PA-457, being developed by biotech Panacos pharmaceuticals, is a
derivative of the natural product betulinic acid whose anti-HIV
activity was first announced at the 10th Retrovirus Conference in
2003. HIV particles produced in the presence of this drug are
non-infectious and have distorted capsids (the 'core' of HIV
containing the RNA genome). Further investigation found that PA-457 is
unique in its mechanism of action. It inhibits neither a viral enzyme
like current classes, nor a host factor like CCR5, but a protein
produced by HIV-infected cells which would normally become a component
of new HIV particles. During the viral life cycle the protein
components making up new viruses are synthesized as one long protein
chain. HIV protease then snips these into individual viral components;
protease inhibitors block this action. What PA-457 does is to create a
chemical bridge between two protein components so that HIV protease
cannot separate them. To use a metaphor, while protease inhibitors
blunt HIV's scissors, PA-457 makes its cloth impossible to cut.

In an initial study, Panacos gave a single dose of PA-457 to 24 men
with HIV who were either drug-naive or who had not taken HAART for at
least four weeks. Six men each were given 75, 150 or 220 mg of the
drug or a placebo. The 150mg and 250mg doses cut the median via load
roughly threefold (by 0.45 and 0.51 logs respectively). This is a
respectable amount for a single dose of drug. Presenter David Martin
compared this with the drugs tenofovir and d-d4FC (Reverset), which in
single dose studies produced median reductions of 0.33 and 0.45 logs
respectively. The 75mg dose produced a reduction statistically
equivalent to zero, and a minority of subjects had little response to
the larger doses, which may indicate that response to this drug may
vary according to host factors. The most interesting finding was that
the viral reduction appeared to be sustained for many days. PA-457 has
a half-life of 2-3 days, and a viral load reduction of more than 0.35
logs was maintained for eight to nine days after treatment in the two
larger doses. Martin announced that a 10-day study of PA-457
monotherapy is ongoing and phase II efficacy studies are planned to
start towards the end of 2005.

L-870810 - integrase inhibitor
In contrast to PA-457, which is a recent and serendipitous discovery,
drugs to inhibits the third HIV enzyme integrase, which splices the
HIV genome into the human one, have been hypothesised ever since HIV's
life cycle was first understood; the first conference specifically
dedicated to this target took place in January 1995. Ten years later,
Susan Little of the University of California San Diego was finally
able to announce the results of the first 10-day study of monotherapy
with an integrase inhibitor, Merck's L-870810, in HIV-infected
subjects. In the trial, 30 HIV positive patients were given placebo
(six patients) or 200 or 400mg of L-870810 (seven and 17 patients
respectively). Fifteen of the 24 patients given the drug were
ARV-experienced. After 10 days of twice-daily doses, the mean viral
load decrease in the 200mg and 400mg doses was 1.73 and 1.77 logs
respectively (the latter is a sixty-fold reduction in viral load).
There was a wide range of response, from 0.95 to 2.49 logs, but no
non-responders.

Six out of 16 patients on the higher dose (37.5%) had a viral load
below 400 by day 10. After dosing was stopped viral load increased
again and was back to baseline by day 24 in most subjects. This was
the last study that will ever be performed on this specific compound.
Research on L-870810 has now been stopped after unacceptable liver and
kidney cell toxicity was found in dogs. One of the reasons for the
slow progress on integrase inhibition is that many candidates have
turned out to be toxic and to inhibit other vital cellular functions.
However Little said that there was no evidence of human toxicity in
the current study and that studies in rats had shown none. There were
four discontinuations in this study, none related to drug toxicity and
three solely due to the suspension of the study when the dog toxicity
data was released. Research on the related drug candidate L-870812 is
proceeding.

24. Therapeutic Vaccine Plus Interleukin-2 Shows Best Viral Control in
Treatment Breaks
AIDSmap.org (2/27/05) Cairns G

A French trial combining a therapeutic HIV vaccine with interleukin-2
(IL-2) shots and treatment interruptions has shown that after nearly
two years, individuals who received the vaccine and IL-2 saw their
viral load stabilise during treatment interruption at levels tenfold
lower than unvaccinated participants. The regimen also halved the
amount of time they spent on HAART. The ANRS 093 trial randomised
placebo-controlled study started with subjects receiving a schedule of
four shots of a combined vaccine, or a placebo, spaced four weeks
apart. The vaccine consisted of two components, the ALVAC 1433 vaccine
which encloses HIV env and gag proteins inside a canarypox vector, and
HIV lipopeptide, which consists of HIV gag protein fragments attached
to lipid 'tails'. The subjects were then given, again at four-weekly
intervals, three cycles of interleukin-2 or placebo injections (two
injections a day for five days).

Eight weeks after the last IL-2 cycle – 40 weeks into the study -
subjects were taken off HAART and their viral load measured every four
weeks. They were not put back on treatment unless their viral load was
over 50,000 at one measurement or over 10,000 at two consecutive
measurements. The final results of two years of follow-up were
presented at the 12th Retrovirus Conference (Levy Y, Abstract: 133LB).
Interim results were published in 2003. By the end of the 100-week
study, which was competed by all but one of 37 subjects, vaccinated
subjects spent 42.8 per cent of the time in treatment interruptions
compared with 26.5 per cent for control subjects. Their full-time
HAART was reduced by 45 per cent compared with 23 per cent for the
controls.

During subsequent treatment breaks the 'set point' viral load reached
in vaccinated subjects (defined as the viral load four weeks into a
break) declined in vaccinated subjects but not in controls, with the
difference reaching statistical significance in the second and
subsequent breaks. By the third treatment interruption the set-point
vial load in vaccinated subject was nearly a log lower than controls
(3.66 compared with 4.53 logs, or 4,500 versus 35,000). All subjects
experienced CD4 declines over the study but the fall in vaccinated
subjects was only a third of that in control subjects (57 versus 179).
AIDS-related illnesses were experienced by no vaccinated subjects but
five control subjects (two thrombcytopenia (low platelet count), two
shingles and one Kaposi's sarcoma).

25.ADVOCACY ALERT: Call Your U.S. Senators Before March 7-- Or We May
Lose Medicaid for People Living with AIDS and HIV
(2/25/05)

President Bush's proposed FY 2005-06 federal budget includes $60
billion in Medicaid cuts over the next ten years, including billions
in direct cuts to case management programs that serve thousands of
Americans living with AIDS and HIV. Cuts this big will translate
straight into severe benefit and eligibility cuts at the state level.
States are already cutting benefits and services to poor and disabled
Americans - they'll make even more severe cuts to individual
beneficiaries and front-line service providers if the Bush Medicaid
cuts are approved by Congress. And cuts this big could mean the end of
Medicaid as we know it - Congress could impose caps that would
dismantle the entitlement structure that protects consumers and
ensures comprehensive and needed care is provided.

On March 7, the Senate and House Budget Committees will begin work on
a budget resolution that could protect Medicaid or destroy it with
huge funding cuts. We've got to put the heat on Congress - and
especially our Senators - NOW to get them to block any cuts or caps to
Medicaid funding.

CALL YOUR SENATORS THIS WEEK TOLL FREE AT 877-762-8762 AND GIVE THEM A
SIMPLE MESSAGE:

" I am calling to urge you to oppose a budget resolution that contains
any cuts or caps to the Medicaid program. Medicaid is the single
largest source of funding for HIV/AIDS care in America, and hundreds
of thousands of people living with AIDS and HIV depend on it.
Comprehensive, guaranteed health care through Medicaid is a
life-and-death issue for Americans living with AIDS and HIV, and we
oppose any attempts to weaken Medicaid - don't let Medicaid cuts into
the budget resolution."

If you need help finding the names of your Senators, go to
www.vote-smart.org.

The HIV Medicaid/Medicare Working Group is a national coalition of
advocates working to protect and expand Medicaid and Medicare for
people living with HIV/AIDS. For more information about the working
group, please write to theaccessproject@aol.com.

--------------------------------------------------------------------------------

This Week @The CFA





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